2004年06月, 日本乳癌学会, 研究奨励賞　　　　　　　　　　　　　　　

Eribulin versus S-1 as first or second-line chemotherapy to assess health-related quality of life and overall survival in HER2-negative metastatic breast cancer (RESQ study): a non-inferiority, randomised, controlled, open-label, phase 3 trial.
Masato Takahashi, Yuichiro Kikawa, Kosuke Kashiwabara, Naruto Taira, Tsuguo Iwatani, Kojiro Shimozuma, Shoichiro Ohtani, Tetsuhiro Yoshinami, Junichiro Watanabe, Masahiro Kashiwaba, Ken-Ichi Watanabe, Masahiro Kitada, Koichi Sakaguchi, Yuko Tanabe, Tomohiko Aihara, Hirofumi Mukai
EClinicalMedicine, 74, 102715, 102715, 2024年08月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Eribulin prolongs overall survival (OS) of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), particularly in later chemotherapy (ChT) treatment. However, the health-related quality of life (HRQoL) and efficacy of first or second-line therapy in eribulin-treated patients remain unknown. Using eribulin in the first- or second-line may demonstrate the non-inferiority of HRQoL compared to S-1, an oral 5-fluorouracil derivative, while maintaining OS. METHODS: This randomised, controlled, open-label, phase III trial was conducted at 50 hospitals in Japan. Patients were enrolled from June 2016 and October 2019. Patients with HER2-negative MBC once under or no previous ChT were randomly assigned (1:1) to receive eribulin or S-1. HRQoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) every six weeks until week 24 and every nine weeks until week 42. The primary endpoint was the deterioration defined as more than 10 points worsening of the general health score of QLQ-C30 or death within one year after randomisation. The secondary endpoints included OS. (Trial ID: UMIN000021398). FINDINGS: Three hundred and two patients were enrolled, with 152 and 148 assigned to the eribulin and S-1 groups, respectively. The questionnaire compliance rate was 85.6%. Risk difference of global health status deterioration through one year was -0.66% (95% CI: -12.47-11.16; non-inferiority P = 0.077) for eribulin compared to S-1 groups. Median time to first deterioration for global health status score was 5.64 (95% CI: 3.51-8.00) and 5.28 months (95% CI: 3.28-7.80) in the eribulin and S-1 groups, respectively. The median OS was 34.7 and 27.8 months, (HR: 0.72, 95% CI: 0.54-0.96; P = 0.026); the median progression-free survival was 7.57 and 6.75 months in the eribulin and S-1 groups, (HR: 0.88, 95% CI: 0.67-1.16; P = 0.35), respectively. No new adverse events occurred. INTERPRETATION: The time of the first clinical deterioration was similar between the two groups and OS significantly increased in eribulin-treated patients. FUNDING: This study was funded by CSPOR-BC and Eisai CO., Ltd.

HER2陽性進行・再発乳癌に対するHP療法にタキサン併用とエリブリン併用を比較する第III相JBCRG-M06試験　　　　　　　　　　　　　　　
佐治 重衡, 山下 年成, 高野 利実, 内藤 陽一, 常泉 道子, 吉村 章代, 高橋 將人, 鶴谷 純司, 岩谷 胤生, 北田 正博, 多田 寛, 森 菜採子, 斎藤 毅, 岩朝 勤, 荒木 和浩, 坂井 和子, 長谷川 広季, 内田 洋平, 森田 智視, 増田 慎三
日本乳癌学会総会プログラム抄録集, 32回, 66, 66, (一社)日本乳癌学会, 2024年07月
日本語

乳癌術後23年目に肺の小結節を指摘され,2年の経過を経て肺転移と診断された1例
荒町 優香里, 細田 充主, 小金澤 千夏, 守谷 結美, 羽田 光輝, 押野 智博, 竹中 淳規, 加藤 扶美, 高橋 將人
北海道外科雑誌, 69, 1, 51, 54, 北海道外科学会, 2024年06月
日本語, 乳癌は晩期再発症例が多いとされているものの,9割以上が術後10年以内での再発である。今回,右乳癌術後23年目に偶発的に肺小結節を指摘され,経過観察2年で1mmの増大を認め,性状の変化から手術を行い乳癌肺転移と診断された1例を経験した。患者は80歳女性,55歳時に右乳癌に対して右乳房全切除術と腋窩郭清が施行された。術後は23年間,転移・再発は指摘されなかった。未破裂脳動脈瘤に対してカテーテル治療を行う方針となり,治療前のスクリーニングCTで左肺S3の小結節を指摘された。CTで半年毎にフォローし,2年後に小結節のわずかな増大を認めた。肺癌を疑い胸腔鏡下左肺部分切除を行った。肺腫瘍の病理結果は乳癌の転移を疑わせる所見であり当科紹介となった。総合的に既往乳癌の肺転移と判断し,現在,レトロゾール単剤で7ヵ月間治療継続中である。(著者抄録)

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial
Ian E. Krop, Norikazu Masuda, Toru Mukohara, Shunji Takahashi, Takahiro Nakayama, Kenichi Inoue, Hiroji Iwata, Yutaka Yamamoto, Ricardo H. Alvarez, Tatsuya Toyama, Masato Takahashi, Akihiko Osaki, Shigehira Saji, Yasuaki Sagara, Joyce O'Shaughnessy, Shoichi Ohwada, Kumiko Koyama, Tatsuya Inoue, Li Li, Parul Patel, Joseph Mostillo, Yoshimi Tanaka, David W. Sternberg, Dalila Sellami, Kan Yonemori
Journal of Clinical Oncology, 41, 36, 5550, 5560, American Society of Clinical Oncology (ASCO), 2023年12月20日
研究論文（学術雑誌）, PURPOSE

Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study.

METHODS

Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion.

RESULTS

One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred.

CONCLUSION

HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.

Overall survival in Japanese patients with ER+/HER2- advanced breast cancer treated with first-line palbociclib plus letrozole.
Masato Takahashi, Tomofumi Osako, Hiroyuki Yasojima, Kenichi Inoue, Masahiro Kawashima, Hideki Maeda, Akemi Ichikawa, Yasuaki Muramatsu, Norikazu Masuda
Breast cancer (Tokyo, Japan), 2023年10月26日, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: An open-label, single-arm, Japanese phase 2 study (J-Ph2) investigated the efficacy and safety of first-line (1L) palbociclib (PAL) + letrozole (LET) in postmenopausal Japanese women with ER+/HER2- advanced breast cancer (ABC). In the final analysis, median progression-free survival was 35.7 months (95% CI 21.7-46.7); but overall survival (OS) data were immature. Here, we report the findings from a follow-up study of J-Ph2 (NCT04735367) evaluating OS and subsequent therapy in these Japanese women. METHODS: Patients (N = 42) who participated in J-Ph2 were enrolled in the OS follow-up study. The primary endpoint was OS and secondary endpoints included type and duration of subsequent therapy. RESULTS: Patients were a median age of 62.5 years; 48% had visceral metastases. At a median follow-up of 89.7 months, the median OS was 85.4 months (95% CI 64.3-not estimable). Median OS was longer in patients with nonvisceral versus visceral metastases (not reached vs 67.3 months), or with treatment-free interval > 12 months versus ≤ 12 months (85.4 vs 45.4 months), or with treatment duration ≥ 24 months versus < 24 months (not reached vs 47.5 months). Of patients who received a first subsequent therapy (81%), most (67%) continued endocrine-based therapy, while 7% received chemotherapy. The median duration of the first subsequent therapy was 8.3 months (95% CI 3.9-12.2), and the median chemotherapy-free survival was 69.1 months (95% CI 24.2-85.4). CONCLUSIONS: In this population of Japanese women with ER+/HER2- ABC, median OS was over 7 years with 1L PAL + LET, supporting the use of 1L PAL + endocrine therapy. TRIAL NUMBER: NCT04735367.

治療前CD163はニボルマブ+化学療法における予後不良因子(WJOG9917BTR)　　　　　　　　　　　　　　　
尾崎 由記範, 岩朝 勤, 北野 滋久, 山下 万貴子, 鶴谷 純司, 高橋 將人, 向原 徹, 増田 慎三, 二村 学, 南 博信, 松本 光史, 田辺 裕子, 川端 英孝, 吉村 健一, 高野 利実
日本癌治療学会学術集会抄録集, 61回, O25, 3, (一社)日本癌治療学会, 2023年10月
英語

Efficacy of probiotics and trimebutine maleate for abemaciclib-induced diarrhea: A randomized, open-label phase II trial (MERMAID, WJOG11318B).
Hiroko Masuda, Yuko Tanabe, Hitomi Sakai, Koji Matsumoto, Akihiko Shimomura, Mihoko Doi, Yasuo Miyoshi, Masato Takahashi, Yasuaki Sagara, Shinya Tokunaga, Tsutomu Iwasa, Naoki Niikura, Kenichi Yoshimura, Toshimi Takano, Junji Tsurutani
Breast (Edinburgh, Scotland), 71, 22, 28, 2023年10月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Abemaciclib-induced diarrhea (AID) impairs quality of life (QOL) and treatment adherence in patients with breast cancer. Supportive treatment with loperamide is associated with constipation. We hypothesized that probiotics and trimebutine maleate (TM) would decrease the frequency of AID without causing constipation. METHODS: Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients were randomized into the probiotic Bifidobacterium (A) or probiotic Bifidobacterium and TM (B) groups. Endocrine therapy, Abemaciclib and probiotic Bifidobacterium three times a day for 28 days, was administered to both arms. Arm B was treated with TM upon the onset of diarrhea. The primary endpoint was the percentage of patients who experienced grade ≥2 diarrhea. The secondary endpoints were safety, frequency, and duration of all-grade diarrhea; frequency of emesis and constipation; usage of loperamide; and health-related QOL/patient-reported outcome during the study. We evaluated whether the primary endpoint of each arm exceeded the predetermined threshold. RESULTS: Fifty-one patients completed treatment. Grade 2 diarrhea occurred in 52% and 50% of patients in Arm A and Arm B, respectively. One patient experienced grade 3 diarrhea in each arm. The median duration of grade2 diarrhea was 2 and 2.5day, and only one patient required dose reduction. Grade ≥2 constipation was observed in 4% of Arm A and 3.6% of Arm B. CONCLUSIONS: Probiotic Bifidobacterium or the combination of probiotic Bifidobacterium with TM did not decrease the incidence of grade 2 or greater diarrhea compared with historical control, although the grade 3 or greater diarrhea was reduced. CLINICAL TRIAL REGISTRATION: jRCT (Japan registry of clinical trials). jRCTs031190154.

Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial)
Jun Masuda, Hitomi Sakai, Junji Tsurutani, Yuko Tanabe, Norikazu Masuda, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kiyoshi Yoshimura, Chiyo K Imamura, Sakiko Miura, Toshiko Yamochi, Hidetaka Kawabata, Hiroyuki Yasojima, Nobumoto Tomioka, Kenichi Yoshimura, Toshimi Takano
Journal for ImmunoTherapy of Cancer, 11, 9, e007126, e007126, BMJ, 2023年09月13日
研究論文（学術雑誌）, Background

Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies.

Methods

This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers.

Results

From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy.

Conclusions

Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs.

Trial registration number

JapicCTI-194782, jRCT2080224706, UMIN000036970.

A Case of Pneumothorax Required Surgical Treatment as a Complication of Paclitaxel with Bevacizumab Treatment
Yumi Moriya, Tomohiro Oshino, Mitsuchika Hosoda, Karin Shikishima, Shun Miura, Jun Muto, Tatsuya Kato, Masato Takahashi
Case Reports in Oncology, 16, 1, 797, 802, S. Karger AG, 2023年09月04日
研究論文（学術雑誌）, A 63-year-old woman had a history of neoadjuvant chemotherapy, mastectomy, and adjuvant endocrine therapy for 5 years before being diagnosed with recurrent lesions involving the right anterior chest wall, multiple lymph nodes, and pulmonary metastases. The patient was subsequently initiated on a paclitaxel and bevacizumab regimen. During this treatment, the patient complained of palpitations and malaise. Chest radiography revealed a left pneumothorax. Despite attempts at conservative treatment, the pneumothorax did not improve and a thoracoscopic approach was required. One of the metastatic tumors in the left lower lobe appeared to rupture, and this area was estimated to be the cause of air leak. The tumor was covered with a tissue seal sheet, and the patient’s condition improved with no recurrence of pneumothorax. This case highlights the importance of early conversion to surgical treatment when conservative treatment for pneumothorax is unresponsive due to the potential side effects of bevacizumab. The findings of this case report may be of interest to oncologists, pulmonologists, and other healthcare professionals involved in the care of patients with breast cancer and pulmonary metastases who are undergoing bevacizumab chemotherapy.

HER2陰性転移再発乳癌に対するニボルマブ+ベバシズマブ+パクリタキセル併用療法の第II相試験(WJOG9917B)　　　　　　　　　　　　　　　
尾崎 由記範, 鶴谷 純司, 向原 徹, 岩朝 勤, 高橋 將人, 田辺 裕子, 川端 英孝, 増田 慎三, 二村 学, 南 博信, 松本 光史, 吉村 健一, 北野 滋久, 高野 利実
日本乳癌学会総会プログラム抄録集, 31回, 65, 65, (一社)日本乳癌学会, 2023年06月
英語

再発乳癌とstage IV乳癌における免疫状態や免疫チェックポイント阻害薬に対する反応性の違い WJOG9917BTR　　　　　　　　　　　　　　　
尾崎 由記範, 北野 滋久, 山下 万貴子, 五十嵐 大樹, 鶴谷 純司, 岩朝 勤, 高橋 將人, 向原 徹, 増田 慎三, 二村 学, 南 博信, 松本 光史, 田辺 裕子, 川端 英孝, 吉村 健一, 高野 利実
日本乳癌学会総会プログラム抄録集, 31回, 73, 73, (一社)日本乳癌学会, 2023年06月
日本語

実臨床下における浸潤性小葉癌の予後及びエリブリンの有効性の検討　　　　　　　　　　　　　　　
田辺 裕子, 井上 賢一, 高橋 將人, 向井 博文, 山中 隆司, 柄川 千代美, 内田 洋平, 東別府 洋一, 阪田 幸則, 鶴谷 純司
日本乳癌学会総会プログラム抄録集, 31回, 126, 126, (一社)日本乳癌学会, 2023年06月
日本語

HER2陰性転移性乳癌における1次・2次治療としてのエリブリンとS-1のHRQOLを比較する無作為化第III相試験　　　　　　　　　　　　　　　
田辺 裕子, 柏原 康佑, 木川 雄一郎, 平 成人, 岩谷 胤生, 下妻 晃二郎, 大谷 彰一郎, 吉波 哲大, 渡邉 純一郎, 柏葉 匡寛, 渡邊 健一, 北田 正博, 阪口 晃一, 相原 智彦, 向井 博文, 高橋 將人
日本乳癌学会総会プログラム抄録集, 31回, 73, 73, (一社)日本乳癌学会, 2023年06月
日本語

HER2陰性転移性乳癌における1次・2次治療としてのエリブリンとS-1のHRQOLを比較する無作為化第III相試験　　　　　　　　　　　　　　　
田辺 裕子, 柏原 康佑, 木川 雄一郎, 平 成人, 岩谷 胤生, 下妻 晃二郎, 大谷 彰一郎, 吉波 哲大, 渡邉 純一郎, 柏葉 匡寛, 渡邊 健一, 北田 正博, 阪口 晃一, 相原 智彦, 向井 博文, 高橋 將人
日本乳癌学会総会プログラム抄録集, 31回, 73, 73, (一社)日本乳癌学会, 2023年06月
日本語

Association of Genetic Polymorphism with Taxane-induced Peripheral Neuropathy: Sub-analysis of a Randomized Phase II Study to Determine the Optimal Dose of 3-week Cycle Nab-Paclitaxel in Metastatic Breast Cancer Patients.
Yuko Abe, Naruto Taira, Kosuke Kashiwabara, Junji Tsurutani, Masahiro Kitada, Masato Takahashi, Hiroaki Kato, Yuichiro Kikawa, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Tsutomu Takashima, Tomohiko Aihara, Hirofumi Mukai, Fumikata Hara, Tadahiko Shien, Hiroyoshi Doihara, Shinichi Toyooka
Acta medica Okayama, 76, 6, 661, 671, 2022年12月, ［国内誌］
英語, 研究論文（学術雑誌）, Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients' quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001-3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01).

Response to: Prognosis of metastatic bone cancer and myeloma patients and long‑term risk of medication‑related osteonecrosis of the jaw (MRONJ): some critical points.
Hironobu Hata, Kenji Imamachi, Michihiro Ueda, Masashi Matsuzaka, Hiroaki Hiraga, Toshihisa Osanai, Toru Harabayashi, Katsuya Fujimoto, Satoshi Oizumi, Masato Takahashi, Kazuhito Yoshikawa, Jun Sato, Yutaka Yamazaki, Yoshimasa Kitagawa
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 30, 12, 9693, 9695, 2022年12月, ［国際誌］
英語

Data of programmed death-ligand 1 expression and VEGF: Nivolumab, bevacizumab and paclitaxel For HER2-negative metastatic breast cancer.
Yukinori Ozaki, Junji Tsurutani, Toru Mukohara, Tsutomu Iwasa, Masato Takahashi, Yuko Tanabe, Hidetaka Kawabata, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Kenichi Yoshimura, Shigehisa Kitano, Toshimi Takano
Data in brief, 45, 108558, 108558, 2022年12月, ［国際誌］
英語, 研究論文（学術雑誌）, The purpose was to explore potential biomarkers of the efficacy and toxicity of triple therapy of nivolumab, bevacizumab and paclitaxel in patients with HER2-negative metastatic breast cancer (MBC). Tumor tissues before treatment and blood samples at pretreatment, during and after treatment were collected. The serum samples were used to measure the concentrations of cytokines. Progression-free survival (PFS), overall survival (OS), and response were analyzed in association with the biomarker data using the Kaplan-Meier method and log-rank tests. Fifty patients were included in the biomarker analysis. Programmed death-ligand 1 (PD-L1) expression on tumor cells and immune cells were evaluated in tumor tissue samples using a Dako 28-8 immunohistochemistry assay and using a VENTANA SP142 immunohistochemistry assay. PD-L1 positive rates using anti-PD-L1 antibodies 28-8 (Combined positive score [CPS] ≥1) and SP142 (Immune cells [IC] ≥1) were 15% and 17%, respectively. The PFS and OS were not significantly different in the subgroups by PD-L1 expression. The median pretreatment vascular endothelial growth factor (VEGF)-A concentration was 116.1 pg/ml (range 0-740.23 pg/ml) on day 1 and decreased to <37 pg/ml on day 8 of cycle 1 in all patients. Subtypes (hormone receptor-positive HER2-negative or triple negative breast cancer), stage (recurrent or de novo stage IV) and liver metastasis (yes or no) were not significantly different between patients in VEGF-A high and VEGF-A low groups. PFS in the VEGF-A high group was similar to that in the VEGF-A low group.

Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: A propensity score-adjusted analysis of a prospective cohort study.
Masataka Sawaki, Naruto Taira, Yukari Uemura, Tsuyoshi Saito, Shinichi Baba, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Hiroji Iwata, Tatsuya Toyama, Koichiro Tsugawa, Takuya Kawahara, Hirofumi Mukai
Breast (Edinburgh, Scotland), 66, 245, 254, 2022年11月07日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To gauge the effects of treatment practices on prognosis for older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This is a prospective cohort study which accompanies the RESPECT that is a randomized-controlled trial (RCT). METHODS: Patients who declined the RCT were treated based on the physician's discretion. We studied the 1) trastuzumab-plus-chemotherapy group, 2) trastuzumab-monotherapy group, and 3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were assessed. RESULTS: We enrolled 123 patients aged over 70 years (median: 74.5). Treatment categories were: trastuzumab-plus-chemotherapy group (n = 36, 30%), trastuzumab-monotherapy group (n = 52, 43%), and non-trastuzumab group (n = 32, 27%). The 3-year DFS was 96.7% in trastuzumab-plus-chemotherapy group, 89.2% in trastuzumab-monotherapy group, and 82.5% in non-trastuzumab group. DFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted hazard ratio; HR: 3.29; 95% CI: 1.15-9.39; P = 0.026). The RFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32-26.2, P < 0.0001). There were no significant intergroup differences in the proportions of patients showing HRQoL deterioration at 36 months (P = 0.717). CONCLUSION: Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Trastuzumab monotherapy could be considered for older patients who reject chemotherapy.

Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer.
Nabeel Kajihara, Takuto Kobayashi, Ryo Otsuka, Junko Nio-Kobayashi, Tomohiro Oshino, Masato Takahashi, Seiichi Imanishi, Ari Hashimoto, Haruka Wada, Ken-Ichiro Seino
Cancer immunology, immunotherapy : CII, 2022年09月14日, ［国際誌］
英語, 研究論文（学術雑誌）, Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment.

Significance of prostate/pancreatic/skin cancer family history for detecting BRCA2 pathogenic variant careers among patients with breast cancer.
Yuko Minoura, Masato Takahashi, Hideki Maeda, Sayuri Kuwahara, Hanae Tachikawa, Mitsugu Yamamoto, Nobumoto Tomioka, Kenichi Watanabe, Akihiro Sakurai
Breast cancer (Tokyo, Japan), 29, 5, 808, 813, 2022年09月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: When considering BRCA1/2 genetic testing for diagnosis of hereditary breast and ovarian cancer (HBOC), family history (FH) of breast and ovarian cancer is commonly considered. However, FH of other HBOC-related cancers, such as prostate, pancreatic, and skin cancer (malignant melanoma), is often overlooked. METHODS: Among 945 patients who received genetic testing of BRCA1/2 at our hospital between October 2010 and September 2021, we compared the FH of 123 patients diagnosed with HBOC and 669 other patients who had breast cancer and had a documented FH. This study focused on the FH of HBOC-related cancers such as breast, ovarian, prostate, pancreatic, and skin cancer, as well as colorectal, gastric, liver, lung, and uterine cancers, which are common among Japanese, and other cancers. RESULTS: FH of prostate, pancreatic, and skin cancer was significantly higher in the BRCA2 pathogenic variant (PV) cases than in the wild-type (WT) cases. The mean number of family members are as follows: BRCA1 PV/ BRCA2 PV/ WT; prostate cancer: 0.05/ 0.34/ 0.09 (P < 0.0001, Kruskal-Wallis multiple comparisons test), pancreatic cancer: 0.13/ 0.21/ 0.10 (P = 0.01637), and skin cancer: 0.03/ 0.07/ 0.01 (P = 0.00129), respectively. CONCLUSIONS: When considering BRCA1/2 genetic testing, FH of prostate, pancreatic, and skin cancers may also be examined as HBOC-related cancers to provide testing for patients who would benefit from it. However, further studies for the association between skin cancer and HBOC will be required because it has not been reported in Japan.

Safety and efficacy of nivolumab plus bevacizumab, paclitaxel for HER2-negative metastatic breast cancer: Primary results and biomarker data from a phase 2 trial (WJOG9917B).
Yukinori Ozaki, Junji Tsurutani, Toru Mukohara, Tsutomu Iwasa, Masato Takahashi, Yuko Tanabe, Hidetaka Kawabata, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Kenichi Yoshimura, Shigehisa Kitano, Toshimi Takano
European journal of cancer (Oxford, England : 1990), 171, 193, 202, 2022年08月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Preclinical models revealed potential synergistic effects of programmed cell death-1 inhibitors and anti-vascular endothelial growth factor (VEGF) antibodies. Therefore, we investigated the use of nivolumab, bevacizumab, and paclitaxel triple therapy for metastatic breast cancer. METHODS: This phase 2, multicentre, single-arm study (NEWBEAT) investigated the safety and efficacy of first-line nivolumab, paclitaxel, and bevacizumab in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer, regardless of programmed cell death-ligand 1 expression. The primary end-point was objective response rate. Key secondary end-points included progression-free survival, overall survival, and toxicities. A biomarker study evaluated tumour programmed cell death-ligand 1 expression and serum VEGF-A levels. RESULTS: Between February 2018 and October 2018, 57 patients were enrolled. An objective response rate was seen in 39/56 patients (70%, 95% confidence interval [CI]: 55.9-81.2%), meeting the primary end-point. The objective response rate was 74% in patients with hormone receptor-positive breast cancer versus 59% in patients with triple-negative breast cancer. The median progression-free survival and overall survival were 14.0 (95% CI 11.0-16.3) and 32.5 (95% CI 26.0-not evaluable) months, respectively (median follow-up: 29.5 months). Grade 3/4 adverse drug reactions occurred in 33 of 57 patients (58%). There were no grade 5 adverse events. Immune-related adverse events occurred in 43 of 57 patients (75%), with grade 3/4 events in eight patients (14%). Biomarker analysis showed that tumour programmed cell death-ligand 1 expression was not correlated with the efficacy of triple therapy. Efficacy outcomes were similar between the serum VEGF-high and VEGF-low groups. CONCLUSIONS: First-line nivolumab, bevacizumab, and paclitaxel therapy showed promising efficacy and manageable toxicity in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer.

Efficacy and safety of talazoparib in Japanese patients with germline BRCA-mutated locally advanced or metastatic breast cancer: results of the phase 1 dose-expansion study.
Haruru Kotani, Norikazu Masuda, Toshinari Yamashita, Yoichi Naito, Tetsuhiko Taira, Kenichi Inoue, Masato Takahashi, Kan Yonemori, Shigeyuki Toyoizumi, Yuko Mori, Takashi Nagasawa, Natsuki Hori, Hiroji Iwata
Breast cancer (Tokyo, Japan), 2022年07月30日, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Talazoparib, a poly(ADP-ribose) polymerase enzyme inhibitor, is approved for the treatment of patients with germline BRCA1/2 (gBRCA1/2)-mutated HER2-negative advanced breast cancer. This two-part study, a recently published dose-escalation part followed by the dose-expansion part reported here, evaluated the efficacy and safety of talazoparib in Japanese patients with gBRCA1/2-mutated advanced breast cancer. METHODS: In this open-label, multicenter phase 1 study (NCT03343054), the primary endpoint of the dose-expansion part was confirmed objective response rate (ORR), determined by investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Patients received the recommended phase 2 dose (1 mg/day; 0.75 mg/day moderate renal impairment). RESULTS: Nineteen Japanese patients with gBRCA1/2-mutated locally advanced or metastatic breast cancer were enrolled. Confirmed ORR was 57.9% (11/19; 90% confidence interval [CI] 36.8-77.0). Stable disease was observed in 36.8% (7/19) of patients. Per investigator assessment, median PFS was 7.2 months (95% CI 4.1-not estimable) and 12-month OS rate was 84.7% (90% CI 57.5-95.1). Median OS was not reached; 17/19 patients were alive and censored at 12 months. All patients experienced treatment-related adverse events (AEs); the majority were hematologic. The most common treatment-related AE was anemia (68.4%; [13/19]). Grade 3/4 treatment-related AEs were observed in 52.6% (10/19) of patients. During the safety period, there were no grade 5 treatment-emergent AEs, treatment-related serious AEs, or deaths. CONCLUSIONS: In Japanese patients with gBRCA mutations and locally advanced or metastatic breast cancer, talazoparib monotherapy was generally well tolerated and resulted in clinically meaningful ORRs. GOV IDENTIFIER: NCT03343054.

Pertuzumab retreatment for HER2-positive advanced breast cancer: A randomized, open-label phase III study (PRECIOUS).
Yutaka Yamamoto, Hiroji Iwata, Naruto Taira, Norikazu Masuda, Masato Takahashi, Tetsuhiro Yoshinami, Takayuki Ueno, Tatsuya Toyama, Takashi Yamanaka, Toshimi Takano, Masahiro Kashiwaba, Koichiro Tsugawa, Yoshie Hasegawa, Kenji Tamura, Hiroshi Tada, Fumikata Hara, Tomomi Fujisawa, Naoki Niikura, Shigehira Saji, Satoshi Morita, Masakazu Toi, Shinji Ohno
Cancer science, 113, 9, 3169, 3179, 2022年06月26日, ［国際誌］
英語, 研究論文（学術雑誌）, No standard options existed for human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer that progresses after second-line trastuzumab emtansine therapy before 2020. The purpose of this study was to examine the efficacy of pertuzumab retreatment after disease progression following pertuzumab-containing therapy for HER2-positive locally advanced or metastatic breast cancer for the first time. This randomized, open-label, multicenter phase III trial was undertaken in 93 sites in Japan. Eligible patients with HER2-positive breast cancer who had received pertuzumab, trastuzumab, and chemotherapy as first- and/or second-line therapy were randomly assigned (1:1) to: (i) pertuzumab, trastuzumab, and physician's choice chemotherapy (PTC), or (ii) trastuzumab and physician's choice chemotherapy (TC). The primary end-point was investigator-assessed progression-free survival (PFS). Between August 1, 2015 and December 31, 2018, 219 patients were randomized to PTC (n = 110) or TC (n = 109). Median follow-up was 14.2 months (interquartile range, 9.0-22.2), and median PFS was 5.3 months (95% confidence interval [CI], 4.0-6.6) with PTC and 4.2 months (95% CI, 3.2-4.8) with TC (stratified hazard ratio 0.76 [95% CI upper limit 0.967]; p = 0.022). Progression-free survival was improved by adding pertuzumab in all prespecified subgroups. The PTC arm showed a trend towards better overall survival and duration of response, but similar objective response and health-related quality of life. The incidence of treatment-related adverse events was similar between groups except for diarrhea. Pertuzumab retreatment contributes to disease control for HER2-positive locally advanced or metastatic breast cancer previously treated with pertuzumab-containing regimens.

臨床研究におけるエンドポイントとしてのHRQOLの意義 Health-related Quality of Lifeを主要評価目的とした第III相ランダム化比較試験RESQの概要とその意義　　　　　　　　　　　　　　　
柏原 康佑, 木川 雄一郎, 北田 正博, 大谷 彰一郎, 渡邉 純一郎, 岩谷 胤生, 吉波 哲大, 柏葉 匡寛, 下妻 晃二郎, 平 成人, 相原 智彦, 向井 博文, 高橋 將人
日本乳癌学会総会プログラム抄録集, 30回, SY11, 3, (一社)日本乳癌学会, 2022年06月
日本語

乳房専用超音波CTによる乳癌検出能の検討　　　　　　　　　　　　　　　
加藤 扶美, 佐藤 恵美, 西田 睦, 竹下 卓志, 押野 智博, 常田 慧徳, 守谷 結美, 上石 崇史, 桑山 真紀, 高橋 將人, 工藤 與亮
日本乳癌学会総会プログラム抄録集, 30回, PO6, 6, (一社)日本乳癌学会, 2022年06月
日本語

Prognosis by cancer type and incidence of zoledronic acid-related osteonecrosis of the jaw: a single-center retrospective study.
Hironobu Hata, Kenji Imamachi, Michihiro Ueda, Masashi Matsuzaka, Hiroaki Hiraga, Toshihisa Osanai, Toru Harabayashi, Katsuya Fujimoto, Satoshi Oizumi, Masato Takahashi, Kazuhito Yoshikawa, Jun Sato, Yutaka Yamazaki, Yoshimasa Kitagawa
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 30, 5, 4505, 4514, 2022年05月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Survival time after bisphosphonate use has been increasingly recognized to be associated with the incidence of medication-related osteonecrosis of the jaw (MRONJ); however, this has not been elucidated sufficiently in the literature. This study aimed to clarify the incidence of MRONJ and the corresponding survival rate of patients treated with zoledronic acid (ZA) for each type of cancer and obtain useful information for the oral/dental supportive care of cancer patients. METHODS: We evaluated 988 patients who were administered ZA at our hospital; among them, 862 patients with metastatic bone tumors or myeloma were included. RESULTS: The median survival time (MST) after ZA initiation was 35, 34, 8, 41, 12, and 6 months for patients with breast, prostrate, lung, myeloma, renal, and other cancers, respectively. Patients with cancers that had a short survival time (lung and other cancers [MST = 8 and 6 months, respectively] and cancers with MST < 10 months) did not develop MRONJ; this could be attributed to the shorter duration of ZA administration. The cumulative incidence of MRONJ in breast cancer, prostate cancer, and multiple myeloma was related to the frequency of anti-resorptive drug use and the increased risk over time. In renal cancer, the cumulative incidence of MRONJ increased early, although the MST was 12 months. CONCLUSION: For the dentists in charge of dental management, it is essential to be aware of prognosis-related factors, predict MRONJ risk for each cancer treatment, and use risk prediction in dental management planning, particularly for cancers with non-poor prognosis.

Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR.
Takayuki Ueno, Shigehisa Kitano, Norikazu Masuda, Daiki Ikarashi, Makiko Yamashita, Tomohiro Chiba, Takayuki Kadoya, Hiroko Bando, Takashi Yamanaka, Shoichiro Ohtani, Shigenori Nagai, Takahiro Nakayama, Masato Takahashi, Shigehira Saji, Kenjiro Aogi, Ravi Velaga, Kosuke Kawaguchi, Satoshi Morita, Hironori Haga, Shinji Ohno, Masakazu Toi
BMC medicine, 20, 1, 136, 136, 2022年04月25日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC's response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC. METHODS: Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. RESULTS: This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8+ T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4+ T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4+ T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4+ T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2). CONCLUSIONS: Intratumoral and stromal CD4+ T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results. TRIAL REGISTRATION: UMIN000023162.

Cost-Effectiveness of Trastuzumab With or Without Chemotherapy as Adjuvant Therapy in HER2-Positive Elderly Breast Cancer Patients: A Randomized, Open-Label Clinical Trial, the RESPECT Trial.
Yuki Takumoto, Takeru Shiroiwa, Kojiro Shimozuma, Hiroji Iwata, Masato Takahashi, Shinichi Baba, Kokoro Kobayashi, Yasuhiro Hagiwara, Takuya Kawahara, Yukari Uemura, Hirofumi Mukai, Naruto Taira, Masataka Sawaki
Clinical drug investigation, 42, 3, 253, 262, 2022年03月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND OBJECTIVE: Trastuzumab is a standard care as adjuvant chemotherapy (AdjCT) for patients with human epidermal growth factor receptor 2 (HER2)-positive primary breast cancer (BC) in Japan. However, no reports have evaluated its economics for patients with HER2-positive BC over 70 years of age. The objective of this study was to evaluate the cost-effectiveness of HER2-targeted trastuzumab + chemotherapy in Japan, comparing it with trastuzumab monotherapy. METHODS: A three-state-partitioned survival model was developed to evaluate the cost-effectiveness of trastuzumab + chemotherapy versus trastuzumab monotherapy for AdjCT in elderly patients with HER2-positive BC. We derived the efficacy data, utilities, and costs of both arms from individual patient data in the RESPECT trial (NCT01104935) and published studies. The costs and quality-adjusted life years (QALYs) were discounted at 2% per annum using a payer perspective. The respective cost estimates were reported in 2019 Japanese Yen (JPY) or US dollars (US$). The primary outcome was the incremental cost-effectiveness ratio (ICER). We assured robustness with deterministic and probabilistic sensitivity analyses. RESULTS: The cost per patient for trastuzumab + chemotherapy was JPY 14.6 million (US$137,000), and their QALYs were 9.308, compared with JPY 14.2 million (US$131,000) and 9.101, respectively, for trastuzumab monotherapy. The ICER of trastuzumab + chemotherapy versus trastuzumab monotherapy was JPY 2.7 milllion/QALY (US$17,200/QALY). The ICER for trastuzumab with chemotherapy varied from "Dominant" to "Dominated" in one-way sensitivity analysis. CONCLUSIONS: The base-case analysis suggests that AdjCT with trastuzumab + chemotherapy is likely to be a cost-effective choice for patients with HER2-positive BC aged 70 years or older. However, the sensitivity analysis suggested uncertainty regarding the cost-effectiveness of trastuzumab + chemotherapy.

Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer.
Peter Schmid, Javier Cortes, Rebecca Dent, Lajos Pusztai, Heather McArthur, Sherko Kümmel, Jonas Bergh, Carsten Denkert, Yeon Hee Park, Rina Hui, Nadia Harbeck, Masato Takahashi, Michael Untch, Peter A Fasching, Fatima Cardoso, Jay Andersen, Debra Patt, Michael Danso, Marta Ferreira, Marie-Ange Mouret-Reynier, Seock-Ah Im, Jin-Hee Ahn, Maria Gion, Sally Baron-Hay, Jean-François Boileau, Yu Ding, Konstantinos Tryfonidis, Gursel Aktan, Vassiliki Karantza, Joyce O'Shaughnessy
The New England journal of medicine, 386, 6, 556, 567, 2022年02月10日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported. METHODS: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed. RESULTS: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS: In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

Significance of boost radiotherapy in early invasive ductal breast cancer with ductal carcinoma in situ component under negative surgical margins.
Naoko Shimizu, Miyako Myojin, Motoshi Tamura, Noriaki Nishiyama, Katsushige Yamashiro, Yuichi Yuyama, Yutaka Okazaki, Yasuhiro Suzuki, Masato Takahashi
Journal of radiation research, 63, 1, 80, 87, 2022年01月20日, ［国際誌］
英語, 研究論文（学術雑誌）, We hypothesize that there is a risk of ipsilateral breast tumor recurrence (IBTR) in surgical margin-free invasive ductal carcinoma (IDC) in the presence of ductal carcinoma in situ (DCIS) component affecting surgical margins in early stage. From 1990 to 2014, 343 patients with IDC in which the DCIS component constitute have received radiotherapy (RT) following breast-conserving surgery (BCS). All patients received whole breast irradiation with a prescribed dose of 50 Gy in 20 fractions (four times a week). This one-arm cohort with boost RT (253 patients) was compared for IBTR with a non-cohort group receiving no boost RT because of freedom from positive margins (90 patients). Median observation months were 98 (boost group) vs 119 (no boost group), respectively. The 15-year local recurrence-free survival (LRFS) rates were 98.5% and 85.6% in the boost and no boost groups, respectively (Cox proportional hazards model univariate analysis; p = 0.013, HR 0.13). Similarly, for other background factors, there was a significant difference in the LRFS between age groups. The 15-year LRFS rate was 91.8% in patients aged 45 years or younger and 94.6% in patients older than 46 years (p = 0.031, HR 0.21), respectively. Only these two factors were independently significant in Cox proportional hazards model multivariate analysis. IBTR risk in margin-free IDC with DCIS component was independently decreased by boost RT in the cohort setting. Tumor size, extensive intraductal component (EIC), boost dose, the presence of lymph node (LN) metastasis and hormonal therapy were not IBTR risk factors in this study.

Health-related quality of life and estimation of the minimally important difference in the Functional Assessment of Cancer Therapy-Endocrine Symptom score in postmenopausal ER+/HER2- metastatic breast cancer with low sensitivity to endocrine therapy.
Yuichiro Kikawa, Yasuhiro Hagiwara, Tomomi Fujisawa, Kazuhiro Araki, Takayuki Iwamoto, Takafumi Sangai, Tadahiko Shien, Shintaro Takao, Reiki Nishimura, Masato Takahashi, Tatsuya Toyama, Tomohiko Aihara, Hirofumi Mukai, Naruto Taira
PloS one, 17, 11, e0278344, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The HORSE-BC study previously demonstrated that second-line endocrine therapy (ET) for patients with acquired endocrine-resistant metastatic breast cancer (MBC) still provided a clinically meaningful benefit. Herein, we investigated the health-related quality of life (HRQOL) in the HORSE-BC study. METHODS: Patients with acquired endocrine-resistant MBC who were scheduled for second-line ET were recruited. The HRQOL was assessed at baseline, and 1 and 3 months after second-line ET initiation. To investigate the minimally important difference (MID) in the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), we evaluated the means and standard deviations for the distribution-based method, and differences in the change in HRQOL for the anchor-based method. We also investigated the association between FACT-ES total scores and clinical benefit. RESULTS: Overall, 56 patients were enrolled. Of these, 47 were analyzed. When defined as 1/3 standard deviation estimates based on the distribution method, the calculated MID was 5.9. The MIDs of the FACT-ES total scores based on the anchor method were 7.7 for decline and 4.1 for improvement. The MID decline proportions were 6.1% and 14.7% lower in patients who experienced clinical benefits than in those who did not at 1 and 3 months, respectively. The ratios of MID improvement in patients who experienced clinical benefits were 18.3% and 3.2% higher, respectively; the mean change in the FACT-ES total score from baseline improved in patients who experienced clinical benefits. CONCLUSIONS: Maintaining the HRQOL as determined by FACT-ES may be associated with clinical benefits in patients with acquired endocrine-resistant MBC treated with ET.

Prevalence of mutations in BRCA and homologous recombination repair genes and real-world standard of care of Asian patients with HER2-negative metastatic breast cancer starting first-line systemic cytotoxic chemotherapy: subgroup analysis of the global BREAKOUT study.
Su-Jin Koh, Shozo Ohsumi, Masato Takahashi, Eisuke Fukuma, Kyung Hae Jung, Takanori Ishida, Ming-Shen Dai, Chuan-Hsun Chang, Tapashi Dalvi, Graham Walker, James Bennett, Joyce O'Shaughnessy, Judith Balmaña
Breast cancer (Tokyo, Japan), 29, 1, 92, 102, 2022年01月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The multinational BREAKOUT study (NCT03078036) sought to determine the prevalence of germline BRCA1/2 (gBRCA1/2) and somatic BRCA1/2 (sBRCA1/2) mutations and mutations in other homologous recombination repair (HRR) genes in women with HER2-negative metastatic breast cancer (MBC) starting first-line chemotherapy. METHODS: Genetic testing for gBRCA, sBRCA, and HRR gene mutations was performed in patients who started first-line chemotherapy for MBC in the last 90 days (341 patients across 14 countries) who were not selected based on risk factors for gBRCA mutations. We report data from the Asian cohort, which included patients in Japan (7 sites), South Korea (10 sites), and Taiwan (8 sites). RESULTS: Of 116 patients screened, 104 patients were enrolled in the Asian cohort. The median age was 53.0 (range 25-87) years. gBRCA1/2, gBRCA1, and gBRCA2 mutations were detected in 10.6% (11/104), 5.8% (6/104), and 4.8% (5/104) of patients, respectively; none had mutations in both gBRCA1 and gBRCA2. gBRCA1/2 mutations were detected in 10.0% (6/60) and 11.6% (5/43) of patients with hormone receptor-positive and triple-negative MBC, respectively. HRR gene mutations were tested in 48 patients without gBRCA mutations, and 5 (10.4%) had at least one HRR mutation in sBRCA, ATM, PALB2, and CHEK2. CONCLUSION: We report for the first time the prevalence of gBRCA and HRR mutations in an Asian cohort of patients with HER2-negative MBC. Our results suggest that BRCA mutation testing is valuable to determine appropriate treatment options for patients with hormone receptor-positive or triple-negative MBC. STUDY REGISTRATION: NCT03078036.

Quality of life in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer.
Naruto Taira, Kosuke Kashiwabara, Junji Tsurutani, Masahiro Kitada, Masato Takahashi, Hiroaki Kato, Yuichiro Kikawa, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Tsutomu Takashima, Tomohiko Aihara, Hirofumi Mukai, Fumikata Hara
Breast cancer (Tokyo, Japan), 29, 1, 131, 143, 2022年01月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). METHODS: Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m2 vs. MD: 220 mg/m2 vs. LD 180 mg/m2). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM). RESULTS: A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P < 0.001, LD vs. SD P < 0.001). Differences from baseline for FACT-Taxane total, physical and emotional well-being, and taxane subscale scores at MD and LD were also higher than at SD. The difference from baseline for the CFS score at LD was lower than at SD (P = 0.013) and those for EQ-5D utility scores at MD and LD were higher than at SD (MD vs. SD P = 0.011, LD vs. SD P < 0.001). CONCLUSION: QoL of patients treated with 220 or 180 mg/m2 of q3w nab-PTX was significantly better than that of patients treated with 260 mg/m2. TRIAL REGISTRATION: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN000015516), on 01/11/2014. Details are available at the following address: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017916.

Japanese subgroup analysis of the phase 3 MONARCH 3 study of abemaciclib as initial therapy for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
Masato Takahashi, Eriko Tokunaga, Joji Mori, Yoshinori Tanizawa, Jan-Stefan van der Walt, Tsutomu Kawaguchi, Matthew P Goetz, Masakazu Toi
Breast cancer (Tokyo, Japan), 29, 1, 174, 184, 2022年01月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: This was a Japanese subpopulation analysis of MONARCH 3, a randomized, double-blind, placebo-controlled phase 3 study of abemaciclib plus nonsteroidal aromatase inhibitors (NSAIs) for initial therapy for advanced breast cancer (ABC). METHODS: Eligibility included postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative ABC who had no prior systemic therapy in the advanced disease setting. Patients (N = 493) were randomized 2:1 to receive abemaciclib or placebo (150 mg) plus either 1 mg anastrozole or 2.5 mg letrozole (physician's choice). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), pharmacokinetics (PK), safety, and health-related quality of life (HRQoL). RESULTS: In Japan, 53 patients were randomized (abemaciclib, n = 38; placebo, n = 15). At final PFS analysis (November 3, 2017), median PFS was 29.1 and 14.9 months in the abemaciclib and placebo groups, respectively (hazard ratio 0.537; 95% confidence interval 0.224-1.289). ORR in measurable disease was 62.1 and 50.0% in the abemaciclib and placebo groups, respectively. The Japanese PK profile was comparable to that of the overall population. Consistent with prior studies, the most frequent adverse events reported were diarrhea (abemaciclib: any grade, 94.7%; grade ≥ 3, 10.5%; placebo: any grade, 46.7%; grade ≥ 3, 0%) and neutropenia (abemaciclib: any grade, 68.4%; grade ≥ 3, 21.1%; placebo: any grade, 0%). HRQoL outcomes were generally similar between treatments except for the diarrhea score, which favored placebo. CONCLUSIONS: Consistent with findings in the overall population, abemaciclib plus NSAI was an effective initial treatment in the Japanese subpopulation, with a manageable safety profile. CLINICAL TRIAL REGISTRATION: NCT02246621; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02246621 .

Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer.
Hirofumi Mukai, Yukari Uemura, Hiromitsu Akabane, Takanori Watanabe, Youngjin Park, Masato Takahashi, Yoshiaki Sagara, Reiki Nishimura, Tsutomu Takashima, Tomomi Fujisawa, Yasuo Hozumi, Takuya Kawahara
British journal of cancer, 125, 9, 1217, 1225, 2021年10月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. METHODS: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. RESULTS: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). CONCLUSIONS: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.

Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy.
Kenichi Inoue, Norikazu Masuda, Hiroji Iwata, Masato Takahashi, Yoshinori Ito, Yasuo Miyoshi, Takahiro Nakayama, Hirofumi Mukai, Jan-Stefan van der Walt, Joji Mori, Sachi Sakaguchi, Tsutomu Kawaguchi, Yoshinori Tanizawa, Antonio Llombart-Cussac, George W Sledge Jr, Masakazu Toi
Breast cancer (Tokyo, Japan), 28, 5, 1038, 1050, 2021年09月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). METHODS: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety. RESULTS: In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380-1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390-1.463). CONCLUSIONS: Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population. CLINICAL TRIAL REGISTRATION: NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703 .

Pharmacokinetics, Safety, and Efficacy of Trastuzumab Deruxtecan with Concomitant Ritonavir or Itraconazole in Patients with HER2-Expressing Advanced Solid Tumors.
Shunji Takahashi, Masato Karayama, Masato Takahashi, Junichiro Watanabe, Hironobu Minami, Noboru Yamamoto, Ichiro Kinoshita, Chia-Chi Lin, Young-Hyuck Im, Issei Achiwa, Emi Kamiyama, Yasuyuki Okuda, Caleb Lee, Yung-Jue Bang
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021年08月23日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To evaluate drug-drug interactions between the human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd; DS-8201a) and the OATP1B/CYP3A inhibitor ritonavir or the strong CYP3A inhibitor itraconazole. PATIENTS AND METHODS: Patients with HER2-expressing advanced solid tumors were enrolled in this phase I, open-label, single-sequence crossover study (NCT03383692) and received i.v. T-DXd 5.4 mg/kg every 3 weeks. Patients received ritonavir (cohort 1) or itraconazole (cohort 2) from day 17 of cycle 2 through the end of cycle 3. Primary endpoints were maximum serum concentration (C max) and partial area under the concentration-time curve from beginning of cycle through day 17 (AUC17d) for T-DXd and deruxtecan (DXd) with (cycle 3) and without (cycle 2) ritonavir or itraconazole treatment. RESULTS: Forty patients were enrolled (cohort 1, n = 17; cohort 2, n = 23). T-DXd C max was similar whether combined with ritonavir [cohort 1, cycle 3/cycle 2; 90% confidence interval (CI): 1.05 (0.98-1.13)] or itraconazole [cohort 2, 1.03 (0.96-1.09)]. T-DXd AUC17d increased from cycle 2 to 3; however, the cycle 3/cycle 2 ratio upper CI bound remained at ≤1.25 for both cohorts. For DXd (cycle 3/cycle 2), C max ratio was 0.99 (90% CI, 0.85-1.14) for cohort 1 and 1.04 (0.92-1.18) for cohort 2; AUC17d ratio was 1.22 (1.08-1.37) and 1.18 (1.11-1.25), respectively. The safety profile of T-DXd plus ritonavir or itraconazole was consistent with previous studies of T-DXd monotherapy. T-DXd demonstrated promising antitumor activity across HER2-expressing solid-tumor types. CONCLUSIONS: T-DXd was safely combined with ritonavir or itraconazole without clinically meaningful impact on T-DXd or DXd pharmacokinetics.

Health-Related Quality of Life With Trastuzumab Monotherapy Versus Trastuzumab Plus Standard Chemotherapy as Adjuvant Therapy in Older Patients With HER2-Positive Breast Cancer.
Naruto Taira, Masataka Sawaki, Yukari Uemura, Tsuyoshi Saito, Shinichi Baba, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Hiroji Iwata, Yasuo Ohashi, Hirofumi Mukai, Takuya Kawahara
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 39, 22, 2452, 2462, 2021年08月01日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: We report findings on quality of life (QoL) in the RESPECT trial, which compared adjuvant trastuzumab monotherapy with trastuzumab plus chemotherapy in older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). PATIENTS AND METHODS: Patients age 70-80 years with human epidermal growth factor receptor 2-positive surgically treated breast cancer were randomly assigned to receive trastuzumab (T) or trastuzumab plus chemotherapy (T + C). QoL was assessed using the Functional Assessment of Cancer Therapy-General (FACT-G), Philadelphia Geriatric Center Morale Scale, Hospital Anxiety and Depression Scale, Patient Neurotoxicity Questionnaire, and Tokyo Metropolitan Institute of Gerontology Index of Competence at baseline and after 2, 12, and 36 months. Comparisons were based on individual changes from baseline and were performed by Fisher's test or mixed-model repeated-measures. RESULTS: Among 275 patients in the parent study, 231 (84%) (average age: 74 years) were included in the analysis. At 2, 12, and 36 months, 198, 177, and 178 patients completed surveys, and the mean FACT-G scores at each survey point were 78.9, 80.4, 82.7, and 79.1 in group T and 79.5, 74.5, 78.4, and 78.5 in group T + C. Compared with group T + C, the proportion of patients showing QoL deterioration (≥ 5 points decrease from baseline in FACT-G) was significantly lower at 2 months (31% v 48%; P = .016) and 12 months (19% v 38%; P = .009). In group T, the Hospital Anxiety and Depression Scale score (P = .003) and the proportion of severe sensory peripheral neuropathy (P = .001) were significantly lower at 2 months, and Philadelphia Geriatric Center Morale Scale and Tokyo Metropolitan Institute of Gerontology Index of Competence scores were significantly higher (P = .024, .042) at 12 months. At 36 months, there were no significant differences in any QoL items. CONCLUSION: Detrimental effects of adjuvant chemotherapy on global QoL, morale, and activity capacity lasted for at least 12 months but were not observed at 36 months.

Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial.
Yasuhiro Hagiwara, Masataka Sawaki, Yukari Uemura, Takuya Kawahara, Kojiro Shimozuma, Yasuo Ohashi, Masato Takahashi, Tsuyoshi Saito, Shinichi Baba, Kokoro Kobayashi, Hirofumi Mukai, Naruto Taira
Breast cancer research and treatment, 188, 3, 675, 683, 2021年08月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To investigate whether postoperative adjuvant trastuzumab plus chemotherapy negatively affected cognitive functioning during the post-chemotherapy period compared with trastuzumab monotherapy in older patients with HER2-positive breast cancer. METHODS: In the randomized RESPECT trial, women aged between 70 and 80 years with HER2-positive, stage I to IIIA invasive breast cancer who underwent curative operation were randomly assigned to receive either 1-year trastuzumab monotherapy or 1-year trastuzumab plus chemotherapy. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) test at enrollment and 1 and 3 years after initiation of the protocol treatment. The primary outcome was change in the MMSE total score from baseline. Secondary outcomes included prevalence of suspected mild cognitive impairment (MMSE total score < 28) and suspected dementia (MMSE total score < 24). RESULTS: The analytical population consisted of 29 and 26 patients in the trastuzumab monotherapy and trastuzumab plus chemotherapy groups, respectively. The group differences in mean changes of the MMSE total score were 0.6 (95% confidence interval [CI] - 0.3 to 1.6) at 1 year and 0.9 (95% CI - 1.0 to 2.8) at 3 years (P = 0.136 for the group difference pooling the two visits). The prevalence of suspected mild cognitive impairment at 3 years was 41.7% in the trastuzumab monotherapy group and 28.6% in the trastuzumab plus chemotherapy group (P = 0.548). CONCLUSION: This randomized sub-study did not show worse cognitive functioning during the post-chemotherapy period with trastuzumab plus chemotherapy than with trastuzumab monotherapy in older patients with HER2-positive breast cancer. TRIAL REGISTRATION NUMBER: NCT01104935 (first posted April 16, 2010).

Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917).
Takahiro Nakayama, Tetsuhiro Yoshinami, Hiroyuki Yasojima, Nobuyoshi Kittaka, Masato Takahashi, Shoichiro Ohtani, Seung Jin Kim, Hiroyuki Kurakami, Naoko Yamamoto, Tomomi Yamada, Takehiko Takata, Norikazu Masuda
BMC cancer, 21, 1, 795, 795, 2021年07月09日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Trastuzumab emtansine (T-DM1) is a second-line standard therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Evidence regarding post-T-DM1 treatments is currently lacking. We evaluated the effectiveness of post-T-DM1 drug therapy in patients with HER2-positive, unresectable and/or metastatic breast cancer. METHODS: In this multicenter, retrospective, observational study, real-world clinical data of female patients with HER2-positive breast cancer who had a history of T-DM1 treatment were consecutively collected from five sites in Japan. We investigated the effectiveness of post-T-DM1 therapy by evaluating the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines. Subgroup and exploratory analyses according to background factors were also undertaken. RESULTS: Of the 205 patients who received T-DM1 treatment between 1 January 2014 and 31 December 2018, 128 were included in this study. Among the 128 patients analyzed, 105 (82%) patients received anti-HER2 therapy and 23 (18%) patients received regimens without anti-HER2 therapy. Median (95% confidence interval [CI]) rwPFS, TTF, and OS were 5.7 (4.8-6.9) months, 5.6 (4.6-6.4) months, and 22.8 (18.2-32.4) months, respectively. CBR and ORR (95% CI) were 48% (38.8-56.7) and 23% (15.1-31.4), respectively. Cox-regression analysis showed that an ECOG PS score of 0, a HER2 immunohistochemistry score of 3+, recurrent type, ≥12 month duration of T-DM1 therapy, and anti-HER2 therapy were independent variables for rwPFS. An exploratory subgroup analysis of regimens after T-DM1 showed that those with anti-HER2 therapy had a median rwPFS of 6.3 and those without anti-HER2 therapy had a median rwPFS of 4.8 months. CONCLUSIONS: In the real-world setting in Japan, several post-T-DM1 regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including continuation of anti-HER2 therapy, showed some effectiveness; however, this effectiveness was insufficient. Novel therapeutic options are still needed for further improvement of PFS and OS in later treatment settings. TRIAL REGISTRATION: UMIN000038296 ; registered on 15 October 2019.

Correction to: The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.
Tatsunori Shimoi, Shigenori E Nagai, Tetsuhiro Yoshinami, Masato Takahashi, Hitoshi Arioka, Mikiya Ishihara, Yuichiro Kikawa, Kei Koizumi, Naoto Kondo, Yasuaki Sagara, Masahiro Takada, Toshimi Takano, Junji Tsurutani, Yoichi Naito, Rikiya Nakamura, Masaya Hattori, Fimikata Hara, Naoki Hayashi, Toshiro Mizuno, Minoru Miyashita, Nami Yamashita, Takashi Yamanaka, Shigehira Saji, Hiroji Iwata, Tatsuya Toyama
Breast cancer (Tokyo, Japan), 28, 4, 985, 986, 2021年07月, ［国内誌］
英語

Indices of peripheral leukocytes predict longer overall survival in breast cancer patients on eribulin in Japan.
Masato Takahashi, Kenichi Inoue, Hirofumi Mukai, Takashi Yamanaka, Chiyomi Egawa, Yasuo Miyoshi, Yukinori Sakata, Kenzo Muramoto, Hiroki Ikezawa, Toshiyuki Matsuoka, Junji Tsurutani
Breast cancer (Tokyo, Japan), 28, 4, 945, 955, 2021年07月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It was reported that eribulin regulates the tumor microenvironment, including the immune system, by inducing vascular remodeling. Lymphocyte counts are a critical index of immune response in patients. The non-Asian, global EMBRACE study has suggested that baseline absolute lymphocyte count (ALC) may be a predictor of the survival benefit of eribulin in breast cancer patients. We examined whether the baseline ALC is a potential predictor of overall survival (OS) in Japanese patients with HER2-negative advanced breast cancer treated with eribulin. METHODS: This was a post hoc analysis of data from a post-marketing observational study of eribulin in Japan. The OS by baseline ALC was estimated using the Kaplan-Meier method, with the cut-off value of 1500/μL for ALC. The OS by baseline neutrophil-to-lymphocyte ratio (NLR), a general prognostic index in breast cancer patients, was also estimated, with the cut-off value of 3. RESULTS: The median OS was longer in patients with an ALC of ≥ 1500/μL than in those with an ALC of < 1500/μL (19.4 vs. 14.3 months; hazard ratio [HR]: 0.628; 95% confidence interval [CI]: 0.492, 0.801). Patients with an NLR of ≥ 3 showed shorter OS than those with an NLR of < 3 (13.2 vs. 18.8 months; HR: 1.552; 95% CI 1.254, 1.921), and NLR also separated OS in patients with an ALC of < 1500/μL. CONCLUSIONS: Consistent with the findings of a previous study involving a non-Asian, Western population, our study suggested that baseline ALC may be a predictive factor for the survival benefit of eribulin in Japanese patients.

Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial.
Norikazu Masuda, Hiroko Bando, Takashi Yamanaka, Takayuki Kadoya, Masato Takahashi, Shigenori E Nagai, Shoichiro Ohtani, Tomoyuki Aruga, Eiji Suzuki, Yuichiro Kikawa, Hiroyuki Yasojima, Hiroi Kasai, Hiroshi Ishiguro, Hidetaka Kawabata, Satoshi Morita, Hironori Haga, Tatsuki R Kataoka, Ryuji Uozumi, Shinji Ohno, Masakazu Toi
Breast cancer research and treatment, 188, 1, 117, 131, 2021年07月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients. METHODS: Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety. RESULTS: The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively. CONCLUSIONS: In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

Clinical significance of comprehensive genomic profiling tests covered by public insurance in patients with advanced solid cancers in Hokkaido, Japan.
Junko Kikuchi, Yoshihito Ohhara, Kohichi Takada, Hiroki Tanabe, Kazuteru Hatanaka, Toraji Amano, Kanako C Hatanaka, Yutaka Hatanaka, Takashi Mitamura, Momoko Kato, Yuka Shibata, Ichiro Yabe, Akira Endoh, Yoshito Komatsu, Yoshihiro Matsuno, Minako Sugiyama, Atsushi Manabe, Akihiro Sakurai, Masato Takahashi, Hirohito Naruse, Yoshihiro Torimoto, Hirotoshi Dosaka-Akita, Ichiro Kinoshita
Japanese journal of clinical oncology, 51, 5, 753, 761, 2021年04月30日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Comprehensive cancer genomic profiling has been used recently for patients with advanced solid cancers. Two cancer genomic profiling tests for patients with no standard treatment are covered by Japanese public health insurance since June 2019. METHODS: We prospectively analyzed data of 189 patients with solid cancers who underwent either of the two-cancer genomic profiling tests at Hokkaido University Hospital and its liaison hospitals and whose results were discussed in molecular tumor board at Hokkaido University Hospital between August 2019 and July 2020. RESULTS: All 189 patients had appropriate results. Actionable gene alterations were identified in 93 patients (49%). Frequent mutations included PIK3CA (12%) mutation, BRCA1/2 alteration (7%), ERBB2 amplification (6%) and tumor mutation burden-High (4%). The median turnaround time from sample shipping to acquisition by the expert panel was 26 days. Although 115 patients (61%) were provided with information for genotype-matched therapies, only 21 (11%) received them. Notably, four of eight patients below the age of 20 years were provided information for genotype-matched therapies, and three received them. Their response rates and disease control rates were 29% and 67%, respectively. Most patients who did not undergo the genotype-matched therapies were provided information for only investigational drugs in phases I and II at distant clinical trial sites in central Japan. Twenty-six patients were informed of suspected germline findings, while 11 patients (42%) received genetic counseling. CONCLUSIONS: The publicly reimbursed cancer genomic profilings may lead to the modest but favorable therapeutic efficacy of genotype-matched therapy for solid cancer patients with no standard therapy. However, poor access to genotype-matched therapy needs to be resolved.

The impact of neoadjuvant systemic therapy on breast conservation rates in patients with HER2-positive breast cancer: Surgical results from a phase II randomized controlled trial.
Takeshi Yamaguchi, Yasuo Hozumi, Yasuaki Sagara, Masato Takahashi, Kimiyasu Yoneyama, Tomomi Fujisawa, Shozo Osumi, Hiromitsu Akabane, Reiki Nishimura, Makiko Naka Mieno, Hirofumi Mukai
Surgical oncology, 36, 51, 55, 2021年03月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Neoadjuvant systemic therapy (NST) induces tumor shrinkage and boosts the chance of breast-conserving thearpy (BCT) in patients with breast cancer. However, only a few trials have evaluated the effect of NST in conversion from BCT ineligibility to BCT eligibility in HER2-positive breast cancer. METHODS: We conducted the surgical sub-study of a phase II randomized trial, which compared standard neoadjuvant treatment or an experimental treatment modified according to the interim Ki-67 evaluation in women with stage II or III HER2-positive breast cancer. The treating surgeons assessed eligibility for BCT before and after NST. We evaluated the change in BCT eligibility following NST. We also analyzed the type of surgery performed and the success rate of BCT. RESULTS: Two hundred six patients were included in this study. Of these, 44.0% were considered BCT candidates at baseline, while 69.8% were deemed eligible for BCT after NST (P < 0.001). Among non-BCT candidates at baseline, 46% successfully converted to BCT candidates. Of 139 patients deemed eligible for BCT following NST, 84.2% attempted BCT, and successful BCT, defined as tumor-free at all surgical margins, was achieved in 96.8% of patients. Different treatment arms did not affect the rate of post-NST BCT eligibility (70.0% vs 69.7%). CONCLUSIONS: This study demonstrated that NST resulted in an absolute increase of 25.8% in the rate of BCT eligibility in HER2-positive breast cancer. About a half of non-BCT candidates converted to BCT candidates. BCT was successful in most patients who attempted BCT. There were still patients who chose mastectomy even though they were deemed eligible for BCT. Patients considered BCT-ineligible due to large tumor size most likely converted to BCT-eligible with NST. On the other hand, NST had less impact on the surgical indication of patients with multicentric disease or probable poor cosmetic outcome.

Randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer
Junji Tsurutani, Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro Kikawa, Hiroaki Kato, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Naruto Taira, Tsutomu Takashima, Kosuke Kashiwabara, Tomohiko Aihara, Hirofumi Mukai
Breast, 55, 63, 68, Churchill Livingstone, 2021年02月01日
英語, 研究論文（学術雑誌）, Background: Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin–bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX. Methods: We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was <
0.75 or >
1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded. Results: One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42–1.28) in MD220 vs SD260, 0.77 (95% CI 0.47–1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56–1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180. Conclusions: Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC.

Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR+, HER2-metastatic breast cancer: WJOG11418B NEWFLAME trial
Jun Masuda, Junji Tsurutani, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kenichi Yoshimura, Toshimi Takano
CANCER RESEARCH, 81, 4, AMER ASSOC CANCER RESEARCH, 2021年02月
英語

Immunological analysis of the combination therapy of nivolumab, paclitaxel and bevacizumab in patients with HER2negative MBC in NEWBEAT trial (WJOG9917BTR)
Yukinori Ozaki, Shigehisa Kitano, Junji Tsurutani, Tsutomu Iwasa, Masato Takahashi, Toru Mukohara, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Hidetaka Kawabata, Makiko Yamashita, Kenichi Yoshimura, Toshimi Takano
CANCER RESEARCH, 81, 4, AMER ASSOC CANCER RESEARCH, 2021年02月
英語

Prospective observational study of bevacizumab combined with paclitaxel as first- or second-line chemotherapy for locally advanced or metastatic breast cancer: the JBCRG-C05 (B-SHARE) study.
Yutaka Yamamoto, Hiroyasu Yamashiro, Uhi Toh, Naoto Kondo, Rikiya Nakamura, Masahiro Kashiwaba, Masato Takahashi, Koichiro Tsugawa, Takashi Ishikawa, Takahiro Nakayama, Shoichiro Ohtani, Toshimi Takano, Tomomi Fujisawa, Tatsuya Toyama, Hidetoshi Kawaguchi, Kojiro Mashino, Yuichi Tanino, Satoshi Morita, Masakazu Toi, Shinji Ohno
Breast cancer (Tokyo, Japan), 28, 1, 145, 160, 2021年01月, ［国内誌］
英語, 研究論文（学術雑誌）, PURPOSE: To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice. METHODS: In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors. RESULTS: Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively. CONCLUSIONS: In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously. TRIAL REGISTRATION: Trial no. UMIN000009086.

The efficacy and safety of pertuzumab plus trastuzumab and docetaxel as a first-line therapy in Japanese patients with inoperable or recurrent HER2-positive breast cancer: the COMACHI study.
Masato Takahashi, Shoichiro Ohtani, Shigenori E Nagai, Seiki Takashima, Miki Yamaguchi, Michiko Tsuneizumi, Yoshifumi Komoike, Tomofumi Osako, Yoshinori Ito, Masahiko Ikeda, Kazushige Ishida, Takahiro Nakayama, Tsutomu Takashima, Takashi Asakawa, Sho Matsumoto, Daisuke Shimizu, Norikazu Masuda
Breast cancer research and treatment, 185, 1, 125, 134, 2021年01月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: In the CLEOPATRA study of patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer, the Japanese patient subgroup did not demonstrate the improved progression-free survival (PFS) of pertuzumab plus trastuzumab and docetaxel vs. placebo that was seen in the overall population. Therefore, COMACHI was conducted to confirm the efficacy and safety of this treatment regimen in this patient subgroup. METHODS: This was a phase IV study of pertuzumab plus trastuzumab and docetaxel in Japanese patients with histologically/cytologically confirmed inoperable or recurrent HER2-positive breast cancer. All patients received pertuzumab, trastuzumab, and docetaxel intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), investigator-assessed objective response rate, and duration of response (DoR). Safety was also assessed. RESULTS: At final analysis, median investigator-assessed PFS was 22.8 months (95% CI 16.9-37.5). From first dose, OS rate at 1 year was 97.7%; and at 2 and 3 years were 88.5% and 79.1%, respectively. Of the 118 patients with measurable disease at baseline, response rate was 83.9% (95% CI 77.3-90.5) and median investigator-assessed DoR was 26.3 months (95% CI 17.1-not evaluable). Treatment was well tolerated, with no new safety signals detected. CONCLUSIONS: Our results suggest similar efficacy and safety for pertuzumab plus trastuzumab and docetaxel in Japanese patients compared with the overall population of CLEOPATRA, providing further support for this combination therapy as standard of care for Japanese patients with inoperable or recurrent HER2-positive breast cancer.

Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients.
Masataka Sawaki, Naruto Taira, Yukari Uemura, Tsuyoshi Saito, Shinichi Baba, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Hiroji Iwata, Takuya Kawahara, Yasuo Ohashi, Hirofumi Mukai
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38, 32, 3743, 3752, 2020年11月10日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Adjuvant trastuzumab monotherapy has not been compared with trastuzumab + chemotherapy. We investigated the relative value of trastuzumab monotherapy for older patients with breast cancer. METHODS: This study was an open-label, randomized controlled study with a treatment selection design in which a noninferiority criterion was predefined. Patients aged 70-80 years with surgically treated human epidermal growth factor receptor 2-positive invasive breast cancer received trastuzumab monotherapy or trastuzumab + chemotherapy. The primary end point was disease-free survival (DFS) with assessment of prespecified hazard ratio (HR), relapse-free survival (RFS), adverse events (AEs), health-related quality of life (HRQoL), and restricted mean survival time (RMST). RESULTS: The study involved 275 patients (mean age, 73.5 years) who were followed up for a mean of 4.1 years (range, 0.3-8.0 years). The percentages of patients by cancer stage were as follows: I (pT > 0.5 cm), 43.6%; IIA, 41.7%; IIB, 13.5%; and IIIA, 1.1%. Three-year DFS was 89.5% with trastuzumab monotherapy versus 93.8% with trastuzumab + chemotherapy (HR, 1.36; 95% CI, 0.72 to 2.58; P = .51). At 3 years, RMST differed by -0.39 months between arms (95% CI, -1.71 to 0.93; P = .56). Three-year RFS was 92.4% with trastuzumab monotherapy versus 95.3% with trastuzumab + chemotherapy (HR, 1.33; 95% CI, 0.63 to 2.79; P = .53). Common AEs were anorexia (7.4% v 44.3%; P < .0001) and alopecia (2.2% v 71.7%; P < .0001), and grade 3/4 nonhematologic AEs occurred in 11.9% versus 29.8% (P = .0003) for trastuzumab monotherapy versus trastuzumab + chemotherapy, respectively. Clinically meaningful HRQoL deterioration rate showed significant differences at 2 months (31% for trastuzumab monotherapy v 48% for trastuzumab + chemotherapy; P = .016) and at 1 year (19% v 38%; P = .009). CONCLUSION: The primary objective of noninferiority for trastuzumab monotherapy was not met. However, the observed loss of survival without chemotherapy was < 1 month at 3 years. Therefore, and in light of the lower toxicity and more favorable HRQoL profile, trastuzumab monotherapy can be considered an adjuvant therapy option for selected older patients.

MONARCH 2日本人部分集団解析 進行乳癌におけるabemaciclibとfulvestrant併用での全生存期間　　　　　　　　　　　　　　　
増田 慎三, 井上 賢一, 岩田 広治, 高橋 將人, 伊藤 良則, 三好 康雄, 森 丈治, 坂口 佐知, Sledge Jr. George W., 戸井 雅和
日本乳癌学会総会プログラム抄録集, 28回, 541, 541, (一社)日本乳癌学会, 2020年10月
英語

Effectiveness and safety of eribulin in Japanese patients with HER2-negative, advanced breast cancer: a 2-year post-marketing observational study in a real-world setting.
Kenichi Inoue, Masato Takahashi, Hirofumi Mukai, Takashi Yamanaka, Chiyomi Egawa, Yukinori Sakata, Hiroki Ikezawa, Toshiyuki Matsuoka, Junji Tsurutani
Investigational new drugs, 38, 5, 1540, 1549, 2020年10月, ［国際誌］
英語, 研究論文（学術雑誌）, Background Data on eribulin as the first- or second-line treatment in a clinical setting, especially the overall survival (OS) of patients, are scarce. Therefore, we assessed the effectiveness and safety of eribulin as the first-, second-, and third- or later-line treatments in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in Japan. Methods This multicenter, prospective, post-marketing, observational study enrolled patients from September 2014 to February 2016 in Japan and followed them for 2 years. Patients were categorized by eribulin use into the first-, second-, and third- or later-line treatment groups. Results Of 651 registered patients, 637 patients were included in the safety and effectiveness analysis. In all, first-, second-, and third or later-line treatment groups, median OS (95% confidence interval) were 15.6 (13.8-17.6), 22.8 (17.3-31.0), 16.3 (12.4-19.9), and 12.6 (11.2-15.1) months and time to treatment failure (TTF) (95% confidence interval) were 4.2 (3.7-4.4), 5.2 (3.7-5.9), 4.2 (3.7-5.1), and 3.8 (3.5-4.2) months, respectively. Prolonged TTF was associated with complications of diabetes and the development of peripheral neuropathy after eribulin treatment, according to multivariate Cox regression analysis. Grade ≥ 3 adverse drug reactions (ADRs) were reported in 61.7% of the patients. Neutropenia (49.5%) was the most common grade ≥ 3 ADR in all groups. Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan.

Effect of renal function on neutrophil decreases following eribulin administration.
Norifumi Suzuki, Hiroyuki Tanaka, Hirotoshi Murakami, Nobumoto Tomioka, Kenichi Watanabe, Masayuki Endo, Masato Takahashi
Cancer reports (Hoboken, N.J.), 3, 5, e1258, 2020年10月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Eribulin therapy has recently attracted attention from various viewpoints, including quality of life, and is considered a standard therapy for inoperable or recurrent breast cancer. Although a reduction in renal function reportedly decreases total eribulin clearance, its association with dose-limiting toxicity and the reduction of neutrophils remain unclear. AIM: This study was aimed at analyzing the association between decreased renal function prior to eribulin administration and the occurrence of neutrophil reduction and time to treatment failure in patients with breast cancer. METHODS AND RESULTS: We retrospectively assessed patients with breast cancer, who underwent eribulin therapy between July 2011 and March 2018. Multivariate analysis revealed creatinine clearance <70 mL/min and serum albumin levels <3.9 mg/dL as predictive factors for neutrophil reduction. Even on increasing the relative dose intensity by these factors, no difference in time to treatment failure was observed, suggesting that treatment efficacy is potentially unaffected. CONCLUSIONS: For continuous eribulin therapy, eribulin may need to be administered to individual patients in accordance with renal function and albumin levels before treatment initiation.

Multi-omics analyses identify HSD17B4 methylation-silencing as a predictive and response marker of HER2-positive breast cancer to HER2-directed therapy.
Satoshi Yamashita, Naoko Hattori, Satoshi Fujii, Takeshi Yamaguchi, Masato Takahashi, Yasuo Hozumi, Takahiro Kogawa, Omar El-Omar, Yu-Yu Liu, Nobuaki Arai, Akiko Mori, Hiroko Higashimoto, Toshikazu Ushijima, Hirofumi Mukai
Scientific reports, 10, 1, 15530, 15530, 2020年09月23日, ［国際誌］
英語, 研究論文（学術雑誌）, HER2-positive breast cancers that achieve pathological complete response (pCR) after HER2-directed therapy consistently have good survival. We previously identified HSD17B4 methylation as a marker for pCR by methylation screening. Here, we aimed to identify a new marker by conducting a multi-omics analysis of materials prepared by laser capture microdissection, and adding 71 new samples. In the screening set (n = 36), mutations, methylation, and expression were analyzed by targeted sequencing, Infinium 450 K, and expression microarray, respectively, and 15 genes were identified as differentially expressed and eight genomic regions as differentially methylated between cancer samples with and without pCR. In a validation set (n = 47), one gene showed differential expression, and one region had differential methylation. Further, in the re-validation set (n = 55), all new samples, only HSD17B4 methylation was significantly different. The HSD17B4 methylation was at the transcriptional start site of its major variant, and was associated with its silencing. HSD17B4 was highly expressed in the vast majority of human cancers, and its methylation was present only in breast cancers and one lymphoblastic leukemia cell line. A combination of estrogen receptor-negative status and HSD17B4 methylation showed a positive predictive value of 80.0%. During HER2-directed neoadjuvant therapy, HSD17B4 methylation was the most reliable marker to monitor response to the therapy. These results showed that HSD17B4 methylation is a candidate predictive and response marker of HER2-positive breast cancer to HER2-directed therapy.

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.
Cristina Saura, Mafalda Oliveira, Yin-Hsun Feng, Ming-Shen Dai, Shang-Wen Chen, Sara A Hurvitz, Sung-Bae Kim, Beverly Moy, Suzette Delaloge, William Gradishar, Norikazu Masuda, Marketa Palacova, Maureen E Trudeau, Johanna Mattson, Yoon Sim Yap, Ming-Feng Hou, Michelino De Laurentiis, Yu-Min Yeh, Hong-Tai Chang, Thomas Yau, Hans Wildiers, Barbara Haley, Daniele Fagnani, Yen-Shen Lu, John Crown, Johnson Lin, Masato Takahashi, Toshimi Takano, Miki Yamaguchi, Takaaki Fujii, Bin Yao, Judith Bebchuk, Kiana Keyvanjah, Richard Bryce, Adam Brufsky
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38, 27, 3138, 3149, 2020年09月20日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

The efficacy of sequential second-line endocrine therapies (ETs) in postmenopausal estrogen receptor-positive and HER2-negative metastatic breast cancer patients with lower sensitivity to initial ETs.
Takayuki Iwamoto, Tomomi Fujisawa, Tadahiko Shien, Kazuhiro Araki, Kentaro Sakamaki, Takafumi Sangai, Yuichiro Kikawa, Shintaro Takao, Reiki Nishimura, Masato Takahashi, Tomohiko Aihara, Hirofumi Mukai, Naruto Taira
Breast cancer (Tokyo, Japan), 27, 5, 973, 981, 2020年09月, ［国内誌］
英語, 研究論文（学術雑誌）, PURPOSE: Second-line endocrine therapy (ET) for estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) is offered based on the response to first-line ET. However, no clinical trials have evaluated the efficacy and safety of secondary ETs in patients with poor responses to initial ET. This study evaluated the efficacy of second-line ET in ER-positive and HER2-negative postmenopausal MBC patients with low or very low sensitivity to initial ET. METHODS: This multicenter prospective observational cohort study evaluated the response of 49 patients to second-line ETs in postmenopausal MBC patients with low or very low sensitivity to initial ET. The primary endpoint was the clinical benefit rate (CBR) for 24 weeks. RESULTS: Of the 49 patients assessed, 40 (82%) received fulvestrant in the second line, 5 (10%) received selective estrogen receptor modulators, 3 (6%) received aromatase inhibitors (AIs) alone, and 1 received everolimus with a steroidal AI. The overall CBR was 44.9% [90% confidence interval (CI): 34.6-57.6, p = 0.009]; CBR demonstrated similar significance across the progesterone receptor-positive (n = 39, 51.3%, 90% CI: 39.6-65.2, p = 0.002), very low sensitivity (n = 17, 58.8%, 90% CI: 42.0-78.8, p = 0.003), and non-visceral metastases (n = 25, 48.0%, 90% CI: 34.1-65.9, p = 0.018) groups. The median progression-free survival was 7.1 months (95% CI: 5.6-10.6). CONCLUSION: Second-line ET might be a viable treatment option for postmenopausal patients with MBC with low and very low sensitivity to initial ET. Future studies based on larger and independent cohorts are needed to validate these findings.

Factors affecting enrollment in randomized controlled trials conducted for patients with metastatic breast cancer.
Shozo Ohsumi, Hirofumi Mukai, Masato Takahashi, Yasuo Hozumi, Hiromitsu Akabane, Youngjin Park, Eriko Tokunaga, Tsutomu Takashima, Takanori Watanabe, Yoshiaki Sagara, Tetsuji Kaneko, Yasuo Ohashi
Japanese journal of clinical oncology, 50, 8, 873, 881, 2020年08月04日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It is critical to obtain informed consent from eligible patients to complete clinical trials. We investigated the factors that affect the participation rates of eligible patients. PATIENTS AND METHODS: Patients with metastatic breast cancer who were eligible for SELECT BC or SELECT BC-CONFIRM trials, randomized controlled trials conducted for patients with chemotherapy-naive metastatic breast cancer were recruited to prospective studies, SELECT BC-FEEL and SELECT BC-FEEL II, respectively. SELECT BC FEEL and SELECT BC-FEEL II were conducted to identify the factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed. RESULTS: In total, 232 patients participated in the studies. The patients who agreed to take part in the randomized trials were more likely than the refusers to answer that they decided to participate because: 'My doctor wanted me to participate in this trial' (P = 0.00000), ' My family or friends wanted me to participate in this trial' (P = 0.00000), 'Both treatment regimens used in the trial are suitable to me' (P = 0.00383), 'I know that the trial is conducted to determine which is a better treatment' (P = 0.01196), and ' I think that my participation in the trial will contribute to the benefit to future patients with the same disease' (P = 0.00756). CONCLUSIONS: To enhance the consent rate in randomized trials of metastatic breast cancer patients, concepts of the trials must be considered important and acceptable not only by patients but also by doctors and their families.

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients: extended follow-up of JBCRG-cohort study 01.
Hiroyasu Yamashiro, Hiroji Iwata, Norikazu Masuda, Naohito Yamamoto, Reiki Nishimura, Shoichiro Ohtani, Nobuaki Sato, Masato Takahashi, Takako Kamio, Kosuke Yamazaki, Tsuyoshi Saito, Makoto Kato, Tecchuu Lee, Katsumasa Kuroi, Toshimi Takano, Shinji Yasuno, Satoshi Morita, Shinji Ohno, Masakazu Toi
Breast cancer (Tokyo, Japan), 27, 4, 631, 641, 2020年07月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Previous large trials of trastuzumab (TZM) demonstrated improved outcomes in patients with HER2-positive early breast cancer. However, its effectiveness and safety in Japanese patients is not yet clear. Recently, new anti-HER2 agents were developed to improve treatment outcomes, but the patient selection criteria remain controversial. PURPOSE: The aim of this study was to evaluate the long-term effectiveness of TZM therapy as perioperative therapy for HER2-positive operable breast cancer in daily clinical practice and to create a recurrence prediction model for therapeutic selection. METHODS: An observational study was conducted in Japan (UMIN000002737) to observe the prognosis of women (n = 2024) with HER2-positive invasive breast cancer who received TZM for stage I-III C disease between July 2009 and June 2011. Moreover, a recurrence-predicting model was designed to evaluate the risk factors for recurrence. RESULTS: The 5- and 10-year disease-free survival (DFS) rates were 88.9 (95% CI 87.5-90.3%) and 82.4% (95% CI 79.2-85.6%), respectively. The 5- and 10-year overall survival (OS) rates were 96% (95% CI 95.1-96.9%) and 92.7% (95% CI 91.1-94.3%), respectively. Multivariate analysis revealed that the risk factors for recurrence were an age of ≥ 70 years, T2 or larger tumors, clinically detected lymph node metastasis, histological tumor diameter of > 1 cm, histologically detected lymph node metastasis (≥ n2), and the implementation of preoperative treatment. The 5-year recurrence rate under the standard treatment was estimated to be > 10% in patients with a score of 3 or greater on the recurrence-predicting model. CONCLUSION: The recurrence-predicting model designed in this study may improve treatment selection of patients with stage I-III C disease. However, further studies are needed to validate the scores generated by this model.

Palbociclib-letrozole as first-line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study.
Masato Takahashi, Norikazu Masuda, Reiki Nishimura, Kenichi Inoue, Shinji Ohno, Hiroji Iwata, Satoshi Hashigaki, Yasuaki Muramatsu, Yoshiko Umeyama, Masakazu Toi
Cancer medicine, 9, 14, 4929, 4940, 2020年07月, ［国際誌］
英語, 研究論文（学術雑誌）, Palbociclib is a highly selective, reversible, oral inhibitor of cyclin-dependent kinases 4 and 6 that is approved to treat hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. An open-label, single-arm, Japanese phase 2 study was conducted to investigate the efficacy and safety of palbociclib plus letrozole as first-line treatment in 42 postmenopausal patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. The probability of progression-free survival originally reported at 1 year was 75.0% (90% confidence interval, 61.3-84.4), but median progression-free survival was not attained at the primary analysis. In this report, updated efficacy and safety results with a longer follow-up period are presented. The median duration of treatment in the updated analysis was 33.0 months (range, 1.8-49.2). The probability of progression-free survival at 1 year was 75.6% (90% confidence interval, 62.4-84.7). Median progression-free survival was 35.7 months (95% confidence interval, 21.7-46.7). Objective response rate and disease control rate were 47.6% (95% confidence interval, 32.0-63.6) and 85.7% (95% confidence interval, 71.5-94.6), respectively. Common treatment-related adverse events (all grades; grade 3/4) were neutropenia (100%; 93%), leukopenia (83%; 60%), and stomatitis (76%; 0%). Treatment-related febrile neutropenia was reported in one patient. In general, no clinically meaningful deterioration in health-related quality of life was observed. Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in this updated analysis.

Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer: results of a randomised Phase 2 study.
Hirofumi Mukai, Takeshi Yamaguchi, Masato Takahashi, Yasuo Hozumi, Tomomi Fujisawa, Shozo Ohsumi, Hiromitsu Akabane, Reiki Nishimura, Tsutomu Takashima, Youngjin Park, Yasuaki Sagara, Tatsuya Toyama, Shigeru Imoto, Toshiro Mizuno, Satoshi Yamashita, Satoshi Fujii, Yukari Uemura
British journal of cancer, 122, 12, 1747, 1753, 2020年06月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated. METHODS: Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4-56.7; P = 0.025). CONCLUSIONS: The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: UMIN-CTR as UMIN000007074.

Trastuzumab, pertuzumab, and eribulin mesylate versus trastuzumab, pertuzumab, and a taxane as a first-line or second-line treatment for HER2-positive, locally advanced or metastatic breast cancer: study protocol for a randomized controlled, non-inferiority, phase III trial in Japan (JBCRG-M06/EMERALD).
Toshinari Yamashita, Norikazu Masuda, Shigehira Saji, Kazuhiro Araki, Yoshinori Ito, Toshimi Takano, Masato Takahashi, Junji Tsurutani, Kei Koizumi, Masahiro Kitada, Yasuyuki Kojima, Yasuaki Sagara, Hiroshi Tada, Tsutomu Iwasa, Takayuki Kadoya, Tsuguo Iwatani, Hiroki Hasegawa, Satoshi Morita, Shinji Ohno
Trials, 21, 1, 391, 391, 2020年05月07日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2+ mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade. METHODS/DESIGN: This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2+ mBC who meet the following requirements: (1) age 20-70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m2 on days 1 and 8) or taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested. DISCUSSION: If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2+ mBC in Japan. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.

A double-blind, randomized, multicenter phase 3 study of palonosetron vs granisetron combined with dexamethasone and fosaprepitant to prevent chemotherapy-induced nausea and vomiting in patients with breast cancer receiving anthracycline and cyclophosphamide.
Koji Matsumoto, Masato Takahashi, Kazuhiko Sato, Akihiko Osaki, Toshimi Takano, Yoichi Naito, Kazuo Matsuura, Kenjiro Aogi, Kimiko Fujiwara, Kenji Tamura, Motoi Baba, Shinya Tokunaga, Gen Hirano, Shigeru Imoto, Chieko Miyazaki, Kazuhiro Yanagihara, Chiyo K Imamura, Yasutaka Chiba, Toshiaki Saeki
Cancer medicine, 9, 10, 3319, 3327, 2020年05月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To investigate whether palonosetron is better than granisetron in preventing chemotherapy-induced nausea and vomiting (CINV) in a three-drug combination with dexamethasone and fosaprepitant (Fos) in patients with breast cancer who are placed on anthracycline and cyclophosphamide (AC-based regimen). PATIENTS AND METHODS: Chemo-naive women with primary breast cancer were randomly administered either palonosetron 0.75 mg (day 1) or granisetron 1 mg (day 1) combined with dexamethasone (12 mg at day 1, 8 mg at day 2 and day 3) and Fos 150 mg (day 1) before receiving AC-based regimen in a double-blind study. The primary endpoint was the complete response (CR) rate of emesis in cycle 1 in the delayed phase. This was defined as neither vomiting nor rescue drug usage for emesis at >24-120 hours after chemotherapy. Secondary endpoints were the CR in the acute/overall phase (0-24/0-120 hours, respectively, after chemotherapy), no nausea and vomiting, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and safety. RESULTS: From December 2012 to October 2014, 326 patients were treated and evaluated (164/162 evaluable patients in granisetron/palonosetron arm, respectively). The CR during the delayed phase was 60.4% in the granisetron regimen and 62.3% in the palonosetron regimen. The CR during acute phase (73.2% vs 75.9%, respectively) and the CR during overall phase (54.9% in both regimens) were very identical. A significantly higher number of patients in the palonosetron arm were free from nausea during the delayed phase (28% vs 40.1%; P = .029). Adverse events were also identical, although infusion site reactions (ISR) were higher (20.3%-23.3%) than preceding studies in both regimens. CONCLUSION: In combination with dexamethasone and Fos, this study suggests that palonosetron is not better than granisetron in chemo-naive patients with primary breast cancer receiving AC-based regimen. Administration of Fos in peripheral veins after AC-based regimen increased ISR.

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.
Tatsunori Shimoi, Shigenori E Nagai, Tetsuhiro Yoshinami, Masato Takahashi, Hitoshi Arioka, Mikiya Ishihara, Yuichiro Kikawa, Kei Koizumi, Naoto Kondo, Yasuaki Sagara, Masahiro Takada, Toshimi Takano, Junji Tsurutani, Yoichi Naito, Rikiya Nakamura, Masaya Hattori, Fimikata Hara, Naoki Hayashi, Toshiro Mizuno, Minoru Miyashita, Nami Yamashita, Takashi Yamanaka, Shigehira Saji, Hiroji Iwata, Tatsuya Toyama
Breast cancer (Tokyo, Japan), 27, 3, 322, 331, 2020年05月, ［国内誌］
英語, 研究論文（学術雑誌）, PURPOSE: We present the English version of The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition. METHODS: The JBCS formed a task force to update the JBCS Clinical Practice Guidelines, 2015 edition, according to Minds Handbook for Clinical Practice Guideline Development 2014. First, we set multiple outcomes for each clinical question (CQ). Next, quantitative or qualitative systematic review was conducted for each of the multiple outcomes, and the strength of recommendation for the CQ was taken into consideration during meetings, with the aim of finding a balance between benefit and harm. Finalized recommendations from each session were confirmed through discussion and voting at the recommendation decision meeting. RESULTS: The recommendations, the strength of recommendation and the strength of evidence were determined based on systemic literature reviews and the meta-analyses for each CQ. CONCLUSION: The JBCS updated the Clinical Practice Guidelines for systemic treatment of breast cancer.

A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer.
Hiroshi Ishiguro, Norikazu Masuda, Nobuaki Sato, Kenji Higaki, Takashi Morimoto, Yasuhiro Yanagita, Makiko Mizutani, Shoichiro Ohtani, Koji Kaneko, Tomomi Fujisawa, Masato Takahashi, Takayuki Kadoya, Nobuki Matsunami, Yutaka Yamamoto, Shinji Ohno, Toshimi Takano, Satoshi Morita, Sachiko Tanaka-Mizuno, Masakazu Toi
Breast cancer research and treatment, 180, 3, 715, 724, 2020年04月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC. METHODS: We randomized patients with stage I-III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2. RESULTS: We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years. CONCLUSIONS: Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC. TRIAL REGISTRATION: UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

Pembrolizumab for Early Triple-Negative Breast Cancer.
Peter Schmid, Javier Cortes, Lajos Pusztai, Heather McArthur, Sherko Kümmel, Jonas Bergh, Carsten Denkert, Yeon Hee Park, Rina Hui, Nadia Harbeck, Masato Takahashi, Theodoros Foukakis, Peter A Fasching, Fatima Cardoso, Michael Untch, Liyi Jia, Vassiliki Karantza, Jing Zhao, Gursel Aktan, Rebecca Dent, Joyce O'Shaughnessy
The New England journal of medicine, 382, 9, 810, 821, 2020年02月27日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively. CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

CYP2D6 Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study.
Kenji Tamura, Chiyo K Imamura, Toshimi Takano, Shigehira Saji, Takeharu Yamanaka, Kan Yonemori, Masato Takahashi, Junji Tsurutani, Reiki Nishimura, Kazuhiko Sato, Akira Kitani, Naoto T Ueno, Taisei Mushiroda, Michiaki Kubo, Yasuhiro Fujiwara, Yusuke Tanigawara
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38, 6, 558, 566, 2020年02月20日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether CYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome. METHODS: Patients who needed first-line tamoxifen therapy were enrolled. Based on individual CYP2D6 genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes. RESULTS: Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% v 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM v 51.1 nM; P < .0001) and were also higher compared with wt/wt patients (72.0 nM; P = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months (P = .43). CONCLUSION: In patients with CYP2D6-variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen.

Patient-reported outcomes in a randomized, optimal dose finding, phase II study of triweekly nab-paclitaxel in patients with metastatic breast cancer (the ABROAD study)
Hiroaki Kato, Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro Kikawa Yuichiro Kikawa, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Junji Tsurutani, Naruto Taira, Tsutomu Takashima, Kosuke Kashiwabara, Tomohiko Aihara Tomohiko Aihara, Hirofumi Mukai
CANCER RESEARCH, 80, 4, AMER ASSOC CANCER RESEARCH, 2020年02月, ［査読有り］
英語

Phase II study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with ER-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B
Hiroko Masuda, Tsutomu Iwasa, Toru Mukohara, Shinya Tokunaga, Koji Matsumoto, Naoki Niikura, Yasuaki Sagara, Yasuo Miyoshi, Akihiko Shimomura, Masato Takahashi, Takeshi Nagashima, Mihoko Doi, Manabu Futamura, Kenichi Yoshimura, Toshimi Takano, Junji Tsurutani
CANCER RESEARCH, 80, 4, AMER ASSOC CANCER RESEARCH, 2020年02月, ［査読有り］
英語

Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME trial)
Jun Masuda, Junji Tsurutani, Norikazu Masuda, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Masato Takahashi, Hiroji Iwata, Tsutomu Iwasa, Toru Mukohara, Kenichi Yoshimura, Takayuki Ueno, Toshimi Takano
CANCER RESEARCH, 80, 4, AMER ASSOC CANCER RESEARCH, 2020年02月, ［査読有り］
英語

A multicenter phase II study evaluating the efficacy of nivolumab plus paclitaxel plus bevacizumab triple-combination therapy as a first-line treatment in patients with HER2-negative metastatic breast cancer: WJOG9917B NEWBEAT trial
Yukinori Ozaki, Toru Mukohara, Junji Tsurutani, Masato Takahashi, Koji Matsumoto, Manabu Futamura, Norikazu Masuda, Shigehisa Kitano, Kenichi Yoshimura, Hironobu Minami, Toshimi Takano
CANCER RESEARCH, 80, 4, AMER ASSOC CANCER RESEARCH, 2020年02月, ［査読有り］
英語

Multicenter study of primary systemic therapy with docetaxel, cyclophosphamide and trastuzumab for HER2-positive operable breast cancer: the JBCRG-10 study.
Takayuki Ueno, Norikazu Masuda, Nobuaki Sato, Shoichiro Ohtani, Jun Yamamura, Nobuki Matsunami, Masahiro Kashiwaba, Toshimi Takano, Masato Takahashi, Koji Kaneko, Shinji Ohno, Satoshi Morita, Masakazu Toi
Japanese journal of clinical oncology, 50, 1, 3, 11, 2020年01月24日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The original aim of this study was to evaluate the treatment sequence and anthracycline requirement in docetaxel, cyclophosphamide and trastuzumab therapy. After one death in the anthracycline-containing arm, the protocol was amended to terminate the randomization. The single-docetaxel, cyclophosphamide and trastuzumab arm was continued to examine the efficacy and safety of the anthracycline-free regimen. METHODS: Women with human epidermal growth factor receptor-2-positive, operable and primary breast cancer were randomized to receive 5-fluorouracil, epirubicin and cyclophosphamide (four cycles) followed by docetaxel, cyclophosphamide and trastuzumab (four cycles), or docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide, or docetaxel, cyclophosphamide and trastuzumab (six cycles). After the protocol amendment, patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm alone. The primary endpoint was a pathological complete response. RESULTS: In total, 103 patients were enrolled between September 2009 and September 2011: 21, 22 and 24 patients in the 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel, cyclophosphamide and trastuzumab; docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide and docetaxel, cyclophosphamide and trastuzumab arms, respectively, and 36 patients in the docetaxel, cyclophosphamide and trastuzumab arm after the protocol amendment. In total, 60 patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm, in which the pathological complete response rate was 45.8%, and disease-free survival at 3 years was 96.6%. Patients with stage I or IIA in the docetaxel, cyclophosphamide and trastuzumab arm showed good disease-free survival (100% at 3 years). The comparison of efficacy among the three arms was statistically underpowered. Left ventricular ejection fraction decreased significantly after 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel-docetaxel, cyclophosphamide and trastuzumab (P = 0.017), but not after docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide or docetaxel, cyclophosphamide and trastuzumab. CONCLUSIONS: The pathological complete response rate for docetaxel, cyclophosphamide and trastuzumab was similar to previous reports of anthracycline-containing regimens. Docetaxel, cyclophosphamide and trastuzumab might be an option for primary systemic therapy in human epidermal growth factor receptor-2-positive early breast cancer. A larger confirmatory study is necessary.

A prospective real-world study of eribulin for HER2-negative recurrent breast cancer patients: final results
Hirofumi Mukai, Kenichi Inoue, Masato Takahashi, Takashi Yamanaka, Chiyomi Egawa, Yukinori Sakata, Hiroki Ikezawa, Toshiyuki Matsuoka, Mika Ishii, Junji Tsurutani
ANNALS OF ONCOLOGY, 30, 85, 85, OXFORD UNIV PRESS, 2019年10月, ［査読有り］
英語

Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy.
Akihiko Shimomura, Kan Yonemori, Masayuki Yoshida, Teruhiko Yoshida, Hiroyuki Yasojima, Norikazu Masuda, Kenjiro Aogi, Masato Takahashi, Yoichi Naito, Satoru Shimizu, Rikiya Nakamura, Akinobu Hamada, Hirofumi Michimae, Jun Hashimoto, Harukaze Yamamoto, Asuka Kawachi, Chikako Shimizu, Yasuhiro Fujiwara, Kenji Tamura
Translational oncology, 12, 10, 1386, 1394, 2019年10月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We conducted a phase I/II clinical trial to evaluate the efficacy of eribulin and olaparib in a tablet form (EO study) for triple-negative breast cancer (TNBC) patients. We hypothesized that somatic BRCA mutations and homologous recombination repair (HRR)-related gene alterations might affect efficacy. METHODS: Our analyses identified mutations in HRR-related genes and BRCA1/2, and we subsequently evaluated their association to response by the EO study participants. Tissue specimens were obtained from primary or metastatic lesion. Tissue specimens were examined for gene mutations or protein expression using a Foundation Medicine gene panel and immunohistochemistry. RESULTS: In the 32 tissue specimens collected, we detected 33 gene mutations, with the most frequent nonsynonymous mutations found in TP53. The objective response rates (ORRs) in patients with and without HRR-related gene mutation were 33.3% and 40%, respectively (P = .732), and the ORRs in patients with and without somatic BRCA mutations were 60% and 33.3%, respectively (P = .264), with the ORR numerically higher in the somatic BRCA-mutation group but not statistically significant. There was no correlation between immunohistochemistry status and response or between BRCA status or HRR-related gene mutation and survival. Immunohistochemical analysis indicated that EGFR-negative patients had a tendency for better progression-free survival (log-rank P = .059) and significantly better overall survival (log-rank P = .046); however, there was no correlation between the status of other immunohistochemistry markers and survival. CONCLUSION: These findings suggested somatic BRCA mutation and EGFR-negativity as a potential biomarker for predicting the efficacy of eribulin/olaparib combination therapy. (UMIN000018721).

Clinical significance of evaluating hormone receptor and HER2 protein using cell block against metastatic breast cancer: a multi-institutional study.
Akira Matsui, Yuya Murata, Norikazu Masuda, Kiyoshi Mori, Masato Takahashi, Katsushige Yamashiro, Kenjirou Aogi, Shigeto Maeda, Masahiro Itou, Shinji Ozaki, Kazuya Kuraoka, Yasuyuki Satou, Shu Ichihara, Eriko Tokunaga, Kenichi Taguchi, Takanori Watanabe, Hiroyoshi Suzuki, Aiko Nagayama, Rieko Nishimura
Oncotarget, 10, 55, 5680, 5689, 2019年10月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Hormone receptor and human epidermal growth factor receptor 2 (HER2) protein tests in metastatic breast cancer tissue are recommended in the guidelines of the American Society of Clinical Oncology/American Pathology Association. As part of a multi-institutional study by the National Hospital Organization, we conducted an investigation to examine these molecular markers, using cytological specimens as a substitute for tissue specimens from breast cancer metastasis. To confirm the usefulness of receptors tested in metastatic lesions, the treatment course of registered metastatic breast cancer patients was analyzed. During the April 2015 to March 2016 registration period, there were 62 registrations. Types of metastatic lesions include pleural fluid (44 samples), ascites (14 samples), lymph nodes (2 samples), pericardial fluid (1 sample), and dorsal subcutaneous mass (1 sample). A stable test result was obtained by adopting the receptor examination method, using cell block for immunostaining cytological specimens. The discordance rates of estrogen receptor (ER), progesterone receptor (PR), and HER2 protein expression were 18.2% (95% confidence interval (CI): 7.9-28.8%), 36.4% (95% CI: 23.7-49.1%), and 8.2% (95% CI: 0.1-16.3%), respectively, between the primary tumor and metastatic lesion. Patients who changed from primary negative to metastatic positive ER status had taken a significantly longer time for metastatic foci to appear. Patients with positive ER status in metastatic lesions had significantly better prognosis than ER-negative cases (P = 0.030) by the Log-Rank test. The ER status of the metastatic lesion and the metastatic site were independent prognostic factors by Cox multivariate analysis. Receptor examination with cytological specimens in metastatic lesions has been useful as it provides guidance for the treatment of metastatic breast cancer.

Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer.
Koichi Sakaguchi, Hisako Ono, Katsuhiko Nakatsukasa, Takashi Ishikawa, Yoshie Hasegawa, Masato Takahashi, Naoki Niikura, Kei Koizumi, Teruhisa Sakurai, Hideo Shigematsu, Shunji Takahashi, Shinichiro Taira, Masato Suzuki, Kazutaka Narui, Daishu Miura, Kimito Yamada, Mana Yoshimura, Hisashi Shioya, Eiichi Konishi, Yokota Isao, Kojiro Imai, Kei Fujikawa, Tetsuya Taguchi
Medicine, 98, 32, e16770, 2019年08月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. PATIENTS AND METHODS: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I-IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1-L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were ETHICS AND DISSEMINATION:: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.

内分泌療法耐性ER陽性転移乳癌に対する二次内分泌療法のコホート研究 HORSE-BC-研究報告　　　　　　　　　　　　　　　
藤澤 知巳, 平 成人, 荒木 和浩, 岩本 高行, 木川 雄一郎, 坂巻 顕太郎, 相原 智彦, 高橋 將人, 向井 博文, 三階 貴史, 高尾 信太郎
日本乳癌学会総会プログラム抄録集, 27回, 716, 716, (一社)日本乳癌学会, 2019年07月
日本語

Neratinib after trastuzumab-based adjuvant therapy in patients from Asia with early stage HER2-positive breast cancer.
Hiroji Iwata, Norikazu Masuda, Sung-Bae Kim, Kenichi Inoue, Yoshiaki Rai, Takashi Fujita, Joanne Chiu, Shoichiro Ohtani, Masato Takahashi, Toshiko Miyaki, Yen-Shen Lu, Binghe Xu, Yoon Sim Yap, Anita Bustam, Bin Yao, Bo Zhang, Richard Bryce, Arlene Chan
Future oncology (London, England), 15, 21, 2489, 2501, 2019年07月, ［国際誌］
英語, 研究論文（学術雑誌）, Aim: To evaluate the efficacy and safety of neratinib as extended adjuvant therapy in patients from Asia based on exploratory analyses of the Phase III ExteNET trial. Patients & methods: A total of 2840 women with early stage HER2-positive breast cancer were randomly assigned to neratinib 240 mg/day or placebo for 1 year after trastuzumab-based adjuvant therapy. Results: A total of 341 patients were from Asia (neratinib, n = 165; placebo, n = 176). 2-year invasive disease-free survival rates were 92.8 and 90.8% with neratinib and placebo, respectively (HR: 0.70; 95% CI: 0.31-1.55), and 5-year rates were 91.9 and 87.2%, respectively (HR: 0.57; 95% CI: 0.27-1.13). Diarrhea was the most common adverse event with neratinib. Conclusion: Extended adjuvant therapy with neratinib reduces disease recurrences in Asian women with HER2-positive breast cancer. Trial registration: Clinicaltrials.gov NCT00878709.

Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.
Fabrice André, Eva Ciruelos, Gabor Rubovszky, Mario Campone, Sibylle Loibl, Hope S Rugo, Hiroji Iwata, Pierfranco Conte, Ingrid A Mayer, Bella Kaufman, Toshinari Yamashita, Yen-Shen Lu, Kenichi Inoue, Masato Takahashi, Zsuzsanna Pápai, Anne-Sophie Longin, David Mills, Celine Wilke, Samit Hirawat, Dejan Juric
The New England journal of medicine, 380, 20, 1929, 1940, 2019年05月16日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. METHODS: In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. RESULTS: A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. CONCLUSIONS: Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).

Randomized, optimal dose-finding, phase II study of tri-weekly nab-paclitaxel in patients with metastatic breast cancer (ABROAD).
Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro Kikawa, Hiroaki Kato, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Junji Tsurutani, Naruto Taira, Tsutomu Takashima, Kosuke Kashiwabara, Tomohiko Aihara, Hirofumi Mukai
JOURNAL OF CLINICAL ONCOLOGY, 37, 15, AMER SOC CLINICAL ONCOLOGY, 2019年05月, ［査読有り］
英語

Palbociclib in combination with letrozole in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-2 subgroup analysis of Japanese patients.
Hirofumi Mukai, Chikako Shimizu, Norikazu Masuda, Shoichiro Ohtani, Shinji Ohno, Masato Takahashi, Yutaka Yamamoto, Reiki Nishimura, Nobuaki Sato, Shozo Ohsumi, Hiroji Iwata, Yuko Mori, Satoshi Hashigaki, Yasuaki Muramatsu, Takashi Nagasawa, Yoshiko Umeyama, Dongrui R Lu, Masakazu Toi
International journal of clinical oncology, 24, 3, 274, 287, 2019年03月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: In PALOMA-2, palbociclib-letrozole significantly improved progression-free survival (PFS) vs placebo-letrozole in women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC) in the first-line setting. We evaluated the efficacy, safety, and pharmacokinetics of palbociclib in Japanese women in PALOMA-2. METHODS: In this phase 3 study, 666 postmenopausal women with ER+/HER2- ABC were randomized 2:1 to palbociclib (125 mg/day [3 weeks on/1 week off]) plus letrozole (2.5 mg daily) or placebo plus letrozole. A prespecified, exploratory, subgroup analysis of Japanese patients (n = 46) was conducted to compare results with those of the overall population. RESULTS: At the February 26, 2016 cutoff, median PFS among the 46 Japanese patients was 22.2 months (95%CI, 13.6‒not estimable) with palbociclib-letrozole vs 13.8 months (5.6‒22.2) with placebo-letrozole (hazard ratio, 0.59 [95%CI, 0.26-1.34]). The most common adverse events (AEs) were hematologic and more frequent among Japanese patients than the overall population (neutropenia: 93.8% [87.5% grade 3/4] vs 79.5% [66.4%]; leukopenia: 62.5% [43.8%] vs 39.0% [24.8%]); no Japanese patients had febrile neutropenia. Palbociclib dose reductions due to toxicity (mainly neutropenia) were more common in Japanese patients (62.5% vs 36.0%); few permanently discontinued due to AEs. Although mean palbociclib trough concentration was higher in Japanese patients vs non-Asians (95.4 vs 61.7 ng/mL), the range of individual values of the Japanese patients was within that of non-Asians. CONCLUSIONS: These results from PALOMA-2 suggest that palbociclib-letrozole merits consideration as a first-line treatment option for postmenopausal Japanese patients with ER+/HER2‒ ABC. ClinicalTrials.gov: NCT01740427.

A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes.
Kan Yonemori, Akihiko Shimomura, Hiroyuki Yasojima, Norikazu Masuda, Kenjiro Aogi, Masato Takahashi, Yoichi Naito, Satoru Shimizu, Rikiya Nakamura, Jun Hashimoto, Harukaze Yamamoto, Akihiro Hirakawa, Hirofumi Michimae, Akinobu Hamada, Teruhiko Yoshida, Tamie Sukigara, Kenji Tamura, Yasuhiro Fujiwara
European journal of cancer (Oxford, England : 1990), 109, 84, 91, 2019年03月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We conducted a multicenter phase I/II trial of olaparib plus eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer (TNBC) to determine the recommended phase II dose (RP2D) (phase I) and to examine the efficacy and safety (phase II) (UMIN00009498) of the combined therapy. PATIENTS AND METHODS: In phase I, olaparib tablet was orally administered twice daily from level 1:25 mg BID to level 7:300 mg BID, with 1.4 mg/m2 of eribulin on days 1 and 8. In phase II, patients were treated with RP2D to assess the response rate (independent review). The planned sample size was 24 with a threshold of 10%. RESULTS: One of the 24 patients enrolled in phase I experienced dose-limiting toxicity. The RP2D was established as 300 mg twice daily for olaparib and 1.4 mg/m2 for eribulin. Among the 24 patients in phase II, the median number of administered courses was 5.5 (range: 1-28). Grade ≥III adverse events included neutropenia (83.3%), leucopenia (83.3%), anaemia (41.7%), febrile neutropenia (33.3%) and thrombosis (8.3%). The response rate was 29.2% (independent; N = 7/24; 90% confidence interval [CI]; 14.6-47.9). Median progression-free survival and overall survival were 4.2 (95% CI, 3.0-7.4) and 14.5 (95% CI, 4.8-22.0) months, respectively. Germline BRCA1/2 mutation status was observed in three patients in phase I and 2 patients in phase II, respectively. The Cmax and area under the curve for olaparib increased in a dose-dependent manner, and these parameters for eribulin and olaparib were not influenced by each other. CONCLUSIONS: Combination therapy of olaparib with eribulin shows antitumour activity against advanced or metastatic TNBC, but caution must be exercised in the presence of febrile neutropenia.

Associations in tumor infiltrating lymphocytes between clinicopathological factors and clinical outcomes in estrogen receptor-positive/human epidermal growth factor receptor type 2 negative breast cancer.
Yuichiro Miyoshi, Tadahiko Shien, Akiko Ogiya, Naoko Ishida, Kieko Yamazaki, Rie Horii, Yoshiya Horimoto, Norikazu Masuda, Hiroyuki Yasojima, Touko Inao, Tomofumi Osako, Masato Takahashi, Nobumoto Tomioka, Yumi Wanifuchi-Endo, Mitsuchika Hosoda, Hiroyoshi Doihara, Hiroko Yamashita
Oncology letters, 17, 2, 2177, 2186, 2019年02月, ［国際誌］
英語, 研究論文（学術雑誌）, The value of assessing tumor infiltrating lymphocytes (TILs) in estrogen receptor (ER) positive/human epidermal growth factor receptor type 2 (HER2) negative breast cancer has yet to be determined. In the present study, a total of 184 cases with early distant recurrence detected within 5 years following the primary operation, 134 with late distant recurrence diagnosed following 5 years or longer and 321 controls without recurrence for >10 years following starting the initial treatment for ER-positive/HER2 negative breast cancer, registered in 9 institutions, were analyzed. The distributions of TILs and their clinical relevance were investigated. TIL distributions did not differ significantly among the early, late and no recurrence groups, employing a 30% cut-off point as a dichotomous variable. In those who had received adjuvant chemotherapy as well as endocrine therapy, a trend toward higher TIL proportions was detected when the early recurrence group was compared with the no recurrence group employing the 30% cut-off point (P=0.064). The TIL distributions were significantly associated with nodal metastasis (P=0.004), ER status (P=0.045), progesterone receptor (PgR) status (P=0.002), tumor grade (P=0.021), and the Ki67 labeling index (LI) (P=0.002) in the no recurrence group and with the Ki67 LI in the recurrence groups (P=0.002 in early recurrence group, P=0.023 in late recurrence group). High TIL distributions also predicted shorter survival time following the detection of recurrence (P=0.026). However, these prognostic interactions were not significant in multivariate analysis (P=0.200). The present retrospective study demonstrated no significant interaction between TIL proportions and the timing of recurrence. However, higher TIL proportions were observed in breast cancer patients with aggressive biological phenotypes, which tended to be more responsive to chemotherapy. The clinical relevance of stromal TILs for identifying patients who would likely benefit from additional therapies merits further investigation in a larger patient population.

MONARCH 2 HR+HER2-進行乳癌fulvestrant併用abemaciclib第3相試験 日本人サブ解析　　　　　　　　　　　　　　　
井上 賢一, 戸井 雅和, 増田 慎三, 岩田 広治, 高橋 將人, 伊藤 良則, 三好 康雄, 中山 貴寛, 向井 博文, 井上 晃一, 森 丈治, 坂口 佐知, 江夏 総太郎, Llombart-Cussac Antonio, Sledge George W.
日本癌治療学会学術集会抄録集, 56回, O7, 2, (一社)日本癌治療学会, 2018年10月
英語

BRCA12変異陽性乳がん患者に対する適切なマネージメント リスク低減乳房切除術の意義を含め
阿多 亜里沙, 明石 定子, 井手 佳美, 吉田 敦, 澤木 正孝, 津川 浩一郎, 柳田 康弘, 川端 英孝, 山内 清明, 高橋 將人, 武井 寛幸, 菰池 佳史, 遠山 竜也, 指宿 睦子, 西村 誠一郎, 土井原 博義, 北田 正博, 三木 義男, 新井 正美, 横山 士郎, 中村 清吾
日本外科学会雑誌, 119, 5, 598, 605, (一社)日本外科学会, 2018年09月
日本語

A randomized, open-label, Phase III trial of pertuzumab retreatment in HER2-positive locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab and chemotherapy: the Japan Breast Cancer Research Group-M05 PRECIOUS study.
Yutaka Yamamoto, Hiroji Iwata, Takayuki Ueno, Naruto Taira, Masahiro Kashiwaba, Masato Takahashi, Hiroshi Tada, Koichiro Tsugawa, Tatsuya Toyama, Naoki Niikura, Fumikata Hara, Tomomi Fujisawa, Tetsuhiro Yoshinami, Shigehira Saji, Toshimi Takano, Norikazu Masuda, Satoshi Morita, Masakazu Toi, Shinji Ohno
Japanese journal of clinical oncology, 48, 9, 855, 859, 2018年09月01日, ［国際誌］
英語, 研究論文（学術雑誌）, The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional treatment in HER2-positive locally advanced (LA)/metastatic breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one-sided 5% level of significance.

Radiofrequency Ablation of Breast Cancer: A Retrospective Study.
Toshikazu Ito, Shoji Oura, Shinji Nagamine, Masato Takahashi, Naohito Yamamoto, Noboru Yamamichi, Mitsuharu Earashi, Hiroyoshi Doihara, Shigeru Imoto, Shoshu Mitsuyama, Kohei Akazawa
Clinical breast cancer, 18, 4, e495-e500, 2018年08月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To validate the safety and efficacy of percutaneous radiofrequency ablation (RFA) of breast carcinomas. METHODS: This retrospective study was conducted by the Breast Cancer Society for Minimally Invasive Therapy following approval from institutional review boards, and with the written informed consent of patients. A total of 386 patients with breast cancer treated with RFA at 10 institutions between July 2003 and June 2009 were identified and included in the analysis. Patients underwent a standard RFA procedure with ultrasound guidance and were followed up every 6 to 12 months. In this study, feasibility of RFA procedure and related safety and ipsilateral breast tumor recurrence (IBTR) were examined. Fisher exact or χ2 test evaluated associations between clinicopathological factors and IBTR, and local recurrence-free survival was estimated using the Kaplan-Meier method. RESULTS: RFA-related adverse events included local pain in 9 patients, skin burns in 15, and nipple retraction in 7. Patients were followed for a median of 50 months. IBTR was more frequently observed in patients with initial tumor sizes > 2 cm (3 of 30, 10%) than in those with initial tumors ≤ 2 cm (8 of 355, 2.3%; P = .015). IBTR-free rates 5 years after RFA were 97%, 94%, and 87% in patients with initial tumor sizes ≤ 1.0 cm, 1.1 to 2.0 cm, and > 2.0 cm, respectively. CONCLUSIONS: RFA in breast cancer is a safe and promising minimally invasive treatment for tumors ≤ 2 cm in diameter. Further studies are needed to optimize the technique and evaluate its future role as local therapy.

A randomized phase II trial of trastuzumab plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP.
Toshimi Takano, Junji Tsurutani, Masato Takahashi, Takeharu Yamanaka, Kazuko Sakai, Yoshinori Ito, Junya Fukuoka, Hideharu Kimura, Hidetaka Kawabata, Kenji Tamura, Koji Matsumoto, Kenjiro Aogi, Kazuhiko Sato, Kazuto Nishio, Kazuhiko Nakagawa, Toshiaki Saeki
Breast (Edinburgh, Scotland), 40, 67, 75, 2018年08月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: For human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) with progression on trastuzumab-based therapy, continuing trastuzumab beyond progression and switching to lapatinib combined with chemotherapy are both valid options. We conducted an open-label, randomized phase II trial to compare the efficacy of these strategies. PATIENTS AND METHODS: Women with HER2-positive MBC previously treated with trastuzumab and taxanes were randomly assigned to receive trastuzumab plus capecitabine (HX) or lapatinib plus capecitabine (LX). The primary endpoint was progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and the objective response rate (ORR). To explore the predictive value of the differential benefit of anti-HER2 drugs, PIK3CA mutations were assessed using circulating tumor DNA. RESULTS: Eighty-six patients (43 in each arm) were enrolled. The median PFS was 6.1 months in the HX arm and 7.1 months in the LX arm (hazard ratio, 0.81; 90% CI, 0.55-1.21; p = 0.39); the median OS was 31.0 months in the HX arm and was not reached in the LX arm (hazard ratio, 0.58; 95% CI, 0.26-1.31; p = 0.18). The ORR was 40% in the HX arm and 41% in the LX arm. PIK3CA mutations were detected in 23% of the 35 analyzed patients, and in patients without PIK3CA mutations, LX yielded relatively longer PFS and OS than HX. CONCLUSION: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, no significant differences in PFS and OS were observed between patients treated with LX and HX. TRIAL REGISTRATION NUMBER: UMIN000005219.

Hormonal Therapy Resistant Estrogen-receptor Positive Metastatic Breast Cancer Cohort (HORSE-BC) Study : Current Status of Treatment Selection in Japan.
Takayuki Iwamoto, Naruto Taira, Tomomi Fujisawa, Kazuhiro Araki, Kentaro Sakamaki, Takafumi Sangai, Yuichiro Kikawa, Tadahiko Shien, Shintaro Takao, Masako Sato, Yoshinari Goto, Takashi Yoshida, Masato Takahashi, Tomohiko Aihara, Hirofumi Mukai
Acta medica Okayama, 72, 4, 369, 374, 2018年08月, ［国内誌］
英語, 研究論文（学術雑誌）, The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study.

Bi-weekly eribulin therapy for metastatic breast cancer: a multicenter phase II prospective study (JUST-STUDY).
Shoichiro Ohtani, Takahiro Nakayama, Tetsuhiro Yoshinami, Ken-Ichi Watanabe, Fumikata Hara, Yasuaki Sagara, Hidetoshi Kawaguchi, Kenji Higaki, Nobuki Matsunami, Yoshie Hasegawa, Masato Takahashi, Makiko Mizutani, Takashi Morimoto, Masako Sato, Mitsuya Itoh, Satoshi Morita, Norikazu Masuda
Breast cancer (Tokyo, Japan), 25, 4, 438, 446, 2018年07月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. METHODS: Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated. RESULTS: Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events. CONCLUSION: This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491).

Phase II study of a combination therapy of nivolumab, bevacizumab and paclitaxel in patients with HER2-negative metastatic breast cancer as a first-line treatment (WJOG9917B, NEWBEAT trial).
Yukinori Ozaki, Koji Matsumoto, Masato Takahashi, Toru Mukohara, Manabu Futamura, Norikazu Masuda, Junji Tsurutani, Kenichi Yoshimura, Hironobu Minami, Toshimi Takano
JOURNAL OF CLINICAL ONCOLOGY, 36, 15, AMER SOC CLINICAL ONCOLOGY, 2018年05月, ［査読有り］
英語

A randomized phase II trial evaluating CYP2D6 genotype-guided tamoxifen dosing in hormone receptor-positive metastatic breast cancer: TARGET-1
Toshimi Takano, Chiyo K. Imamura, Kenji Tamura, Shigehira Saji, Takeharu Yamanaka, Kan Yonemori, Masato Takahashi, Junji Tsurutani, Reiki Nishimura, Kazuhiko Sato, Akira Kitani, Naoto T. Ueno, Taisei Mushiroda, Michiaki Kubo, Yasuhiro Fujiwara, Yusuke Tanigawara
JOURNAL OF CLINICAL ONCOLOGY, 36, 15, AMER SOC CLINICAL ONCOLOGY, 2018年05月, ［査読有り］
英語

Predictive value of genetic analysis for pathological complete response to preoperative treatment in HER2 positive, HR negative early breast cancer (PASSION trial).
Takeshi Yamaguchi, Hirofumi Mukai, Masato Takahashi, Fumikata Hara, Chikako Yamauchi, Satoshi Yamashita, Toshikazu Ushijima
Japanese journal of clinical oncology, 48, 4, 388, 391, 2018年04月01日, ［国際誌］
英語, 研究論文（学術雑誌）, We previously reported a potential predictive value of HSD17B4 hypermethylation for pathological complete response after preoperative trastuzumab plus chemotherapy in HER2-positive breast cancer. We will prospectively evaluate the predictive performance of HSD17B4 hypermethylation in patients with HER2-positive/HR-negative breast cancer treated with sequential chemo-radiotherapy. The primary endpoint is the rate of pathological complete response, defined as the absence of invasive and intraductal tumor cells in the breast at surgery, in breast cancer with HSD17B4 hypermethylation. If the pCR rates are extremely high, the ultimate breast-conserving treatment excluding the need for surgery could be a future treatment option. A total of 200 patients will be enrolled. This trial is registered at the UMIN Clinical Trials Registry as UMIN000028065 and is financially supported by the Japan Agency for Medical Research and Development, AMED.

Palbociclib in combination with letrozole as first-line treatment for advanced breast cancer: A Japanese phase II study.
Norikazu Masuda, Reiki Nishimura, Masato Takahashi, Kenichi Inoue, Shinji Ohno, Hiroji Iwata, Yuko Mori, Satoshi Hashigaki, Yasuaki Muramatsu, Takashi Nagasawa, Yoshiko Umeyama, Masakazu Toi
Cancer science, 109, 3, 803, 813, 2018年03月, ［国際誌］
英語, 研究論文（学術雑誌）, This single-arm, open-label, phase II study in 42 Japanese postmenopausal patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer evaluated the efficacy, safety, and pharmacokinetics of first-line palbociclib (125 mg once daily, 3 weeks on/1 week off) coadministered with letrozole (2.5 mg once daily). Primary endpoint of investigator-assessed 1-year progression-free survival (PFS) probability was 75.0% (90% CI, 61.3%-84.4%), far surpassing the 40% lower limit of the 90% CI supporting efficacy. Median duration of treatment was 438 days. Among secondary efficacy measures, median PFS was not reached (95% CI, 16.7: not estimable), 17/42 patients (40.5%) had an objective response, 36/42 (85.7%) maintained disease control, and 27/42 (64.3%) remained in follow-up. Median overall survival was not reached, and 1-year survival probability was 92.9% (95% CI, 79.5%-97.6%). Results of intensive pharmacokinetics in a subset of 6 patients showed palbociclib steady-state mean area under the plasma concentration-time curve over the dosing interval [τ] and mean maximum plasma concentration were 1979 ng·h/mL and 124.7 ng/mL, respectively. For day 15 plasma samples from cycles 1 and 2, geometric mean of the within-patient mean trough concentration was 90.1 ng/mL. The most common treatment-related adverse events were neutropenia (100%) and stomatitis (73.8%). There was 1 case of treatment-related febrile neutropenia. Toxicities were generally tolerated and manageable by dose modifications and/or medical care. Efficacy and safety of first-line palbociclib plus letrozole therapy is supported in Japanese postmenopausal patients with treatment-naive ER+/HER2- advanced breast cancer.

BRCA12変異陽性乳がん患者に対する適切なマネージメント-リスク低減乳房切除術の意義を含め-
阿多亜里沙, 明石定子, 井手佳美, 吉田敦, 澤木正孝, 津川浩一郎, 柳田康弘, 川端英孝, 山内清明, 高橋將人, 武井寛幸, 菰池佳史, 遠山竜也, 指宿睦子, 西村誠一郎, 土井原博義, 北田正博, 三木義男, 新井正美, 横山士郎, 中村清吾, 中村清吾
日本外科学会雑誌, 119, 5, 216, 216, (一社)日本外科学会, 2018年
日本語

The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC).
Nobumoto Tomioka, Manabu Azuma, Mayuko Ikarashi, Mitsugu Yamamoto, Masako Sato, Ken-Ichi Watanabe, Katsushige Yamashiro, Masato Takahashi
Breast cancer (Tokyo, Japan), 25, 1, 34, 42, 2018年01月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor for triple negative breast cancer (TNBC). Recent studies have shown that programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) is expressed on T lymphocytes or tumor cells modulating antitumor immunity. The regulation of immune checkpoints between tumor cells and T lymphocytes may serve as a target for improvement of TNBC prognosis. We investigated TILs and PD-L1 status in TNBCs before or after preoperative systemic therapy (PST) to elucidate the clinical significance of PD-L1 expression. METHODS: Ninety patients received PST, and materials of core needle biopsies (CNB) taken before PST were available for 32 patients. TILs were scored as "% stromal", and tumors were defined as High-TILs (≥30%) or Low-TILs (<30%). The expression of PD-L1 was assessed by immunohistochemistry. RESULTS: TILs status in CNB is significant in pathological therapeutic grade: 1 vs. 2 or 3 (p = 0.0359). Disease-free survival (DFS) in patients with Low-TIL tumors were significantly worse than those with High-TIL tumors (p = 0.0383), but overall survival (OS) showed no significance (p = 0.0772). However, in patients with Low-TIL tumors, both DFS and OS in patients with High-PD-L1 expression were extremely unfavorable than in patients with Low-PD-L1 expression (p = 0.0032, p = 0.0002). CONCLUSION: The patients with TNBCs with combined Low-TILs and High-PD-L1 status in pre-PST situation showed unfavorable prognosis. The subset of TNBCs with Low-TILs and High-PD-L1 status could be the therapeutic target for immune checkpoint inhibitor.

Safety and effectiveness of eribulin in Japanese patients with locally advanced or metastatic breast cancer: a post-marketing observational study.
Junichiro Watanabe, Yoshinori Ito, Shozo Ohsumi, Mitsuhiro Mizutani, Hideya Tashiro, Kenichi Sakurai, Masato Takahashi, Tsuyoshi Saito, Junji Tsurutani, Hirofumi Mukai, Tetsuhiro Yoshinami, Shintaro Takao, Yasuhisa Yamamoto, Toshiyuki Matsuoka, Hirotaka Iwase, Hiroji Iwata, Seigo Nakamura, Toshiaki Saeki
Investigational new drugs, 35, 6, 791, 799, 2017年12月, ［国際誌］
英語, 研究論文（学術雑誌）, Background This large-scale study was conducted to evaluate the safety and effectiveness of eribulin for the treatment of inoperable or recurrent breast cancer in real-world settings in Japan. Methods Between July and December 2011, eligible patients with inoperable or recurrent breast cancer receiving eribulin for the first time were centrally registered and observed for 1 year. Eribulin was administered intravenously (1.4 mg/m2) on days 1 and 8 of every 3-week cycle. The primary endpoint was the frequency and intensity of adverse drug reactions (ADRs). Secondary endpoints included overall response rate (ORR) and time to treatment failure (TTF). Results Of 968 patients registered at 325 institutions, 951 and 671 were included in the safety and effectiveness analyses, respectively. In the safety population, ADRs were observed in 841 patients (88.4%). The most common (≥15% incidence) were neutropenia (66.6%), leukopenia (62.4%), lymphopenia (18.4%), and peripheral neuropathy (16.8%). The most common grade ≥ 3 ADRs (>5% incidence) were neutropenia (59.8%), leukopenia (50.5%), lymphopenia (16.1%), and febrile neutropenia (7.7%). In the effectiveness population, ORR was 16.5% (95% confidence interval: 13.7, 19.4). The median TTF was 127 days (95% confidence interval: 120, 134). Conclusions The safety and effectiveness profile of eribulin was consistent with prior studies. Eribulin had a favorable risk-benefit balance when used in real-world clinical settings.

内分泌療法耐性転移乳癌に対する二次内分泌療法のコホート研究 治療選択の現状　　　　　　　　　　　　　　　
三階 貴史, 藤澤 知巳, 平 成人, 荒木 和浩, 岩本 高行, 木川 雄一郎, 枝園 忠彦, 高尾 信太郎, 佐藤 雅子, 後藤 與四成, 吉田 崇, 高橋 將人, 相原 智彦, 坂巻 顕太郎, 向井 博文
日本癌治療学会学術集会抄録集, 55回, O18, 2, (一社)日本癌治療学会, 2017年10月
日本語

Erratum to: Post-relapse survival in patients with the early and late distant recurrence in estrogen receptor-positive HER2-negative breast cancer.
Akiko Ogiya, Kieko Yamazaki, Rie Horii, Tadahiko Shien, Yoshiya Horimoto, Norikazu Masuda, Touko Inao, Mitsuchika Hosoda, Naoko Ishida, Tomofumi Osako, Masato Takahashi, Yumi Endo, Yuichiro Miyoshi, Hiroyuki Yasojima, Nobumoto Tomioka, Hiroko Yamashita
Breast cancer (Tokyo, Japan), 24, 4, 642, 642, 2017年07月, ［国内誌］
英語, 研究論文（学術雑誌）

Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
José Baselga, Seock-Ah Im, Hiroji Iwata, Javier Cortés, Michele De Laurentiis, Zefei Jiang, Carlos L Arteaga, Walter Jonat, Mark Clemons, Yoshinori Ito, Ahmad Awada, Stephen Chia, Agnieszka Jagiełło-Gruszfeld, Barbara Pistilli, Ling-Ming Tseng, Sara Hurvitz, Norikazu Masuda, Masato Takahashi, Peter Vuylsteke, Soulef Hachemi, Bharani Dharan, Emmanuelle Di Tomaso, Patrick Urban, Cristian Massacesi, Mario Campone
The Lancet. Oncology, 18, 7, 904, 916, 2017年07月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. METHODS: The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. FINDINGS: Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. INTERPRETATION: The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. FUNDING: Novartis Pharmaceuticals Corporation.

Post-relapse survival in patients with the early and late distant recurrence in estrogen receptor-positive HER2-negative breast cancer.
Akiko Ogiya, Kieko Yamazaki, Rie Horii, Tadahiko Shien, Yoshiya Horimoto, Norikazu Masuda, Touko Inao, Mitsuchika Hosoda, Naoko Ishida, Tomofumi Osako, Masato Takahashi, Yumi Endo, Yuichiro Miyoshi, Hiroyuki Yasojima, Nobumoto Tomioka, Hiroko Yamashita
Breast cancer (Tokyo, Japan), 24, 3, 473, 482, 2017年05月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. METHODS: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. RESULTS: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months. CONCLUSION: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

First-line bevacizumab plus paclitaxel in Japanese patients with HER2-negative metastatic breast cancer: subgroup results from the randomized Phase III MERiDiAN trial.
Norikazu Masuda, Masato Takahashi, Kazuhiko Nakagami, Yasuhiro Okumura, Takahiro Nakayama, Nobuaki Sato, Kazumitsu Kanatani, Kosei Tajima, Masahiro Kashiwaba
Japanese journal of clinical oncology, 47, 5, 385, 392, 2017年05月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Background: In the double-blind placebo-controlled randomized Phase III MERiDiAN trial (ClinicalTrials.gov NCT01663727), adding bevacizumab to paclitaxel for HER2-negative metastatic breast cancer (mBC) significantly improved progression-free survival (PFS; stratified hazard ratio [HR] 0.68, 99% confidence interval [CI], 0.51-0.91). We assessed the efficacy and tolerability of first-line bevacizumab-paclitaxel in the subset of Japanese patients in MERiDiAN. Methods: Eligible patients had HER2-negative mBC previously untreated with chemotherapy. Plasma vascular endothelial growth factor (VEGF)-A was measured before randomization to paclitaxel 90 mg/m2 on Days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on Days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were: baseline plasma VEGF-A level, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary endpoints were investigator-assessed PFS in the intent-to-treat (ITT) population and in the subgroup with high plasma VEGF-A. This exploratory analysis evaluated efficacy and safety in the subpopulation treated in Japanese centers. Results: Of 481 patients randomized in MERiDiAN, 54 (11%) were Japanese. The stratified PFS HR in the Japanese subgroup was 0.64 (95% CI, 0.29-1.40). Median PFS was 9.2 months with placebo-paclitaxel (n = 30) versus 12.7 months with bevacizumab-paclitaxel (n = 24). Bevacizumab was associated with increased incidences of Grade ≥3 neutropenia, peripheral sensory neuropathy and hypertension, but there was no Grade ≥3 proteinuria, bleeding or gastrointestinal perforation. Conclusions: Bevacizumab-paclitaxel efficacy in Japanese patients was consistent with the MERiDiAN ITT population. No new safety signals were seen and tolerability was consistent with previous experience.

Pathological complete response of HER2-positive breast cancer to trastuzumab and chemotherapy can be predicted by HSD17B4 methylation.
Satoshi Fujii, Satoshi Yamashita, Takeshi Yamaguchi, Masato Takahashi, Yasuo Hozumi, Toshikazu Ushijima, Hirofumi Mukai
Oncotarget, 8, 12, 19039, 19048, 2017年03月21日, ［国際誌］
英語, 研究論文（学術雑誌）, Human epidermal growth factor (HER) 2-directed therapy is the standard treatment for HER2-positive breast cancer. Patients who achieved a pathological complete response (pCR) to the therapy are associated with excellent disease-free survival. However, few molecular markers are available to predict pCR. Here, we aimed to establish a DNA methylation marker to predict the response to trastuzumab and chemotherapy. A total of 67 patients were divided into screening (n = 21) and validation (n = 46) sets. Genome-wide DNA methylation analysis of the screening set identified eight genomic regions specifically methylated in patients with pCR. Among these, HSD17B4 encoding type 4 17β-hydroxysteroid dehydrogenase was most significantly differentially methylated. The differential methylation was confirmed by pyrosequencing (P = 0.03), and a cutoff value was determined. This association was successfully validated in the validation set (P < 0.001), and patients with pCR were predicted with a high specificity (79%). Multivariate analysis, including tumor stage and hormone receptor status, showed that HSD17B4 methylation was an independent predictive factor (odds ratio: 10.0, 95% confidence interval 2.54-39.50, P = 0.001). Combination with ER status and HSD17B4 methylation improved the specificity up to 91%. Identification of HER2-positive breast cancer patients who would achieve pCR only by trastuzumab and chemotherapy may lead to surgery-free treatment for this group of breast cancer patients.

[SENTINEL LYMPH NODE BIOPSY AND AXILLARY DISSECTION].
Masato Takahashi
Nihon Geka Gakkai zasshi, 117, 6, 509, 15, 2016年11月, ［国内誌］
日本語, 研究論文（学術雑誌）, Dr. William Stewart Halsted first advocated performing total mastectomy with pectoral muscle resection and axillary lymph node dissection as the standard surgery for breast cancer. The effectiveness of the sentinel lymph node biopsy was confirmed 100 years later. When a sentinel lymph node biopsy shows no cancer cells in the lymph node, the standard method is to omit axillary dissection. In recent years, there have been some reports of the validity of omitting axillary dissection when sentinel lymph node biopsy is positive for metastasis. When micrometastasis is present in sentinel lymph nodes, it is reasonable to omit axillary dissection. However, when macrometastasis is present, it is necessary to determine whether axillary dissection should be omitted by referring to the inclusion criteria of the Z0011 study. Complications of axillary lymph node dissection may include upper arm edema, glenohumeral joint excursion obstacles, and neuropathy. Early rehabilitation regimens can maintain glenohumeral joint excursion. Good sanitation including the nails, the use of moisturizers, and early administration of antiinflammatory agents for injuries can prevent lymphedema. If lymphedema develops, the wearing of an elastic bandage or sleeve, manual lymph drainage, and kinesiology exercises with a qualified instructor are effective.

Clinicopathological factors predicting early and late distant recurrence in estrogen receptor-positive, HER2-negative breast cancer.
Hiroko Yamashita, Akiko Ogiya, Tadahiko Shien, Yoshiya Horimoto, Norikazu Masuda, Touko Inao, Tomofumi Osako, Masato Takahashi, Yumi Endo, Mitsuchika Hosoda, Naoko Ishida, Rie Horii, Kieko Yamazaki, Yuichiro Miyoshi, Hiroyuki Yasojima, Nobumoto Tomioka
Breast cancer (Tokyo, Japan), 23, 6, 830, 843, 2016年11月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer. METHODS: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than 10 years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age. RESULTS: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy. CONCLUSION: Predictors of early and late distant recurrence might differ according to menopausal status and age.

Differences in expression of the cancer stem cell marker aldehyde dehydrogenase 1 among estrogen receptor-positive/human epidermal growth factor receptor type 2-negative breast cancer cases with early, late, and no recurrence.
Yuichiro Miyoshi, Tadahiko Shien, Akiko Ogiya, Naoko Ishida, Kieko Yamazaki, Rie Horii, Yoshiya Horimoto, Norikazu Masuda, Hiroyuki Yasojima, Touko Inao, Tomofumi Osako, Masato Takahashi, Nobumoto Tomioka, Yumi Endo, Mitsuchika Hosoda, Hiroyoshi Doihara, Shinichiro Miyoshi, Hiroko Yamashita
Breast cancer research : BCR, 18, 1, 73, 73, 2016年07月02日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown. METHODS: In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group. RESULTS: The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p < 0.001) in the early recurrence group. Multivariate analysis revealed ALDH1 expression to be significantly higher in the early recurrence group than in the no recurrence group (adjusted OR 2.140, 95 % CI 1.144-4.003, p = 0.016). Moreover, there was a significant difference in ALDH1 expression between the early and no recurrence groups receiving adjuvant endocrine therapy and chemotherapy (adjusted OR 4.625, 95 % CI 1.881-12.474, p < 0.001). However, there was no difference in ALDH1 expression between the late and no recurrence groups in univariate analysis (OR 1.507, 95 % CI 0.738-2.998, p = 0.253). In multivariate analysis, ALDH1 was not a factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059). CONCLUSIONS: Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

Strong cytoplasmic expression of NF-κB/p65 correlates with a good prognosis in patients with triple-negative breast cancer.
Motoi Baba, Masato Takahashi, Katsushige Yamashiro, Hideki Yokoo, Moto Fukai, Masanori Sato, Mitsuchika Hosoda, Toshiya Kamiyama, Akinobu Taketomi, Hiroko Yamashita
Surgery today, 46, 7, 843, 51, 2016年07月, ［国内誌］
英語, 研究論文（学術雑誌）, PURPOSE: Recent studies have indicated that constitutive NF-κB activity could be involved in the proliferation of triple-negative breast cancer. METHODS: The NF-κB/p65 expression and the effects of a NF-κB inhibitor, (-)-DHMEQ, were examined in triple-negative MDA-MB-231 breast cancer cells. Women with triple-negative breast cancer treated with neoadjuvant chemotherapy between 2002 and 2012 were retrospectively analyzed for their expression of NF-κB/p65, Bcl2 and Ki67 by immunohistochemistry in pre- and post-treatment specimens. The factors predicting the response to neoadjuvant chemotherapy and the prognosis were analyzed. RESULTS: NF-κB/p65 was predominantly expressed in the cytoplasm of MDA-MB-231 cells. Of 34 triple-negative breast cancer patients, positive staining for NF-κB/p65 expression was detected in the nuclei of a few cells in seven tumors before neoadjuvant chemotherapy, while the expression of NF-κB/p65 in the cytoplasm was detected in almost all tumor cells of 33 tumors. The expression levels of NF-κB/p65 were not associated with the response to neoadjuvant chemotherapy, although the cytoplasmic NF-κB/p65 staining intensity was significantly decreased in the post-treatment tumor samples compared with the pretreatment samples. All patients whose tumors showed strong cytoplasmic NF-κB/p65 expression before neoadjuvant chemotherapy are currently disease free. CONCLUSION: Our results suggest that strong cytoplasmic NF-κB/p65 expression could be a prognostic marker for patients with triple-negative breast cancer.

【日本乳癌学会乳癌診療ガイドライン2015年版】乳癌の薬物療法に関する日本乳癌学会乳癌診療ガイドライン2015年版(【Japanese Breast Cancer Society Guidelines 2015】The Japanese Breast Cancer Society Clinical Practice Guideline for systemic treatment of breast cancer, 2015 edition)
Aihara Tomohiko, Toyama Tatsuya, Takahashi Masato, Yamamoto Yutaka, Hara Fumikata, Akabane Hiromitsu, Fujisawa Tomomi, Ishikawa Takashi, Nagai Shigenori, Nakamura Rikiya, Tsurutani Junji, Ito Yoshinori, Mukai Hirofumi, The Japanese Breast Cancer Society
Breast Cancer, 23, 3, 329, 342, シュプリンガー・ジャパン(株), 2016年05月
英語

The Japanese Breast Cancer Society Clinical Practice Guideline for systemic treatment of breast cancer, 2015 edition.
Tomohiko Aihara, Tatsuya Toyama, Masato Takahashi, Yutaka Yamamoto, Fumikata Hara, Hiromitsu Akabane, Tomomi Fujisawa, Takashi Ishikawa, Shigenori Nagai, Rikiya Nakamura, Junji Tsurutani, Yoshinori Ito, Hirofumi Mukai
Breast cancer (Tokyo, Japan), 23, 3, 329, 42, 2016年05月, ［国内誌］
英語, 研究論文（学術雑誌）

乳腺 乳がんホルモン療法とその問題点 エストロゲンレセプター陽性乳癌における早期再発、晩期再発症例の検討　　　　　　　　　　　　　　　
山下 啓子, 荻谷 朗子, 石田 直子, 細田 充主, 枝園 忠彦, 三好 雄一郎, 堀本 義哉, 増田 慎三, 八十島 宏行, 稲尾 瞳子, 大佐古 智文, 高橋 將人, 富岡 伸元, 遠藤 友美, 堀井 理絵
日本癌治療学会誌, 50, 3, 362, 362, (一社)日本癌治療学会, 2015年09月
日本語

ER陽性HER2陰性乳癌における再発時期予測因子としての腫瘍浸潤リンパ球の意義の検討　　　　　　　　　　　　　　　
三好 雄一郎, 枝園 忠彦, 荻谷 朗子, 石田 直子, 細田 充主, 堀本 義哉, 増田 慎三, 八十島 宏行, 稲尾 瞳子, 大佐古 智文, 高橋 將人, 富岡 伸元, 遠藤 友美, 堀井 理絵, 山下 啓子
日本癌治療学会誌, 50, 3, 556, 556, (一社)日本癌治療学会, 2015年09月
日本語

Earlier and better high-resolution single breast imaging during bilateral breast dynamic scans at 3-T MRI: comparison with post dynamic high-resolution imaging.
Fumi Kato, Noriko Oyama-Manabe, Yusuke Sakuhara, Suzuko Mito, Masato Takahashi, Tetsuro Sakamoto, Mitsuchika Hosoda, Satoshi Terae, Hiroki Shirato
Breast cancer (Tokyo, Japan), 22, 5, 475, 9, 2015年09月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Breast MRI protocols have been improved by using a combination of dynamic scans for bilateral breasts and high-resolution imaging for a single breast which can be obtained during dynamic scans by recent technological advances. The purpose of this study was to compare high-resolution imaging during dynamic scans (HR-intra) with high-resolution imaging obtained post dynamic scans (HR-post). METHODS: Fifty-five women with pathologically proven breast cancer who underwent breast dynamic scans at 3-T MRI from February to September 2009 were enrolled in this study. Tumoral contrasts to the background breast tissue were compared by three radiologists independently in a blinded fashion. Results of visual assessment were categorized into three groups as follows: HR-intra being better (IB), equal (E), and HR-post being better (PB). The contrast to noise ratio (CNR) of the tumor and the signal to noise ratio of the normal breast gland (SNR) were compared between HR-intra and HR-post. RESULTS: Two patients were excluded because of poor MR imaging quality. Three radiologists separately categorized 64.2, 79.2, and 77.4 % of lesions as IB. The CNR of the tumor of HR-intra (mean ± SD = 6.9 ± 4.0) was significantly higher than that of HR-post (6.0 ± 3.7, p < 0.0001). The SNR of the normal breast gland of HR-intra (9.5 ± 1.7) was significantly lower than that of HR-post (10.0 ± 1.9, p < 0.0001). CONCLUSION: HR-intra during dynamic MRI provided earlier and better tumor to normal breast gland contrast than HR-post.

Prevalence and differentiation of hereditary breast and ovarian cancers in Japan.
Seigo Nakamura, Masato Takahashi, Mitsuhiro Tozaki, Takahiro Nakayama, Tadashi Nomizu, Yoshio Miki, Yoshie Murakami, Daisuke Aoki, Takuji Iwase, Seiichiro Nishimura, Hideko Yamauchi, Shozo Ohsumi, Shinichi Baba, Tadao Shimizu
Breast cancer (Tokyo, Japan), 22, 5, 462, 8, 2015年09月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We assembled needed data on the prevalence and characteristics of BRCA1/2 in Japan. MATERIALS AND METHODS: Our study of BRCA1/2 collected data at eight institutions in Japan on 320 individuals with a strong family history of breast cancer, according to the NCCN guidelines, by the end of March 2012. RESULTS: Among 260 proband cases, 46 (17.7 %) were positive for BRCA1, and 35 (13.5 %) were BRCA2-positive. Therefore, the total pathological mutation rate was 30.7 %. Pathology data after breast surgery were obtained from 37 cases of BRCA1 mutation, 23 (62.2 %) of which were triple negative (TN). On the other hand, 29 cases (82.9 %) of BRCA2 mutations were Luminal type. The most prevalent BRCA1 mutation site was L63X, found in 10 families. L63X was reported previously by studies in Japan, and it may be a founder mutation. We found two cases of large deletion detected by multiplex ligation-dependent probe amplification. One was an entire deletion of exon 20 and the lacked exons 1-9. TN with a family history of ovarian cancer was 11/20 (55 %). TN under 40-year-old (y.o.) 15/23 (65.2 %) and TN with one or more breast cancers in family history 17/32 (53.1 %) showed higher incidences of BRCA1 mutation. CONCLUSION: Hereditary breast and ovarian cancer (HBOC) may have nearly the same prevalence in Japan as in the US or Europe. If TN cases are taken into account, the ratio of BRCA1 is higher. L63X may be one of the founder mutations in Japan. A nationwide database of HBOC is important to develop risk models for BRCA1/2 carriers in Japan.

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients.
Hiroyasu Yamshiro, Hiroji Iwata, Norikazu Masuda, Naohito Yamamoto, Reiki Nishimura, Shoichiro Ohtani, Nobuaki Sato, Masato Takahashi, Takako Kamio, Kosuke Yamazaki, Tsuyoshi Saito, Makoto Kato, Tecchuu Lee, Shinji Ohno, Katsumasa Kuroi, Toshimi Takano, Masahiro Takada, Shinji Yasuno, Satoshi Morita, Masakazu Toi
International journal of clinical oncology, 20, 4, 709, 22, 2015年08月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Previous large trials with trastuzumab (TZM) showed improved outcome in patients with HER2-positive early-stage breast cancer. However, the efficacy and safety of TZM in Japanese patients have not been fully evaluated. We have therefore conducted an observational study in Japan. METHODS: This was a retrospective and a prospective observational study in which data on women with histologically confirmed HER2-positive invasive breast cancer who received TZM for stage I-IIIC disease were collected from 56 institutions that participated in the Japan Breast Cancer Research Group and the efficacy of each treatment regimen analyzed. RESULTS: A total of 2,024 patients treated between July 2009 and June 2011 were initially enrolled in this study; in August 2013, the patient cohort comprised 2,009 patients. Of these, 142 (7.5 %) were aged ≥70 years, 1,097 (58.1 %) had clinically node-negative (cN0) breast cancer, and 883 (47.4 %) were estrogen receptor-positive. Treatment options were neoadjuvant therapy (662 patients) and adjuvant therapy with TZM (1,228 patients). Three-year overall survival (OS) rates in the entire cohort and in the neoadjuvant and adjuvant cohorts, respectively, were 98.9 [95 % confidence interval (CI) 98.2-99.3], 98.3 (95 % CI 96.8-99.1 %), and 99.2 % (95 % CI 98.4-99.6), respectively. Three-year disease-free survival (DFS) rates in the entire cohort and in the neoadjuvant and adjuvant cohorts, respectively were 94.2 (95 % CI 93.0-95.2), 94.8 (95 % CI 93.0-95.9), and 93.1 (95 % CI 90.7-94.9 %), respectively. Multivariate analysis showed that age and nodal status negatively correlated with DFS. Age was the only factor which correlated with OS rate. Adverse events (AEs) associated with TZM and grade 3/4 AEs were reported in 356 (18.8 %) and 14 (0.6 %) patients, respectively. Grade 3/4 cardiac toxicities were reported in 11 patients. CONCLUSION: Based on data from our patient cohort of Japanese women with HER2-positive early-stage breast cancer, the efficacy and safety of systemic therapy with TZM are comparable to data from previously conducted large trials. Progress in anti-HER2 therapy for patients aged ≥70 years who have a poorer prognosis is needed.

[Adjuvant hormonal treatment for estrogen receptor-positive breast cancer-a questionnaire survey conducted by Japanese breast cancer society-authorized facilities in Hokkaido].
Masato Takahashi, Tousei Ohmura, Masahiro Kitada, Goro Kutomi, Mitsuchika Hosoda, Hideji Masuoka, Kenichi Watanabe, Yoshiki Watanabe, Hiroko Yamashita, Koichi Hirata
Gan to kagaku ryoho. Cancer & chemotherapy, 42, 5, 575, 9, 2015年05月, ［国内誌］
日本語, 研究論文（学術雑誌）, According to the Japanese Breast Cancer Society national breast cancer registration, 71.8%of breast cancer cases reported in 2004 and 79.8% of cases reported in 2010 were estrogen receptor(ER)positive. The frequency of ER-positive breast cancer is increasing annually in Japan. Many clinical trials have proven that adjuvant hormonal treatment affects both progression- free survival and overall survival in ER-positive breast cancer cases. However, some clinical questions remain, including those regarding the definition of preoperative hormonal treatment, appropriate dosage period, and therapeutic drug choice. In January 2013, we conducted a questionnaire survey of 53 medical doctors engaged in breast cancer treatment at 15 Japanese Breast Cancer Society-authorized facilities in Hokkaido. This survey included 6 clinical questions about preoperative hormonal treatment, 5 clinical questions about postoperative hormonal treatment for premenopausal breast cancer, and 4 clinical questions about postoperative hormonal treatment for postmenopausal breast cancer. We obtained replies from 35 medical doctors at 27 facilities. The response rate was 66%. We accumulated and analyzed these data. The discussion of questionnaire results in the medical administration field facilitates the sharing of information regarding differences in the approaches of different facilities to breast cancer patients. As a result, standardization of the breast cancer medical treatment system in this area has been accomplished.

The Japanese Breast Cancer Society Clinical Practice Guideline for systemic treatment of breast cancer.
Hirofumi Mukai, Tomohiko Aihara, Yutaka Yamamoto, Masato Takahashi, Tatsuya Toyama, Yasuaki Sagara, Hiroshi Yamaguchi, Hiromitsu Akabane, Junji Tsurutani, Fumikata Hara, Tomomi Fujisawa, Naohito Yamamoto, Shozo Ohsumi
Breast cancer (Tokyo, Japan), 22, 1, 5, 15, 2015年01月, ［国内誌］
英語, 研究論文（学術雑誌）

Tamoxifen versus tamoxifen plus doxorubicin and cyclophosphamide as adjuvant therapy for node-positive postmenopausal breast cancer: results of a Japan Clinical Oncology Group Study (JCOG9401).
Tadahiko Shien, Hiroji Iwata, Kenjiro Aogi, Takashi Fukutomi, Kenichi Inoue, Takayuki Kinoshita, Masato Takahashi, Akira Matsui, Taro Shibata, Haruhiko Fukuda
International journal of clinical oncology, 19, 6, 982, 8, 2014年12月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Cancer subtype has recently become an increasingly important consideration when deciding the treatment strategy for breast cancer. For the estrogen receptor positive (ER+) subtype, the efficacy of adjuvant endocrine therapy is definitive, but that of adjuvant chemotherapy is controversial. METHODS: In order to evaluate the effect of adding doxorubicin (A) and cyclophosphamide (C) to tamoxifen (TAM) (ACT) on the overall survival (OS) of node-positive postmenopausal breast cancer (PMBC) patients, we conducted a randomized trial. Eligibility criteria included pathologically node-positive (n = 1-9) PMBC, stage I-IIIA disease. Patients were randomized to receive either TAM (20 mg daily) for 2 years or A (40 mg/m(2)) and C (500 mg/m(2)) plus TAM (ACT) as adjuvant therapy following surgery. RESULTS: One hundred twenty-nine patients were recruited (TAM 64, ACT 65) between October 1994 and July 1999. The hazard ratios for OS and relapse-free survival (RFS) were 0.58 (95 % CI 0.24-1.39; log-rank p = 0.22) and 0.45 (95 %CI 0.24-0.86; log-rank p = 0.013), respectively, in favor of ACT. The 5-year OS and RFS were 76.9 % (ER+ 87.1 %, ER- 53.3 %) and 54.9 % (ER+ 59.3 %, ER- 42.9 %) for TAM and 85.0 % (ER+ 90.0 %, ER- 77.1 %) and 76.7 % (ER+ 76.9 %, ER- 76.0 %) for ACT. A higher proportion of the patients receiving ACT than those receiving TAM experienced grade 3 decreased white blood cell count and grade 2-3 nausea. CONCLUSION: The efficacy of adding AC to TAM was not high for ER+, node-positive PMBC. However, adjuvant ACT therapy was considered to be effective for ER-, node-positive PMBC.

2013年度日本乳癌学会班研究中間報告 晩期再発乳癌の生物学的特徴と予測因子に関する研究　　　　　　　　　　　　　　　
山下 啓子, 稲尾 瞳子, 荻谷 朗子, 枝園 忠彦, 堀本 義哉, 増田 慎三, 大佐古 智文, 高橋 將人, 遠藤 友美, 細田 充主
日本乳癌学会総会プログラム抄録集, 22回, 227, 227, (一社)日本乳癌学会, 2014年07月
日本語

[Effect of capecitabine therapy on the blood levels of antiepileptic drugs - report of two cases].
Hiroyuki Tanaka, Hiromi Jotoku, Masahiko Takasaki, Yukihiro Ibayashi, Kenichi Watanabe, Masato Takahashi
Gan to kagaku ryoho. Cancer & chemotherapy, 41, 4, 527, 30, 2014年04月, ［国内誌］
日本語, 研究論文（学術雑誌）, We report the cases of 2 breast cancer patients who received capecitabine(CAP)and concomitant anticonvulsant therapy with either phenytoin(PHT)or valproate(VPA)for brain metastasis. The effect of CAP on the blood levels of the 2 anticonvulsants was different and it depended on the variation in metabolism of each drug. Case 1 involved a 59-year-old woman with recurrent breast cancer. After radiation therapy for brain metastases, the patient received PHT(400mg/day)to prevent convulsions. After 5 days of PHT administration, CAP therapy was initiated, and her blood PHT levels increased to 33.8 mg/mL. Although the PHT dose was reduced to 300mg/day, the blood PHT levels markedly increased to 45.5 mg/mL 7 days after the withdrawal of CAP. Case 2 involved a 60-year-old woman with breast cancer who underwent surgery for brain metastases and subsequently received controlled-release VPA tablets(400mg/day). No remarkable change was observed in her blood VPA levels during CAP treatment or after CAP withdrawal(the blood VAP level after 7 days of treatment was, 78.4 mg/mL; after 14 days of treatment, 73.2 mg/mL; and 7 days after withdrawal, 79.7 mg/mL). CAP has been reported to inhibit nucleic acid synthesis and/or folic acid activity rather than cytochrome P450(CYP)directly. CAP had a significant effect on the blood levels of PHT, which is metabolized via the CYP pathway. However, VPA levels remained unchanged because VPA metabolism involves other pathways, such as the beta-oxidation and conjugation pathways.

乳癌局所治療における新展開 先進医療制度に承認された新しい乳がん局所療法としてのラジオ波熱焼灼療法(RFA)多施設共同研究
木下 貴之, 山本 尚人, 藤澤 知巳, 土井原 博義, 青儀 健二郎, 和田 徳昭, 高橋 将人, 増田 慎三, 大谷 彰一郎, 麻賀 創太
日本外科学会雑誌, 115, 臨増2, 120, 120, (一社)日本外科学会, 2014年03月
日本語

Single-nucleotide polymorphisms and copy number variations of the FCGR2A and FCGR3A genes in healthy Japanese subjects.
Hiroyuki Moriya, Katsuhiko Saito, Nuala Helsby, Naomi Hayashi, Shigekazu Sugino, Michiaki Yamakage, Takeru Sawaguchi, Masahiko Takasaki, Masato Takahashi, Nahoko Kurosawa
Biomedical reports, 2, 2, 265, 269, 2014年03月, ［国際誌］
英語, 研究論文（学術雑誌）, FcγRII and FcγRIII are low-affinity Fcγ receptors that are encoded by the FCGR2A and FCGR3A genes, respectively. These genes contain functional single-nucleotide polymorphisms (SNPs), which alter the binding affinities of these receptors for the γ chain of the Fc fragment of immunoglobulin G. The known SNPs in FCGR2A and FCGR3A are rs1801274 (A>G; H131R) and rs396991 (T>G; F158V), respectively. It is also known that there are copy number variations (CNVs) in the genetic locus (1q23) where FCGR2A and FCGR3A are located. However, the frequencies of these SNPs and CNVs have not been determined in the Japanese population. The aim of this study was to investigate SNPs and CNVs in FCGR2A and FCGR3A among 113 healthy individuals. The SNPs and CNVs in FCGR2A and FCGR3A were determined using the TaqMan® SNP Genotyping and the TaqMan® Copy Number assays. Our results revealed that the incidence of FCGR2A (rs1801274) genotypes were as follows: A/A, 69.9%; A/G, 29.2%; and G/G, 0.9%. The incidence of the FCGR3A (rs396991) genotypes were as follows: T/T, 56.7%; T/G, 38.9%; and G/G, 4.4%). No CNVs were detected for FCGR2A. To the best of our knowledge, this finding has not been previously reported in the Japanese population. By contrast, CNVs were observed in FCGR3A (3 subjects were found to harbour a gene deletion and 5 subjects had 3 copies of the gene). Using simple commercially available assays we were able to confirm previous findings regarding FCGR2A and FCGR3A alleles and CNVs. These assays may provide a basis for the investigation of the role of these genes in the efficacy of antibody-based drugs, such as trastuzumab and rituximab, in Japanese subjects.

Probiotic Beverage with Soy Isoflavone Consumption for Breast Cancer Prevention: A Case-control Study.
Masakazu Toi, Saya Hirota, Ai Tomotaki, Nobuaki Sato, Yasuo Hozumi, Keisei Anan, Takeshi Nagashima, Yutaka Tokuda, Norikazu Masuda, Shozo Ohsumi, Shinji Ohno, Masato Takahashi, Hironori Hayashi, Seiichiro Yamamoto, Yasuo Ohashi
Current nutrition and food science, 9, 3, 194, 200, 2013年08月, ［国際誌］
英語, 研究論文（学術雑誌）, The purpose of this study is to evaluate how beverages containing Lactobacillus casei Shirota (BLS) and soy isoflavone consumption since adolescence affected the incidence of breast cancer. In a population-based case-control study, three hundred and six cases with breast cancer and 662 controls aged 40 to 55 were matched for age and residential area and included in the analyses. Diet, lifestyle and other breast cancer risk factors were investigated using the self-administered questionnaire and interview. Odds ratios (ORs) of BLS and soy isoflavone consumption for breast cancer incidence were independently and jointly estimated using a conditional logistic regression. The ORs of BLS consumption (≥ four times a week against < four times a week) was 0.65 and statistically significant (p = 0.048). The analysis of association between soy consumption and breast cancer incidence showed the more the isoflavone consumption is, the lower the odds of breast cancer becomes. Adjusted ORs for breast cancer in the second, the third and the fourth quartiles of soy consumption against the first quartile were 0.76, 0.53 and 0.48, respectively (trend test, p = 0.0002). The BLS-isoflavone interaction was not statistically significant; however, a biological interaction was suggested. Regular consumption of BLS and isoflavones since adolescence was inversely associated with the incidence of breast cancer in Japanese women.

Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat).
Makoto Kubo, Noriko Kanaya, Karineh Petrossian, Jingjing Ye, Charles Warden, Zheng Liu, Reiki Nishimura, Tomofumi Osako, Masayuki Okido, Kazuo Shimada, Masato Takahashi, Peiguo Chu, Yate-Ching Yuan, Shiuan Chen
Breast cancer research and treatment, 137, 1, 93, 107, 2013年01月, ［国際誌］
英語, 研究論文（学術雑誌）, Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest and induced apoptosis. LBH589 treatment also reduced the level of NF-κB1 which is overexpressed when AI resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-κB1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-κB1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-κB1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 suppressed NF-κB1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-κB1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-κB1 pathway.

Efficacy of zoledronic acid in postmenopausal Japanese women with early breast cancer receiving adjuvant letrozole: 12-month results.
Shunji Takahashi, Takuji Iwase, Norio Kohno, Takashi Ishikawa, Tetsuya Taguchi, Masato Takahashi, Jun Horiguchi, Seigo Nakamura, Yasuo Hozumi, Masao Fukunaga, Shinzaburo Noguchi
Breast cancer research and treatment, 133, 2, 685, 93, 2012年06月, ［国際誌］
英語, 研究論文（学術雑誌）, Aromatase inhibitor-associated bone loss has not been proved in the Japanese or Asian women. The aim of this study was to evaluate an upfront or delayed strategy of bone protection therapy with zoledronic acid administered at 4 mg every 6 months in postmenopausal Japanese women with early breast cancer to compare with results of the Z-FAST and ZO-FAST studies in western countries. Postmenopausal women with hormone receptor positive early breast cancer receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months). The delayed group received zoledronic acid when lumbar spine (L(2)-L(4)) bone mineral density (BMD) decreased to less than young adult mean -2.0SD or when a nontraumatic fracture occurred. The primary endpoint of this study was to compare the percent change in L(1)-L(4) BMD at 12 months between the groups. Secondary endpoints included percent changes in L(2)-L(4) and total hip (TH) BMD. The upfront and delayed groups included 94 and 95 patients, respectively. At 12 months, L(1)-L(4), L(2)-L(4), and TH BMD significantly decreased by 2.0, 2.4, and 2.4%, respectively, in the delayed group. L(1)-L(4) BMD was 4.9% higher in the upfront group than in the delayed group (95% CI 3.9-5.8%; p < 0.001). L(2)-L(4) BMD was 5.6% higher (95% CI 4.5-6.6%; p < 0.001), and TH BMD was 4.4% higher (95% CI 3.3-5.4%; p < 0.001). At 12 months, upfront zoledronic acid therapy prevented bone loss in postmenopausal Japanese women who were receiving adjuvant letrozole, confirming the Z-/ZO-FAST study results in western populations.

α-fetoprotein, vascular endothelial growth factor receptor-1 and early recurrence of hepatoma.
Kamiyama T, Takahashi M, Nakanishi K, Yokoo H, Kamachi H, Kobayashi N, Ozaki M, Todo S
World journal of gastroenterology, 18, 4, 340, 348, BAISHIDENG PUBL GRP CO LTD, 2012年01月, ［査読有り］
英語, 研究論文（学術雑誌）, AIM: To investigate whether a-fetoprotein (AFP) and vascular endothelial growth factor receptor (VEGFR)-1 correlate with early recurrence of hepatoma/hepatocellular carcinoma (HCC).
METHODS: From 2000 to 2005, 114 consecutive patients with HCC underwent primary curative hepatectomy. The mean age was 60.7 (8.7) years and 94 patients were male. The median follow-up period was 71.2 mo (range: 43-100 mo). Immediately prior to commencing laparotomy, 5 nnL bone marrow was aspirated from the sternum and collected in citrate-coated test tubes. The initial 2 mL of bone marrow aspirate was discarded in each case. AFP mRNA and VEGFR-1 mRNA in the bone marrow and peripheral blood (BM- and PH-AFP mRNA and BM- and PH-VEGFR-1 mRNA, respectively) were measured by real-time quantitative reverse transcription polymerase chain reaction. As normal controls, VEGFR-1 mRNA in the bone marrow and peripheral blood was also measured in 11 living liver donors. These data were evaluated for any correlation with early recurrence, comparing clinical and pathological outcomes.
RESULTS: The cut-off value of the BM-AFP mRNA and PH-AFP mRNA level in patients with HCC was set at 1.92 x 10(-7) and zero, respectively, based on data from the controls. A total of 34 (29.8%) and six (5.4%) patients were positive for BM-AFP mRNA and PH-AFP mRNA, respectively. The BM-VEGFR-1 mRNA levels in all HCC patients were higher than those in the normal controls, and this was the case also for PH-VEGFR-1mRNA. The 25-percentile values for the BM- and PH-VEGFR-1 mRNA in HCC patients were used as the cut-off values for assigning the patients into two groups based on these transcript levels. The High group for BM- VEGFR-1 mRNA contained 81(71.1%) HCC cases and the Low group was assigned 33 (28.9%) patients. These numbers for PH-VEGFR-1mRNA were 78 (75.0%) and 26 (25.0%), respectively. HCC recurred in 80 patients; in the remnant liver in 48 cases, in the remnant liver and remote tissue in 20, and in the remote tissue alone in 12. BM-AFP nnRNA-positive cases showed a significantly higher rate of early recurrence (within 1 year of surgical treatment) compared with BM-AFP mRNA-negative patients (P = 0.0091). Patients were classified into four groups according to the level/status of their BM-VEGFR-1 and BM-AFP mRNA as follows: group A (n = 23), BM-VEGFR-1/BM-AFP mRNA = low/negative; group B (n = 57) high/negative; group C (n = 10)low/positive; group D (n = 24), high/positive. This classification was found to correlate with a recurrence of this disease within 1 year (P = 0.0228). The disease-free survival curve of group A was significantly better than that of groups B, C or D (P = 0.0437, P = 0.0325, P = 0.0225). No other classification (i.e., PH-VEGF-R1/BM-AFP, BM-VEGF-R1/PH-AFP, and PH-VEGF-R1/PH-AFP mRNA) showed such a correlation.
CONCLUSION: The evaluation of BM-AFP and BM-VEGFR-1 mRNA in patients with HCC may be a valuable predictor of disease recurrence following curative resection. (C) 2012 Baishideng. All rights reserved.

Does primary tumor resection improve outcomes for patients with incurable advanced breast cancer?
Susumu Shibasaki, Hiromi Jotoku, Kenichi Watanabe, Masato Takahashi
Breast (Edinburgh, Scotland), 20, 6, 543, 7, 2011年12月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Metastatic breast cancer (MBC) is considered incurable, and surgery has only limited benefit in the treatment of this disease. However, recent reports have indicated that primary tumor resection may improve patient outcomes. We retrospectively analyzed the surgical benefits and prognostic factors for patients with MBC who were treated at our center. METHODS: Ninety-two women, who had tumors of greater than 5 cm and distant metastasis at diagnosis, were included in this study. The effect of surgical treatment on survival was evaluated. Patient demographics and tumor characteristics were also investigated. RESULTS: Thirty-six patients had surgery for resection of primary tumors. There were no substantive differences between individuals, or between tumor characteristics, for patients who underwent surgery versus patients who did not. The median survival time for surgically treated patients was 25.0 months versus 24.8 months for patients who did not undergo surgical resection (P=0.352). Only three patients relapsed within three months of surgery. For the remaining majority of patients, primary tumor resection gave some relief from the often severe symptoms that come from harboring a large tumor for an extended time. In univariate and subsequent multivariate analyses of predictive indicators, a diagnosis of triple-negative breast cancer and/or metastasis to more than three sites was significantly associated with a severe prognosis. CONCLUSION: Primary tumor resection failed to prolong overall survival times in patients with incurable advanced breast cancer that was greater than 5 cm. However, surgery did improve the quality of life in patients who were expected to have a relatively long prognosis.

Inhibition of nuclear factor-kappaB suppresses peritoneal dissemination of gastric cancer by blocking cancer cell adhesion
Kazuhiro Mino, Michitaka Ozaki, Kazuaki Nakanishi, Sanae Haga, Masanori Sato, Masaya Kina, Masato Takahashi, Norihiko Takahashi, Akihiko Kataoka, Kazuyoshi Yanagihara, Takahiro Ochiya, Toshiya Kamiyama, Kazuo Umezawa, Satoru Todo
CANCER SCIENCE, 102, 5, 1052, 1058, WILEY-BLACKWELL, 2011年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Currently, patients with peritoneal dissemination of gastric cancer must accept a poor prognosis because there is no standard effective therapy. To inhibit peritoneal dissemination it is important to inhibit interactions between extracellular matrices (ECM) and cell surface integrins, which are important for cancer cell adhesion. Although nuclear factor-kappa B (NF-kappa B) is involved in various processes in cancer progression, its involvement in the expression of integrins has not been elucidated. We used a novel NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), to study whether NF-kappa B blocks cancer cell adhesion via integrins in a gastric cancer dissemination model in mice and found that DHMEQ is a potent suppressor of cancer cell dissemination. Dehydroxymethylepoxyquinomicin suppressed the NF-kappa B activity of human gastric cancer cells NUGC-4 and 44As3Luc and blocked the adhesion of cancer cells to ECM when compared with the control. Dehydroxymethylepoxyquinomicin also inhibited expression of integrin (alpha 2, alpha 3, beta 1) in in vitro studies. In the in vivo model, we injected 44As3Luc cells pretreated with DHMEQ into the peritoneal cavity of mice and performed peritoneal lavage after the injection of cancer cells. Viable cancer cells in the peritoneal cavities were evaluated sequentially by in vivo imaging. In mice injected with DHMEQ-pretreated cells and lavaged, live cancer cells in the peritoneum were significantly reduced compared with the control, and these mice survived longer. These results indicate that DHMEQ could inhibit cancer cell adhesion to the peritoneum possibly by suppressing integrin expression. Nuclear factor-kappa B inhibition may be a new therapeutic option for suppressing postoperative cancer dissemination. (Cancer Sci 2011; 102: 1052-1058).

Dynamic MR findings of ductal carcinoma in situ within a fibroadenoma.
Fumi Kato, Tokuhiko Omatsu, Wakana Matsumura, Masato Takahashi, Mitsuchika Hosoda, Hiromasa Takahashi, Kanako Kubota, Noriko Oyama-Manabe, Satoshi Terae, Hiroki Shirato
Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine, 10, 2, 129, 32, 2011年, ［国内誌］
英語, 研究論文（学術雑誌）, We report magnetic resonance (MR) imaging findings of ductal carcinoma in situ (DCIS) within a fibroadenoma in a 42-year-old woman. Dynamic MR imaging revealed the mass to have 2 components with different kinetics. A nodular area within the mass showed faster initial enhancement followed by earlier washout and was histologically proven to be DCIS. Dynamic MR imaging reflected differences in vascularity between the fibroadenoma and DCIS, and parameter color maps generated from the dynamic data clearly demonstrated the extent of the DCIS.

遠隔転移を有する巨大T4乳癌に対する局所制御戦略
柴崎 晋, 上徳 ひろみ, 渡邊 健一, 高橋 將人
北海道外科雑誌, 55, 2, 205, 205, 北海道外科学会, 2010年12月
日本語

Array comparative genomic hybridization analysis revealed four genomic prognostic biomarkers for primary gastric cancers
Nobumoto Tomioka, Keiko Morita, Nozomi Kobayashi, Mitsuhiro Tada, Tomoo Itoh, Soichiro Saitoh, Masao Kondo, Norihiko Takahashi, Akihiko Kataoka, Kazuaki Nakanishi, Masato Takahashi, Toshiya Kamiyama, Michitaka Ozaki, Takashi Hirano, Satoru Todo
CANCER GENETICS AND CYTOGENETICS, 201, 1, 6, 14, ELSEVIER SCIENCE INC, 2010年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Unlike the case with some other solid tumors, whole genome array screening has not revealed prognostic genetic aberrations in primary gastric cancer. Comparative genomic hybridization (CGH) using bacterial artificial chromosome (BAC) arrays for 56 primary gastric cancers resulted in identification of four prognostic loci in this study: 6q21 (harboring FOXO3A; previously FKHRL1), 9q32 (UGCG), 17q21.1 similar to q21.2 (CASC3), and 17q21.32 (HOXB3 through HOXB9). If any one of these four loci was deleted, the prognosis of the patient was significantly worse (P = 0.0019). This was true even for advanced tumors (stage IIIA, JIB, or IV, n = 39) (P = 0.0113), whereas only 1 of the 17 patients with less advanced tumors (stage IA, IB, or II; n = 17) died of disease after surgery. Multivariate analysis according to the status of four BACs or pathological stage based on the Japanese Classification of Gastric Carcinoma (stages IA, IB, and II vs. stages IIIA, IIIB, and IV) demonstrated that the BAC clone status was also an independent prognostic factor (P = 0.006). These findings may help predict which patients with malignant potential need more intensive therapy, or may point to new therapeutic approaches especially for advanced tumors. The parameter here termed the integrated genomic prognostic biomarker may therefore be of clinical utility as a prognostic biomarker. (C) 2010 Elsevier Inc. All rights reserved.

右乳癌術後に乳糜漏をきたし,保存的に加療した1例
江本 慎, 高橋 將人, 細田 充主, 高橋 弘昌, 藤堂 省
日本臨床外科学会雑誌, 71, 8, 1959, 1964, 日本臨床外科学会, 2010年08月, ［査読有り］
日本語, 右乳癌の術後乳糜漏は非常に稀である.今回われわれは保存的に加療しえた本症の1例を経験した.43歳女性.2009年1月乳癌検診にて右乳房に異常を指摘され来院.右乳房CD領域に腫瘤を認め,マンモトーム生検にて浸潤性乳管癌と確定診断され,エストロゲン受容体およびプロゲステロン受容体ともに陽性,human epithelial growth factor recetptor type2は陰性であった.術前化学療法を施行し,8月に内視鏡下右胸筋温存乳房切除術+腋窩郭清(LevelI+II)を施行した.術後,乳糜漏を認めず,術後8日目(post operative day 8,POD8)に退院となった.POD13の初回外来にて皮弁下穿刺で乳糜を認め,POD20に入院.POD28にドレーンを再留置し,POD36に食事を再開.徐々に脂肪制限を緩和したところ,POD48にドレーン排液が再び乳糜となったため,絶食とした.POD62に排液量は著明に減少し,POD64にドレーンを抜去した.乳癌術後の乳糜漏で,ドレーン排液量が少量な場合,保存的加療が可能であると考えられた.(著者抄録)

異所性縦隔内甲状腺腫の1例　　　　　　　　　　　　　　　
大畑 多嘉宣, 大高 和人, 山田 健司, 細田 充主, 高橋 將人, 高橋 弘昌, 藤堂 省
北海道外科雑誌, 55, 1, 75, 75, 北海道外科学会, 2010年06月
日本語

Predictive factors for anthracycline-based chemotherapy for human breast cancer.
Yasuo Miyoshi, Masafumi Kurosumi, Junichi Kurebayashi, Nariaki Matsuura, Masato Takahashi, Eriko Tokunaga, Chiyomi Egawa, Norikazu Masuda, Seishi Kono, Koji Morimoto, Seung Jin Kim, Masatsugu Okishiro, Tetsu Yanagisawa, Satsuki Ueda, Tetsuya Taguchi, Yasuhiro Tamaki, Shinzaburo Noguchi
Breast cancer (Tokyo, Japan), 17, 2, 103, 9, 2010年04月, ［国内誌］
英語, 研究論文（学術雑誌）, Predictive factors for anthracycline-based chemotherapy have yet to be incorporated into daily practice. Meta-analyses of studies using anthracycline-based treatment regimens have shown an improved prognosis for human epidermal growth factor receptor type 2 (HER2)-positive tumors, but not for HER2-negative tumors compared with results of non-anthracycline regimens. Currently it is believed that the positive association between HER2 status and anthracycline sensitivity is indirect, that is, their association may be mediated through topoisomerase II alpha (TOP2A), a target molecule of anthracyclines, since TOP2A is near HER-2 and co-amplification of the TOP2A gene frequently occurs in HER2-amplified tumors. This strongly suggests that TOP2A gene amplification is a predictive factor for anthracyline-based regimens. The Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society has demonstrated that TOP2A-positive and BRCA1-negative subsets evaluated by immunohistochemical staining show a significantly higher pathological complete response when treated with preoperative epirubicin-containing regimens. Combining these findings with the observation that triple-negative tumors and basal-like tumors respond to anthracycline treatment suggests that not only HER2-positive tumors but also a distinct subset of HER2-negative tumors may be sensitive to anthracycline-based regimens.

Comparative studies of paclitaxel injection [SAWAI] and Taxol® injection on pharmacokinetics in dogs and in vitro/vivo antitumor activities
Masato Takahashi, Mitsuchika Hosoda, Hiromasa Takahashi, Satoru Todo
Japanese Journal of Cancer and Chemotherapy, 37, 9, 1699, 1706, Japanese Journal of Cancer and Chemotherapy Publishers Inc., 2010年
日本語, 研究論文（学術雑誌）, We performed bioequivalent assessments of the generic (Paclitaxel Injection [SAWAI] and branded (Taxol® Injection) formulations of paclitaxel injection on pharmacokinetics in dogs and in vitro/vivo antitumor activities. In the pharmacokinetics study in dogs, the 90% confidence intervals (CIs) for the differences in logarithm of C&
binf
max&
einf
and AUC&
binf
0- 48&
einf
were log (1.01) to log (1.17) and log (1.01) to log (1.08), respectively. These were within the bioequivalent criteria of log (0.80) to log (1.25). In the in vitro study, both products showed concentration-dependent inhibition of the growth of 5 cultured human cancer cell lines, MCF7 (breast adenocarcinoma), A2780 (ovarian carcinoma), A549 (lung carcinoma), MKN45 (gastric adenocarcinoma) and MKN74 (gastric adenocarcinoma). The 90% CIs for the differences in logarithm of half maximal inhibitory concentration (IC&
binf
50&
einf
) were log (0.876) to log (1.110), log (0.856) to log (1.097), log (0.977) to log (1.167), log (0.879) to log (1.093) and log (0.936) to log (1.081), respectively. These were within the bioequivalent criteria. In the in vivo study, both products showed concentration-dependent inhibition of the growth of 3 human cancer cells, A2780 (ovarian carcinoma), A549 (lung carcinoma) and MDA-MB-231 (breast adenocarcinoma), xenografted in nude mice. And there are no significant differences between Paclitaxel Injection [SAWAI] and Taxol® Injection. These results showed that Paclitaxel Injection [SAWAI] is bioequivalent to Taxol® Injection.

Akathisia causing secondary severe depression in a cancer patient
Takeshi Inoue, Masato Takahashi, Mitsuchika Hosoda, Tsukasa Koyama
Primary Care Companion to the Journal of Clinical Psychiatry, 12, 4, e1, 2010年, ［査読有り］
英語

妊娠に合併した原発性副甲状腺機能亢進症の3例
横尾 英樹, 高橋 弘昌, 細田 充主, 高橋 将人, 佐々木 文章, 藤堂 省
日本臨床外科学会雑誌 = The journal of the Japan Surgical Association, 70, 6, 1614, 1619, Japan Surgical Association, 2009年06月25日
日本語, 妊娠に合併した原発性副甲状腺機能亢進症3例に対し腫瘍摘出術を施行した．妊娠中の高カルシウム血症で発見された1例は，右下副甲状腺の腫大を認め，保存的治療を行ったがコントロール不良であったため妊娠第三期（妊娠29週）に腫瘍摘出術を行った．出産後に新生児テタニーを契機として発見された2例は各々右下，左下副甲状腺の腫大を認め，腫瘍摘出術を行った．病理組織学的には3例とも副甲状腺腺腫であり，全例良好な術後経過であった．妊娠に原発性副甲状腺機能亢進症を合併した症例は流産，死産，未熟児，新生児テタニーなどの障害を高率に引き起こすとされる．妊娠中の高カルシウム血症や新生児テタニーを認めた場合には，本症の存在を念頭に置いて診断を進める必要がある．

甲状腺低分化癌の1例
旭 よう, 高橋 將人, 鈴木 徹平, 若山 顕治, 細田 充主, 高橋 弘昌, 藤堂 省
北海道外科雑誌, 54, 1, 37, 40, 北海道外科学会, 2009年06月
日本語, 症例は59歳女性。2006年11月に検診にて甲状腺腫瘤を指摘され、当院を受診した。頸部超音波にて、甲状腺右葉に22×19×15mmの腫瘍を認め、穿刺吸引細胞診にて甲状腺乳頭癌と診断し、甲状腺亜全摘術及びD2a郭清を施行した。病理学的検索により、腫瘍の一部に低分化な部分を認めたため、甲状腺低分化癌の診断となった。本症例では周囲脂肪組織に浸潤を認めたが、断端陰性であったので、放射線外照射治療を選択した。術後18ヵ月経過した現在、再発の兆候を認めていない。甲状腺低分化癌は甲状腺悪性腫瘍の1.5〜13%を占める比較的稀な疾患で、5年生存率が約60%と甲状腺乳頭癌より予後不良である。我々は甲状腺亜全摘術に外照射療法を行うことを選択したが、再発予防のための治療法については明確な見解は得られていない。それ故、慎重な経過観察を要する。(著者抄録)

乳房超音波エラストグラフィの診断的意義に関する検討
細田 充主, 高橋 將人, 高橋 弘昌, 藤堂 省
日本臨床外科学会雑誌 = The journal of the Japan Surgical Association, 70, 3, 645, 649, Japan Surgical Association, 2009年03月25日
日本語, 乳房超音波エラストグラフィは非侵襲的診断方法として徐々に普及が進んでいるが，その診断的位置づけは未だ明らかにされていない．2006年11月から2007年11月に当科にてエラストグラフィを施行した72乳腺腫瘤（良性31腫瘤，悪性41腫瘤）を対象にその診断的意義を検討した．機器は日立メディコ製のEUB-7500を使用し，判定にはTsukuba elastography scoreを用いた．平均スコアは，良性腫瘤1.8±0.9，悪性腫瘤3.7±1.3（p<0.001）でスコア4以上を悪性と判定すると，感度は70.9％，特異度は90.3％であった．同時に評価したB modeカテゴリー判定では感度が97.6％，特異度は58.0％であり，エラストグラフィが特異度において良好であった．感度は腫瘤径大，浸潤癌，組織学的高gradeの腫瘤で高い傾向がみられた．乳房超音波エラストグラフィは，B modeに比べて感度は劣るが，特異度は優れていた．単独では悪性疾患の確定にはやや不適当であるが，B mode画像に併用することにより良性疾患の判別が可能となり，無駄な生検の回避には有用である．

乳腺 metaplastic carcinoma の2例
細田 充主, 高橋 將人, 高橋 弘昌, 伊藤 智雄, 藤堂 省
日本臨床外科学会雑誌 = The journal of the Japan Surgical Association, 69, 10, 2479, 2484, Japan Surgical Association, 2008年10月25日
日本語, 乳腺metaplastic carcinomaは極めて稀な乳腺悪性腫瘍あり，悪性度が高く予後も不良であると報告されている．本症例の2例を経験したので報告する．症例1，42歳女性．1989年右乳癌にてBt+Ax施行．経過観察中，左乳房腫瘤を自覚し当科受診．生検にてinvasive carcinomaの診断にてBt+Axを施行した．病理組織上，乳管癌の一部にspindle cellや軟骨化生を伴うmetaplastic carcinomaの像．術後24カ月，再発なく経過観察中である．症例2，60歳女性．左乳房腫瘤と腋窩皮膚潰瘍を主訴に近医を受診．生検にて扁平上皮癌の診断で化学療法を施行するも効なく当科紹介となった．放射線照射後，Bt+Axを施行した．病理組織上，乳管癌の像と扁平上皮癌の混在が認められ，一部で骨を形成しておりmetaplastic carcinomaの診断．局所再発，多発肝転移をきたし手術3カ月後に癌死した．

Topoisomerase IIalpha-positive and BRCA1-negative phenotype: association with favorable response to epirubicin-based regimens for human breast cancers.
Yasuo Miyoshi, Masafumi Kurosumi, Junichi Kurebayashi, Nariaki Matsuura, Masato Takahashi, Eriko Tokunaga, Chiyomi Egawa, Norikazu Masuda, Seung Jin Kim, Masatsugu Okishiro, Tetsu Yanagisawa, Satsuki Ueda, Tetsuya Taguchi, Yasuhiro Tamaki, Shinzaburo Noguchi
Cancer letters, 264, 1, 44, 53, 2008年06月08日, ［国際誌］
英語, 研究論文（学術雑誌）, Epirubicin exerts its anti-tumor effect through binding to topoisomerase IIalpha (TOP2A) and inducing DNA double-strand breaks. BRCA1 is involved in the repair of these breaks. We investigated the relationship between TOP2A or BRCA1 immunohistochemical expression and pathological response in 108 primary breast cancers treated with epirubicin-based regimens. The pCR (pathological complete response) rate for TOP2A-positive (17%) was significantly (P < 0.005) higher than for TOP2A-negative (2%), while the pCR rate for BRCA1-negative (11%) was non-significantly higher than for BRCA1-positive (5%). The pCR rate of TOP2A-positive and BRCA1-negative (30%) was significantly higher than for TOP2A-negative and BRCA1-positive (3%; P < 0.05), or TOP2A-negative and BRCA1-negative (0%; P < 0.005). The TOP2A-positive and BRCA1-negative phenotype associates with a favorable response to epirubicin-based regimens.

Low nuclear grade but not cell proliferation predictive of pathological complete response to docetaxel in human breast cancers.
Yasuo Miyoshi, Masafumi Kurosumi, Junichi Kurebayashi, Nariaki Matsuura, Masato Takahashi, Eriko Tokunaga, Chiyomi Egawa, Norikazu Masuda, Seung Jin Kim, Masatsugu Okishiro, Tetsu Yanagisawa, Satsuki Ueda, Tetsuya Taguchi, Yasuhiro Tamaki, Shinzaburo Noguchi
Journal of cancer research and clinical oncology, 134, 5, 561, 7, 2008年05月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Predictive factors for response to docetaxel in human breast cancers have yet to be identified. The aim of the present study was to investigate the relationship of various clinicopathological and biological parameters with pathological response to docetaxel in the neoadjuvant setting. METHODS: The study population comprised 78 patients with primary breast cancers who were treated with docetaxel [60 mg/m(2); four (median) cycles, range 3-6; q3w] as neoadjuvant therapy and subsequently treated with mastectomy or breast conserving surgery. Tumor samples obtained before chemotherapy were subjected to histological examination and immunohistochemistry of HER-2 and Ki-67. RESULTS: The pathological complete response (pCR) rate was significantly (P=0.04) higher for tumors with low nuclear grade (NG-I or -II) (21%) than for tumors with high NG (NG-III) (5%). The pCR rate (20%) of small (5 cm) tumors (5%). Combined analysis of NG and tumor size showed that low-NG small tumors have a higher response rate (30%) than high-NG small tumors (11%; P=0.13), low-NG large tumors (11%; P=0.15), and high-NG large tumors (0%; P=0.009). No statistically significant association was observed between pCR rate and menopausal status, lymph node status, ER, PR, HER-2, or Ki-67. CONCLUSIONS: Low nuclear grade, but not cell proliferation determined by Ki-67, is associated with a good pathological response to docetaxel. Combination of low nuclear grade and small tumor size may be useful for the selection of breast tumors with a high pCR rate (30%).

Swainsonine reduces 5-fluorouracil tolerance in the multistage resistance of colorectal cancer cell lines.
Jun Hamaguchi, Hiroaki Nakagawa, Masato Takahashi, Takeaki Kudo, Naoya Kamiyama, Bailong Sun, Takahiro Oshima, Yuji Sato, Kisaburo Deguchi, Satoru Todo, Shin-Ichiro Nishimura
Molecular cancer, 6, 58, 58, 2007年09月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Drug resistance is a major problem in cancer chemotherapy. Acquisition of chemo-resistance not only reduces the effectiveness of drugs, but also promotes side effects and markedly reduces the patient's quality of life. However, a number of resistance mechanisms have been reported and are thought to be the reason for the difficulties in solving drug-resistance problems. RESULT: To investigate the mechanisms of drug resistance, a set of cell lines with different levels of sensitivity and possessing different mechanisms of resistance to 5-fluorouracil (5-FU) was established from a colorectal cancer cell line. The expression of thymidylate synthase, orotic acid phosphoribosyltransferase and dihydropyrimidine dehydrogenase, which are well known to be related to drug resistance, differed among these cell lines, indicating that these cell lines acquired different resistance mechanisms. However, swainsonine, an inhibitor of N-glycan biosynthesis, reduced 5-FU-tolerance in all resistant cells, whereas the sensitivity of the parental cells was unchanged. Further analysis of the N-glycan profiles of all cell lines showed partial inhibition of biosynthesis and no cytotoxicity at the swainsonine dosage tested. CONCLUSION: These observations suggest that N-linked oligosaccharides affect 5-FU resistance more widely than do drug-resistance related enzymes in colorectal cancer cells, and that the N-glycan could be a universal target for chemotherapy. Further, swainsonine may enhance the performance of chemotherapy by reducing tolerance.

甲状腺低分化癌の1例　　　　　　　　　　　　　　　
旭 よう, 鈴木 徹平, 若山 顕治, 細田 充主, 高橋 將人, 高橋 弘昌, 久保田 佳奈子, 伊藤 智雄, 藤堂 省
日本臨床外科学会雑誌, 68, 9, 2420, 2420, 日本臨床外科学会, 2007年09月
日本語

術前薬物療法のbreak through 術前化学療法における感受性予測因子の同定　　　　　　　　　　　　　　　
三好 康雄, 野口 眞三郎, 黒住 昌史, 紅林 淳一, 松浦 成昭, 高橋 将人, 徳永 えり子, 柄川 千代美, 増田 慎三
日本乳癌学会総会プログラム抄録集, 15回, 177, 177, (一社)日本乳癌学会, 2007年06月
日本語

N-glycan alterations are associated with drug resistance in human hepatocellular carcinoma
Takeaki Kudo, Hiroaki Nakagawa, Masato Takahashi, Jun Hamaguchi, Naoya Kamiyama, Hideki Yokoo, Kazuaki Nakanishi, Takahito Nakagawa, Toshiya Kamiyama, Kisaburo Deguchi, Shin-Ichiro Nishimura, Satoru Todo
MOLECULAR CANCER, 6, 32, BIOMED CENTRAL LTD, 2007年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Correlations of disease phenotypes with glycosylation changes have been analysed intensively in the tumor biology field. Glycoforms potentially associated with carcinogenesis, tumor progression and cancer metastasis have been identified. In cancer therapy, drug resistance is a severe problem, reducing therapeutic effect of drugs and adding to patient suffering. Although multiple mechanisms likely underlie resistance of cancer cells to anticancer drugs, including overexpression of transporters, the relationship of glycans to drug resistance is not well understood.
Results: We established epirubicin (EPI)- and mitoxantrone (MIT)-resistant cell lines (HLE-EPI and HLE-MIT) from the human hepatocellular carcinoma cell line (HLE). HLE-EPI and HLE-MIT overexpressed transporters MDR1/ ABCB1 and BCRP/ ABCG2, respectively. Here we compared the glycomics of HLEEP1 and HLE-MIT cells with the parental HLE line. Core fucosylated triantennary oligosaccharides were increased in the two resistant lines. We investigated mRNA levels of glycosyltransferases synthesizing this oligosaccharide, namely, N-acetylglucosaminyltransferase (GnT)-IVa, GnT-IVb and alpha 1,6-fucosyltransferase (a1,6-FucT), and found that a1,6-FucT was particularly overexpressed in HLE-MIT cells. In HLE-EPI cells, GnT-IVa expression was decreased, while GnT-IVb was increased. Both GnT-IVs were downregulated in HLE-MIT cells. HLE-MIT cells also showed decreases in fucosylated tetraantennary oligosaccharide, the product of GnT-V. GnT-V expression was decreased in both lines, but particularly so in HLE-MIT cells. Thus both N-glycan and glycosyltransferase expression was altered as cells acquired tolerance, suggesting novel mechanisms of drug resistance.
Conclusion: N-glycan and glycosyltransferase expression in HLE-EPI and HLE-MIT were analysed and presented that glycans altered according with acquired tolerance. These results suggested novel mechanisms of drug resistance.

緊急手術を要した巨大乳腺扁平上皮癌の1例　　　　　　　　　　　　　　　
渡辺 正明, 細田 充主, 寺崎 康展, 高橋 將人, 高橋 弘昌, 藤堂 省, 伊藤 智雄, 田口 和典, 高田 尚幸
北海道外科雑誌, 51, 2, 77, 77, 北海道外科学会, 2006年12月
日本語

AFP mRNA detected in bone marrow by real-time quantitative RT-PCR analysis predicts survival and recurrence after curative hepatectomy for hepatocellular carcinoma
Toshiya Kamiyama, Masato Takahashi, Takahito Nakagawa, Kazuaki Nakanishi, Hirofumi Kamachi, Tomomi Suzuki, Tsuyoshi Shimamura, Masahiko Taniguchi, Michitaka Ozaki, Michiaki Matsushita, Hiroyuki Furukawa, Satoru Todo
ANNALS OF SURGERY, 244, 3, 451, 463, LIPPINCOTT WILLIAMS & WILKINS, 2006年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: To determine whether detection of hepatocellular carcinoma (HCC) cells by real-time quantitative RT-PCR targeting of alpha-fetoprotein mRNA (AFP mRNA) before or after curative hepatectomy predicts HCC recurrence and patient survival.
Summary Background Data: The presence of cancer cells in peripheral blood and/or bone marrow in patients with malignant disease has been reported to correlate with outcome.
Methods: Between July 2000 and June 2005, 136 consecutive HCC patients underwent primary curative hepatectomy. Bone marrow aspirated preoperatively, and peripheral blood samples collected before and after operation were subjected to real-time quantitative RT-PCR analysis using AFP mRNA as a target molecule. Median follow-up was 23 months (range, 6-54 months). Patient survival (PS), disease-free survival (DFS), and clinicopathologic features were compared between patients with positive and negative AFP mRNA.
Results: Twenty-four patients died (22 from HCC). HCC recurred in 66 patients (hepatic in 37 [56.1%]; hepatic and remote in 17 [25.8%], and remote alone in 12 [18.2%]). Bone marrow was positive for AFP mRNA in 38 patients (27.9%) and negative in 98 (72.1%). One- and 3-year PS was 96.6% and 91.4%, respectively, with negative AFP mRNA versus 86.2% and 55.5%, respectively, with positive AFP mRNA (P < 0.0001). One- and 3-year DFS were 73.2% and 44.8%, respectively, with negative AFP mRNA versus 54.5% and 25.8%, respectively, with positive AFP mRNA (P = 0.0399). Portal vascular invasion, tumor size, multiple tumors, and tumor differentiation correlated with inferior PS and DFS on univariate analysis. On multivariate analysis, positive AFP mRNA was the most important risk factor for PS (P = 0.001) and DFS (P = 0.0165). In addition, positive AFP mRNA in peripheral blood after operation tended to predict reduced DFS.
Conclusion: AFP mRNA in the bone marrow and systemic circulation during the perioperative period predicts patient survival and recurrence after curative hepatic resection for HCC.

Expression of ABC transporters in human hepatocyte carcinoma cells with cross-resistance to epirubicin and mitoxantrone
Naoya Kamiyama, Saori Takagi, Chiaki Yamamoto, Takeaki Kudo, Takahito Nakagawa, Masato Takahashi, Kazuaki Nakanishi, Hiromasa Takahashi, Satoru Todo, Ken Iseki
Anticancer Research, 26, 2 A, 885, 888, 2006年03月
英語, 研究論文（学術雑誌）, Background: In order to understand the cross-resistance between epirubicin (EPI) and mitoxantrone (MIT), EPI- and MIT-resistant cells were established and their cross-resistance was evaluated. Materials and Methods: The degrees of growth inhibition of EPI-resistant HLE-EPI cells and MIT-resistant HLE-MIT cells by anticancer drugs were measured. The mRNA expressions of multidrug resistance protein 1 (MDR1)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 were also measured by quantitative real-time RT-PCR. Moreover, intracellular accumulation of EPI was investigated. Results: HLE-EPI cells were resistant to EPI, MIT and docetaxel. HLE-MIT cells were resistant to EPI, MIT and SN-38. HLE-EPI cells overexpressed MDR1 and HLE-MIT cells overexpressed BCRP. The intracellular accumulation of EPI was decreased in HLE-EPI and HLE-MIT cells. Conclusion: The results suggest that both MDR1 and BCRP can up-regulate the efflux of EPI causing resistance to EPI in HLE-EPI and HLE-MIT cells.

Efficacy and toxicity of combination treatment with epirubicin (EPI) plus docetaxel (DOC) in advanced breast cancer
Masato Takahashi, Ken-ichi Watanabe, Hiromasa Takahashi, Kazunori Taguchi, Motoshi Tamura, Yoshinobu Hata, Satoru Todo
Gan to kagaku ryoho. Cancer & chemotherapy, 33, 11, 1583, 1587, 2006年
日本語, 研究論文（学術雑誌）, Thirty women (mean age 50.4 years, range 31-63) with primary advanced breast cancer were given EPI 40-60 mg/m(2) and DOC 50-60 mg/m(2) intravenously every three weeks. The efficacy was evaluated after 4 cycle treatments. There were 5 complete responses (CR) and 14 partial responses (PR), giving an overall response rate of 63.3%. There were 2 pathological CR (8%) which showed complete disappearance of cancer cells. The high dose group showed a better response than the low-dose group. The most common grade 3/4 adverse events were neutropenia (26.7%) and general fatigue (6.7%). The simultaneous combination treatment of EPI and DOC is effective for primary chemotherapy and can be performed safely even for outpatients.

肝細胞癌のmicrometastasis
神山 俊哉, 高橋 将人, 中川 隆公, 中西 一彰, 横尾 英樹, 蒲池 浩文, 嶋村 剛, 古川 博之, 松下 通明, 藤堂 省
外科治療, 94, 1, 91, 93, (株)永井書店, 2006年01月
日本語, 肝細胞癌のmicrometastasisについて検討した.方法は肝細胞癌初回切除136例の肝切除前に骨髄液を採取し,real time RT-PCR法でAFPmRNAとGAPDHmRNAを測定,AFPmRNA/GAPDHmRNA比を求めた.そして,正常対象者の骨髄中のAFPmRNA/GAPDHmRNA比からカットオフ値を1.92×10^-7とし,この値以上を陽性とした.1)136例中38例(27.9%)が陽性,98例(72.1%)が陰性であった.2)臨床病理学的所見,病理組織学的所見との比較では,組織学的門脈侵襲,Stageと有意な相関を認めた.3)3年生存率は陽性例55.5%,陰性例91.4%,3年無再発性存率は陽性例25.8%,陰性例44.8%と有意に陽性例で不良であった.4)骨髄中AFPmRNAの測定は,循環中に存在する癌細胞が原因の転移,再発,腫瘍死の指標となり,肝移植の成績,適応を推定する上で有用な因子と考えられた

The impact of bilateral breast cancer on the prognosis of breast cancer: a comparative study with unilateral breast cancer.
Hiromasa Takahashi, Kenichi Watanabe, Masato Takahashi, Kazunori Taguchi, Fumiaki Sasaki, Satoru Todo
Breast cancer (Tokyo, Japan), 12, 3, 196, 202, 2005年, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The clinical significance of bilateral breast cancer is unclear and its influence on prognosis is controversial. We assessed the impact of synchronous and metachronous bilateral breast cancer on the prognosis compared with unilateral breast cancer. METHODS: Between January 1, 1960 and December 31, 2001, 1,214 women were treated for primary operable breast cancers. Thirteen (1.1%) had synchronous bilateral breast cancer; 33 (2.7%) had a metachronous contralateral breast cancer. We compared age at operation, menopausal status, clinical stage, tumor size and histology, lymph node status, hormone receptor status, and use of adjuvant chemotherapy or hormone therapy, and we analyzed the impact of these factors on recurrence and survival in the 46 patients with bilateral breast cancer and the 1,168 patients with unilateral breast cancer. RESULTS: The 5-and 10-year disease-free survival rates, respectively, were 65% and 65% in metachronous cases, 85.7% and 64.3% in synchronous cases, and 77.9% and 72.1% in unilateral cases. There was no significant difference in overall survival among the three groups. On multivariate analysis, metachronous bilaterality, tumor size, lymph node status and adjuvant hormone therapy were each independent risk factors for recurrence, whereas bilaterality of breast cancer did not influence overall survival. CONCLUSIONS: Our data suggest that metachronous bilateral breast cancer is associated with shorter disease-free survival than synchronous bilateral or unilateral breast cancer, although overall survival does not differ among the 3 groups. Patients with metachronous bilateral breast cancer should be followed particularly closely in order to detect recurrence early and maximize quality of life.

[In vitro chemosensitivity test for hepatocellular carcinoma using collagen-gel droplet embedded cultures].
Nakagawa T, Takahashi H, Kamiyama T, Nakanishi K, Takahashi M, Watanabe K, Taguchi K, Tsukahara M, Nakajima H, Kamachi H, Kurauchi N, Kamiyama N, Khor LW, Abumiya K, Matsushita M, Kobayashi H, Todo S
Gan to kagaku ryoho. Cancer & chemotherapy, 31, 13, 2145, 2149, 2004年12月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, This study evaluated an in vitro assay for chemosensitivity test using a collagen-gel droplet-embedded culture drug sensitivity test (CD-DST) for hepatocellular carcinoma (HCC). In 25 patients with HCC, in vitro chemosensitivity to 5-fluorouracil (5-FU), epirubicin (EPI), and cisplatin (CDDP) was examined by CD-DST, and 5-FU, EPI, and paclitaxel (PTX) were examined in 38 patients with breast cancer. Successful rates of chemosensitive evaluation by CD-DST were 64% for HCC and 79% for breast cancers. Although chemosensitivities of breast cancer were 5-FU 23.1%, EPI 83.3%, and PTX 67.7%, only one HCC sample was sensitive to EPI. Growth rates of HCC for 7 days of culture were significantly lower than those of breast cancers (1.04 vs 3.61). The culture methods for HCC in CD-DST should be improved to estimate accurate results.

Decreased expression of the candidate tumor suppressor gene ING1 is associated with poor prognosis in advanced neuroblastomas.
Masato Takahashi, Toshinori Ozaki, Satoru Todo, Akira Nakagawara
Oncology reports, 12, 4, 811, 6, 2004年10月, ［国際誌］
英語, 研究論文（学術雑誌）, ING1 has been identified as a novel candidate tumor suppressor gene using a genetic suppressor element (GSE) strategy. Ectopic expression of ING1 in mammalian cultured cells causes cell cycle arrest and apoptosis through a p53-dependent and/or p53-independent pathway. However, there has been no report on the prognostic significance of the ING1 expression level in human cancers, though the expression of the wild-type ING1 gene is significantly decreased in breast, lymphoid and gastric cancers as compared with their corresponding normal tissues. In order to explore the possible involvement of ING1 in tumorigenesis of neuroblastoma, we examined the expression levels of ING1 mRNA in 32 primary neuroblastomas by using a quantitative real-time PCR. ING1 mRNA was expressed independently of the disease stages. however, low levels of ING1 mRNA were significantly associated with a poor prognosis (log-rank test, p=0.017). Multivariate analysis showed that the expression level of ING1 was closely related to survival (p=0.020), even after controlling with age (p=0.008) or stage (p=0.025), while it was only marginally significant after controlling with TrkA expression (p=0.063). Mutation analysis revealed that there was no mutation or deletion of the ING1 gene except 1 silent mutation at codon 188 in primary neuroblastomas examined. Taken together, our results suggest for the first time that a decreased level of ING1 expression is a novel indicator of poor prognosis in advanced stages of neuroblastoma, and that ING1 may play a crucial role in genesis and progression of neuroblastoma.

【生体肝移植とその短期および長期成績】疾患別の術後管理,長期対策 肝癌
谷口 雅彦, 古川 博之, 嶋村 剛, 陳 孟鳳, 鈴木 友己, 太田 稔, 萩原 邦子, 高橋 将人, 神山 俊哉, 松下 通明, 藤堂 省
外科, 66, 9, 1050, 1054, (株)南江堂, 2004年09月
日本語, 肝移植後の対策として,肝癌再発の観点から免疫抑制療法,化学療法,画像追跡,腫瘍分子マーカーの観察などが重要であるが,併存するB型,C型肝炎に対する再発予防策も必須である.我が国の肝癌に対する生体肝移植316例の検討では,生存率は74.7%,再発率は12.7%であり,移植後3年以降の再発は認めなかった.また171例(54.1%)はいわゆるミラノ基準逸脱例であり,うち133例(77.8%)は現時点で無再発であった

Magnetic resonance imaging for preoperative evaluation of breast cancer: a comparative study with mammography and ultrasonography.
Tunetake Hata, Hiromasa Takahashi, Kenichi Watanabe, Masato Takahashi, Kazunori Taguchi, Tomoo Itoh, Satoru Todo
Journal of the American College of Surgeons, 198, 2, 190, 7, 2004年02月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The widespread use of mammographic screening has led to increased detection of small tumors that are often difficult to diagnose with conventional imaging modalities such as mammography and ultrasonography. Intraductal spread of breast cancer, a principle risk factor for local recurrence, is also difficult to diagnose with mammography and ultrasonography. We investigated the clinical usefulness of magnetic resonance imaging of the breast in the therapy of breast cancer and we compared it with mammography and ultrasonography. STUDY DESIGN: A total of 183 patients with primary breast cancer underwent surgery at our institute between September 1, 1999, and November 30, 2002. They were examined preoperatively with magnetic resonance imaging, mammography, and ultrasonography. Magnetic resonance imaging evaluation included contrast-enhanced dynamic studies using IV injection of gadolinium-diethylenetriamine pentaacetic acid. RESULTS: Detection rates of breast cancers by magnetic resonance imaging, mammography, and ultrasonography were 93.7%, 84.6%, and 97.3%, respectively (magnetic resonance imaging versus mammography, p < 0.05). Patterns of time-intensity curves in dynamic magnetic resonance imaging differed with histologic types. Sensitivity, specificity, and accuracy of detection of intraductal spread were 66.7%, 64.2%, and 65.6% with MRI; 22.2%, 85.7%, and 50% with mammography; and 20.6%, 85.2%, and 50% with ultrasonography, respectively (sensitivity, specificity, and accuracy; p < 0.05, respectively). CONCLUSIONS: Magnetic resonance imaging can diagnose breast cancer as accurately as ultrasonography and more accurately than mammography. Patterns of time-intensity curves correlated with tumor histology. In addition, magnetic resonance imaging can detect intraductal spread more accurately than the other two methods. Magnetic resonance imaging appears to be indispensable in breast-conserving surgery to minimize local recurrence.

Negative autoregulation of p73 and p53 by ΔNp73 in regulating differentiation and survival of human neuroblastoma cells
Takahito Nakagawa, Masato Takahashi, Toshinori Ozaki, Ken-Ichi Watanabe, Shunji Hayashi, Mitsuchika Hosoda, Satoru Todo, Akira Nakagawara
Cancer Letters, 197, 1-2, 105, 109, Elsevier Ireland Ltd, 2003年07月18日
英語, 研究論文（国際会議プロシーディングス）, p73, mapped to 1p36.2-3, is a p53-related tumor suppressor but is also induced by the oncogene products such as E2F1, raising a question whether p73 is a tumor suppressor gene or oncogene. p73 has several splicing variants including ΔNp73 which lacks the NH2-terminal transactivation domain. In developing neurons, ΔNp73 is expressed abundantly and seems to inhibit the pro-apoptotic function of p53. However, the role of TAp73 and ΔNp73 as well as their regulatory mechanism in cell growth and differentiation of neuroblastoma cells are poorly understood. We have found that TAp73 directly activates the transcription of endogenous ΔNp73 by binding to the TAp73-specific target element located at position-76 to 57 within the ΔNp73 promoter region. ΔNp73 was physically associated with TAp73α, TAp73β and p53, and inhibited their transactivation activities when used reporters of Mdm2, Bax or ΔNp73 itself in SAOS-2 cells. Overexpression of ΔNp73 in SH-SY5Y neuroblastoma cells promoted cell survival by competing with p53 and TAp73 itself. Thus, our results suggest that the negative feedback regulation of TAp73 by its target ΔNp73 is a novel autoregulatory system for modulating cell survival and death, that is also functioning in neuroblastoma cells. © 2003 Published by Elsevier Science Ireland Ltd.

Weekly paclitaxel administration in the adjuvant therapy of primary breast cancer
Hiromasa Takahashi, Masato Takahashi, Kazunori Taguchi, Fumiaki Sasaki, Satoru Todo
Gan to kagaku ryoho. Cancer & chemotherapy, 30, 5, 653, 659, 2003年
日本語, 研究論文（学術雑誌）, PURPOSE: To investigate feasibility and toxicity of weekly paclitaxel administration in the adjuvant therapy of primary breast cancer. PATIENTS AND METHODS: Thirty-one patients with primary breast cancer received sustained weekly infusion of paclitaxel at a dose of 90 mg/body for 6 weeks followed by a 2-week interval. This weekly schedule was repeated twice. Leukocytes were checked immediately before every infusion and the dose was reduced to 80 mg/body when grade 1 neutropenia occurred. All patients were assessable for feasibility and toxicity. RESULTS: A total 349 weekly paclitaxel infusions were administrated to 31 patients (median, 12 infusions/patient). The median delivered dose-intensity was 88.0 mg/body/week (range 80 to 90). Therapy was well tolerated and completed in 27 patients. Four patients refused to continue the therapy because of nausea, fatigue, dizziness and weight gain. Grade 2 neutropenia occurred in 10 patients (32.3%), but grade 3 neutropenia did not occur. Grade 1 peripheral neuropathy occurred in 3 patients (9.7%). Grade 1 nausea occurred in 3 patients (9.7%). CONCLUSION: Weekly paclitaxel administration is well tolerated with a favorable toxicity profile in patients with primary breast cancer in the adjuvant setting. Weekly paclitaxel therapy can be performed safely in the outpatient setting.

Metastatic breast cancer of HER2 scored 2+ by IHC and HER2 gene amplification assayed by FISH has a good response to single agent therapy with trastuzumab: a case report.
Masato Takahashi, Ken-ichi Inoue, Ryoichi Goto, Motoshi Tamura, Kazunori Taguchi, Hiromasa Takahashi, Hiroaki Suzuki, Katsushige Katsushige, Masami Ogita
Breast cancer (Tokyo, Japan), 10, 2, 170, 4, 2003年, ［国内誌］
英語, 研究論文（学術雑誌）, We report that single agent therapy with trastuzumab had a significant effect on metastatic breast cancer, which was confirmed to be HER2 positive by Herceptest showing 2+staining, and gene amplification positively detected by FISH analysis. A 48-year-old woman underwent extended radical mastectomy (T2N0M0 stage II). Three years after the operation supraclavicular lymph node metastasis was noted. Bone scintigraphy showed metastases to the left ribs 5 years after operation. She was treated with chemo-endocrine therapy, but nonetheless could not bear the back pain caused by the bone metastases. Another chemotherapy course could not be permitted because of leukopenia. Immunohistochemistry (IHC) analysis with Herceptest showed 2+staining for HER2 and FISH analysis showed gene amplification of HER2. We started single agent therapy with trastuzumab and she subsequently had remarkably improved back pain. Physical examination and ultrasonography showed disappearance of the previous palpable supraclaviclar lymph nodes. Serum tumor markers were also reduced after the first administration of trastuzumab. The patient is currently alive, with no further progression of the lymph node or bone metastases.

乳腺に発生した巨大なfibrous tumorの1例
後藤 了一, 南 盛一, 高橋 将人, 田村 元, 荻田 征美, 山城 勝重
日本臨床外科学会雑誌, 63, 7, 1641, 1644, 日本臨床外科学会, 2002年07月
日本語, 49歳女.約7年前からの右乳房腫瘤が増大し,穿刺吸引細胞診で細胞は採取されず,core needle biopsyで膠原線維の増生を主体とする組織像であった.悪性所見なく,巨大腫瘍であり正常乳腺が見当たらず,葉状腫瘍の可能性を考慮して単純乳房切除術を施行した.摘出標本肉眼所見では右乳房全体を占める15cm大の白色均一な腫瘍であった.病理組織学的検査で線維芽細胞と周囲に膠原線維の増生を認め,核異型,分裂像などを認めず,fibrous tumorと診断された

Physical interaction of p73 with c-Myc and MM1, a c-Myc-binding protein, and modulation of the p73 function
Ken-Ichi Watanabe, Toshinori Ozaki, Takahito Nakagawa, Kou Miyazaki, Masato Takahashi, Mitsuchika Hosoda, Syunji Hayashi, Satoru Todo, Akira Nakagawara
Journal of Biological Chemistry, 277, 17, 15113, 15123, 2002年04月26日
英語, 研究論文（学術雑誌）, p73 shares high sequence homology with the tumor suppressor p53. Like p53, ectopic overexpression of p73 induces cell cycle arrest and/or apoptosis, and these biological activities are linked to its sequence-specific transactivation function. The COOH-terminal region of p73 is unique and has a function to modulate DNA-binding ability and transactivation activity. To identify and characterize cellular proteins that interact with the COOH-terminal region of p73α and regulate its activity, we employed a yeast-based two-hybrid screen with a human fetal brain cDNA library. We found MM1, a nuclear c-Myc-binding protein, was associated with p73α in both yeast two-hybrid and in vitro pull-down assays. In mammalian cells, MM1 co-immunoprecipitated with p73α, whereas p73β and tumor suppressor p53 did not interact with MM1. Overexpression of MM1 in p53-deficient osteosarcoma SAOS-2 cells enhanced the p73α-dependent transcription from the p53/p73-responsive Bax and PG13 promoters, whereas p73β- and p53-mediated transcriptional activation was unaffected in the presence of MM1. MM1 also stimulated the p73α-mediated growth suppression in SAOS-2 cells. More importantly, we found that c-Myc was physically associated with p73α and significantly impaired the transcriptional activity of p73α on Bax and p21waf1 promoters. Expression of MM1 strongly reduced the c-Myc-mediated inhibitory activity on p73α. These results suggest that MM1 may act as a molecular partner for p73 to prevent the c-Myc-mediated inhibitory effect on its activity.

Identification of the p33(ING1)-regulated genes that include cyclin B1 and proto-oncogene DEK by using cDNA microarray in a mouse mammary epithelial cell line NMuMG.
Masato Takahashi, Naohiko Seki, Toshinori Ozaki, Masaki Kato, Tomoko Kuno, Takahito Nakagawa, Ken-ichi Watanabe, Koh Miyazaki, Miki Ohira, Shunji Hayashi, Mitsuchika Hosoda, Hisashi Tokita, Hiroyuki Mizuguchi, Takao Hayakawa, Satoru Todo, Akira Nakagawara
Cancer research, 62, 8, 2203, 9, 2002年04月15日, ［査読有り］, ［国際誌］
英語, The candidate tumor suppressor p33(ING1) plays an important role in inducinggrowth arrest at G(0)-G(1) phase of the cell cycle and/or promoting apoptosis in cancerous cells. p33(ING1) is reported to act as a transcriptional cofactor by associating with tumor suppressor p53, HAT, or histone deacetyltransferase, suggesting that p33(ING1) is involved in chromatin-mediated transcriptional regulation. However, the molecular mechanism of p33(ING1)-mediated transcriptional regulation is poorly understood. Here we analyzed expression profiles in mouse mammary epithelial cells (NMuMG) by using a cDNA microarray consisting of 2304 mouse cDNAs after inducing transformation with antisense inhibitor of growth 1 (ING1) in retrovirus vector. The subsequent confirmation of the altered expression levels of the selected genes by semiquantitative reverse transcription-PCR demonstrated that overexpression of the antisense ING1 stimulated expression of 14 genes, which included cyclin B1, 12-O-tetradecanoylphorbol-13-acetate-inducible sequence 11, proto-oncogene DEK, and osteopontin, whereas we have detected transcriptional repression of 5 genes, including TPT1. In addition, adenovirus-mediated overexpression of ING1 in NMuMG cells resulted in down-regulation of cyclin B1, 12-O-tetradecanoylphorbol-13-acetate-inducible sequence 11, DEK, and osteopontin, whereas the levels of TPT1 expression were increased. The further analysis using p53(-/-) SAOS2 cells showed that the p33(ING1)-induced cyclin B1 down-regulation was p53 dependent. Thus, our cDNA microarray analysis suggested that p33(ING1) targets the multiple genes, including proto-oncogene DEK and cyclin B1, at least some of which are regulated in a p53-dependent manner, in the cells undergoing cell growth or apoptosis.

Autoinhibitory regulation of p73 by Delta Np73 to modulate cell survival and death through a p73-specific target element within the Delta Np73 promoter.
Takahito Nakagawa, Masato Takahashi, Toshinori Ozaki, Ken-ichi Watanabe Ki, Satoru Todo, Hiroyuki Mizuguchi, Takao Hayakawa, Akira Nakagawara
Molecular and cellular biology, 22, 8, 2575, 85, 2002年04月, ［査読有り］, ［国際誌］
英語, p73 is a p53-related tumor suppressor but is also induced by oncogene products such as E2F-1, raising a question as to whether p73 is a tumor suppressor gene or oncogene. Unlike p53, p73 has several variants, including Delta Np73, which lacks the NH(2)-terminal transactivation domain. Although, in developing neurons, Delta Np73 is expressed abundantly and seems to inhibit the proapoptotic function of p53, the role of p73 and Delta Np73 and their regulatory mechanism in cell growth and differentiation are poorly understood. Here we report that p73, but not p53, directly activates the transcription of endogenous Delta Np73 by binding to the p73-specific target element located at positions -76 to -57 within the Delta Np73 promoter region. The activation of Delta Np73 promoter by p63 was marginal. Delta Np73 was associated with p73 alpha, p73 beta, and p53, as demonstrated by immunoprecipitation assays, and inhibited their transactivation activities when we used reporters of Mdm2, Bax, or Delta Np73 itself in SAOS-2 cells. Furthermore, induction or overexpression of Delta Np73 promoted cell survival by competing with p53 and p73 itself. Thus, our results suggest that the negative feedback regulation of p73 by its target Delta Np73 is a novel autoregulatory system for modulating cell survival and death.

乳癌の再発後生存期間に影響する因子の検討
高橋 弘昌, 高橋 将人, 田口 和典, 佐々木 文章, 藤堂 省
日本臨床外科学会雑誌, 63, 12, 2875, 2882, Japan Surgical Association, 2002年
日本語, 乳癌の再発後生存期間に影響する因子,とくに全身療法の影響を検討した. 1960年から2001年末までに治療を行った再発乳癌229例を,再発時期により1981年以前に再発した群(前期群)と1982年以後に再発し化学内分泌療法を受けた群(後期群)の2群に分けて検討した.単変量解析では,再発時期,臨床病期,手術術式,組織学的リンパ節転移, DFI, 再発形式が予後因子であった.再発形式別では,局所再発,骨転移が肺,肝,脳転移よりも再発後生存期間が長期であった.再発時期別では,骨転移,肺転移,脳転移では,後期群で前期群よりも再発後生存期間が延長していた.多変量解析ではDFI, 再発形式,再発時期,組織学的リンパ節転移が独立した予後因子であった.今回の検討より骨転移,肺転移,脳転移症例では,化学内分泌療法のような全身療法が再発後生存期間を延長しえることが示唆された.

Endoscopic prediction of tumor depth of gastric carcinoma for assessing the indication of its limited resection
T Namieno, K Koito, T Hiigashi, M Takahashi, T Shimamura, K Yamashita, Y Kondo
ONCOLOGY REPORTS, 7, 1, 57, 61, PROFESSOR D A SPANDIDOS, 2000年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Limited surgery for an early gastric carcinoma is advocated, since certain carcinomas have no nodal involvement. However, the endoscopic accuracy of distinguishing each cancer-depth has not been detailed from the standpoint of limited surgery. We retrospectively reviewed a total of 2,628 patients to assess the diagnostic accuracy of their endoscopic infiltration-depth with the nature of the tumors. Endoscopic distinction of early from advanced carcinomas was satisfactory with a reliability of 86.5%, sensitivity of 87.1%, and specificity of 85.9%. In the 1,354 early gastric carcinomas the microscopic infiltration-depth was significantly related to macroscopic appearance, histologic differentiation and tumor size. Accompanying ulcer or scar significantly suggested that the carcinoma had spread vertically and horizontally. Macroscopically elevated and differentiated carcinomas without ulcer are usually limited to the mucosa, and undifferentiated and/or ulcer-positive carcinomas are more invasive than predicted by most present clinical standards. Endoscopically differential diagnosis of the infiltration-depth of gastric carcinomas is reliable, and the indication for limited surgery can be endoscopically determined in many individual patients.

Dominant-negative mutations of the tumor suppressor p53 relating to early onset of glioblastoma multiforme
Masumi Marutani, Hidefumi Tonoki, Mitsuhiro Tada, Masato Takahashi, Haruhiko Kashiwazaki, Yasuhiro Hida, Jun Ich Hamada, Masahiro Asaka, Tetsuya Moriuchi
Cancer Research, 59, 19, 4765, 4769, AMER ASSOC CANCER RESEARCH, 1999年10月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Previous experiments have suggested that some mutant forms of p53 are able to inactivate the endogenous wild-type p53 protein in a dominantnegative fashion. However, it remains unknown whether tumors with such dominant- negative (transdominant) p53 mutants have a biological significance that is different from that of recessive p53 mutants. In this study, we examined the dominant-negative potential of various p53 mutants using a yeast-based assay in which both wild-type and mutant p53 were efficiently expressed. We tested a total of 106 p53 mutants, which were identified in brain tumors, glioblastoma multiforme-derived cell lines, breast cancers, or premalignant lesions and squamous cell carcinomas of oral epithelium or were otherwise created by mutagenesis. In agreement with the previous studies, our results demonstrated that transdominant mutations affected amino acid residues that are essential for the stabilization of the DNA-binding surface in the p53 core domain and for the direct interaction of p53 with its DNA-binding sequence. Among 40 patients with sporadic glioblastomas, the average age at diagnosis was significantly younger in the patients with tumors harboring dominantnegative mutations (30.4 ± 14.7 years, n = 7) than it was in those with recessive mutations (55.2 ± 18.6 years, n = 9, P < 0.012) and in those without mutations (54.7 ± 17.1 years, n = 24, P < 0.003). Our data suggest that dominant-negative p53 mutants accelerate development and/or growth of glioblastoma anlagen.

Basic study on a hybrid artificial liver - Influence of warm ischemia of the surgical liver specimen on hepatocyte isolation and hepatic functions of cultured human hepatocytes　　　　　　　　　　　　　　　
M. Matsushita, M. Takahashi, H. Kon, H. Kamachi, K. Taguchi, M. Nishikawa, M. Koike, H. Noto, K. Sato, H. Matsue, N. Sato, Y. Nakajima, J. Uchino, E. Hashimura
Japanese Journal of Artificial Organs, 23, 2, 453, 458, 1994年
日本語, 研究論文（学術雑誌）, Human hepatocyte procurement from thirteen surgical liver specimens and functions in primary culture were evaluated for the future application on a hybrid artificial liver. The warm ischemia time of the surgical liver specimens (mean weight of 27.3 g) ranged 0-180 minutes. The viability and yield of isolated hepatocytes were the mean values of 88.6% and 10.9 x 106 cells/g liver, respectively. The gluconeogenesis and ureogensis of the cultured hepatocytes were maintained for ten days with values of 26.2-45.5 and 2.7-3.8 ng/μg DNA/min, respectively. Those hepatic functions did not show statistic correlation against the warm ischemia time of the liver specimens. It was concluded that high yield of viable human hepatocytes was effectively isolated from warm ischemia liver up to 180 minutes and isolated human hepatocytes in the primary culture revealed a high level of hepatic metabolic functions. Use of cultured hepatocyte obtained from warm ischemia liver was considered to be promising as a metabolic component of a hybrid artificial liver.

深層学習を用いた造影超音波による原発性乳癌の腋窩リンパ節転移診断能の検討　　　　　　　　　　　　　　　
押野 智博, 竹下 卓志, 守谷 結美, 加藤 扶美, 高橋 將人, 日本乳癌学会総会プログラム抄録集, 30回, PO5, 1, 2022年06月
(一社)日本乳癌学会, 日本語

臨床研究におけるエンドポイントとしてのHRQOLの意義 Health-related Quality of Lifeを主要評価目的とした第III相ランダム化比較試験RESQの概要とその意義　　　　　　　　　　　　　　　
柏原 康佑, 木川 雄一郎, 北田 正博, 大谷 彰一郎, 渡邉 純一郎, 岩谷 胤生, 吉波 哲大, 柏葉 匡寛, 下妻 晃二郎, 平 成人, 相原 智彦, 向井 博文, 高橋 將人, 日本乳癌学会総会プログラム抄録集, 30回, SY11, 3, 2022年06月
(一社)日本乳癌学会, 日本語

リンパ節転移陽性TNBCに対する抗PD-L1抗体の上乗せ効果が得られる機序についての検討　　　　　　　　　　　　　　　
富岡 伸元, 奥山 大, 畑中 佳奈子, 寺井 小百合, 太刀川 花恵, 前田 豪樹, 山本 貢, 渡邊 健一, 鈴木 宏明, 清水 亜衣, 畑中 豊, 高橋 將人, 日本乳癌学会総会プログラム抄録集, 29回, 18, 18, 2021年07月
(一社)日本乳癌学会, 日本語

Estimation of willingness-to-pay for breast cancer treatments through contingent valuation method in Japanese breast cancer patients (JCOG1709A); preliminary study findings
Tsuguo Iwatani, Fumikata Hara, Tadahiko Shien, Masato Takahashi, Norikazu Masuda, Hiroyuki Yasojima, Yasuaki Sagara, Tomonori Mizutani, Keita Sasaki, Kenichi Nakamura, Haruhiko Fukuda, Takaru Shiroiwa, Hiroji Iwata, CANCER RESEARCH, 81, 4, 2021年02月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

A randomized, open-label, phase III trial of pertuzumab re-treatment in HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab, and chemotherapy: The Japan Breast Cancer Research Group-M05 (PRECIOUS) study
Yutaka Yamamoto, Hiroji Iwata, Taira Naruto, Norikazu Masuda, Masato Takahashi, Tetsuhiro Yoshinami, Takayuki Ueno, Tatsuya Toyama, Takashi Yamanaka, Toshimi Takano, Masahiro Kashiwaba, Koichiro Tsugawa, Yoshie Hasegawa, Kenji Tamura, Hiroshi Tada, Fumikata Hara, Shigehira Saji, Satoshi Morita, Masakazu Toi, Shinji Ohno, CANCER RESEARCH, 81, 4, 2021年02月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

HER2陰性転移性乳癌患者に対する一次治療としてのニボルマブ+パクリタキセル+ベバシズマブ併用療法の有効性を評価する多施設第II相試験 WJOG9917B NEWBEAT試験(A multicenter Phase II study evaluating the efficacy of nivolumab plus paclitaxel plus bevacizumab triple-combination therapy as a first-line treatment in patients with HER2-negative metastatic breast cancer: WJOG9917B NEWBEAT trial)　　　　　　　　　　　　　　　
Ozaki Yukinori, Mukohara Toru, Tsurutani Junji, Takahashi Masato, Matsumoto Koji, Futamura Manabu, Masuda Norikazu, Kitano Shigehisa, Yoshimura Kenichi, Minami Hironobu, Takano Toshimi, 日本乳癌学会総会プログラム抄録集, 28回, 32, 32, 2020年10月
(一社)日本乳癌学会, 英語

タキサン起因性末梢神経障害と遺伝子多型に関する検討 ABROAD試験付随研究結果　　　　　　　　　　　　　　　
安部 優子, 平 成人, 原 文堅, 北田 正博, 高橋 將人, 木川 雄一郎, 加藤 弘明, 柏原 康佑, 相原 智彦, 向井 博文, 日本乳癌学会総会プログラム抄録集, 28回, 417, 417, 2020年10月
(一社)日本乳癌学会, 日本語

日本人乳癌患者が考える生命や健康に対する金銭的価値を検証する前向き観察研究 JCOG1709A プレ調査結果　　　　　　　　　　　　　　　
岩谷 胤生, 原 文堅, 枝園 忠彦, 高橋 將人, 増田 慎三, 相良 安昭, 佐々木 啓太, 白岩 健, 岩田 広治, 日本乳癌学会総会プログラム抄録集, 28回, 67, 67, 2020年10月
(一社)日本乳癌学会, 日本語

エリブリンの第3相臨床試験および製造販売後調査における効果予測因子の解析　　　　　　　　　　　　　　　
三好 康雄, 渡邉 純一郎, 吉村 祐太, 齋藤 健一, 村本 賢三, 阪田 幸則, 野本 研一, 井上 賢一, 向井 博文, 鶴谷 純司, 高橋 將人, 日本乳癌学会総会プログラム抄録集, 28回, 507, 507, 2020年10月
(一社)日本乳癌学会, 日本語

A cohort study to evaluate the efficacy and safety of postoperative adjuvant therapy in HER2-positive elderly breast cancer patients (RESPECT-cohort study)
Shinichi Baba, Masataka Sawaki, Yukari Uemura, Tsuyoshi Saito, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Naruto Taira, Hiroji Iwata, Tatsuya Toyama, Koichiro Tsugawa, Yasuo Ohashi, Hirofumi Mukai, CANCER RESEARCH, 80, 4, 2020年02月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

Estimation of willingness-to-pay for breast cancer treatments through contingent valuation method in Japanese breast cancer patients (JCOG1709A)
Tsuguo Iwatani, Fumikata Hara, Hiroji Iwata, Tadahiko Shien, Takashi Hojo, Yasuaki Sagara, Norikazu Masuda, Masato Takahashi, Shigehira Saji, Tomomi Fujisawa, Naoto Kondo, Akihiko Shimomura, CANCER RESEARCH, 80, 4, 2020年02月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

HEALTH-RELATED QUALITY OF LIFE IN 2ND-LINE ENDOCRINE THERAPY FOR PATIENTS WITH ACQUIRED ENDOCRINE-RESISTANT POSTMENOPAUSAL ER-POSITIVE, HER2-NEGATIVE METASTATIC BREAST CANCER: THE HORSE-BC STUDY
Yuichiro Kikawa, Kentaro Sakamaki, Tomomi Fujisawa, Kazuhiro Araki, Takayuki Iwamoto, Takafumi Sangai, Tadahiko Shien, Shintaro Takao, Reiki Nishimura, Masato Takahashi, Tatsuya Toyama, Tomohiko Aihara, Hirofumi Mukai, Naruto Taira, BREAST, 48, S72, S73, 2019年11月
CHURCHILL LIVINGSTONE, 英語, 研究発表ペーパー・要旨（国際会議）

Alpelisib (ALP) plus fulvestrant (FUL) in patients from Japan with advanced breast cancer: Subgroup analysis of SOLAR-1 trial
Hiroji Iwata, Toshinari Yamashita, Kenichi Inoue, Masato Takahashi, Norikazu Masuda, Teruo Yamauchi, Yutaka Yamamoto, Toshimi Takano, Naoki Niikura, Takahiro Nakayama, Seiki Takashima, Koji Matsumoto, Yasuaki Sagara, Takaaki Fujii, Toru Hattori, Risa Sekiguchi, Celine Wilke, ANNALS OF ONCOLOGY, 30, 80, 80, 2019年10月
ELSEVIER, 英語, 研究発表ペーパー・要旨（国際会議）

再発乳癌におけるepithelial-mesenchymal transition(EMT)マーカーに関する検討　　　　　　　　　　　　　　　
森谷 卓也, 大谷 彰一郎, 高橋 將人, 池田 雅彦, 渡邉 純一郎, 日本乳癌学会総会プログラム抄録集, 27回, 579, 579, 2019年07月
(一社)日本乳癌学会, 日本語

MONARCH 3 未治療HR+HER2-進行乳癌におけるabemaciclib第3相試験 日本人サブ解析　　　　　　　　　　　　　　　
高橋 將人, 戸井 雅和, 徳永 えり子, 山中 隆司, 青儀 健二郎, 鶴谷 純司, 清水 千佳子, 井上 晃一, 森 丈治, 坂口 佐知, 江夏 総太郎, Di Leo Angelo, Goetz Matthew P., 日本癌治療学会学術集会抄録集, 56回, O7, 1, 2018年10月
(一社)日本癌治療学会, 英語

BRCA12変異陽性乳がん患者に対する適切なマネージメント リスク低減乳房切除術の意義を含め　　　　　　　　　　　　　　　
阿多 亜里沙, 明石 定子, 井手 佳美, 吉田 敦, 澤木 正孝, 津川 浩一郎, 柳田 康弘, 川端 英孝, 山内 清明, 高橋 將人, 武井 寛幸, 菰池 佳史, 遠山 竜也, 指宿 睦子, 西村 誠一郎, 土井原 博義, 北田 正博, 三木 義男, 新井 正美, 横山 士郎, 中村 清吾, 日本外科学会雑誌, 119, 5, 598, 605, 2018年09月
(一社)日本外科学会, 日本語

BRCA変異陽性転移性乳癌に対するオラパリブ単独療法と化学療法を比較する第III相試験(OlympiAD)
岩田 広治, 増田 慎三, 山内 照夫, 中村 清吾, 徳永 えり子, 高橋 將人, 田村 研治, 雷 哲明, 金 昇晋, 六反田 奈和, 日本乳癌学会総会プログラム抄録集, 26回, 336, 336, 2018年05月
(一社)日本乳癌学会, 日本語

BRCA変異陽性転移性乳癌に対するオラパリブ単独療法と化学療法を比較する第III相試験(OlympiAD)HRQoLの評価
山内 照夫, 増田 慎三, 岩田 広治, 中村 清吾, 徳永 えり子, 高橋 將人, 田村 研治, 雷 哲明, 金 昇晋, 六反田 奈和, 日本乳癌学会総会プログラム抄録集, 26回, 339, 339, 2018年05月
(一社)日本乳癌学会, 日本語

Evaluation of trastuzumab without chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients: Randomized controlled trial (RESPECT).
Masataka Sawaki, Tsuyoshi Saito, Shinichi Baba, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Naruto Taira, Hiroji Iwata, Yukari Uemura, Yasuo Ohashi, Hirofumi Mukai, JOURNAL OF CLINICAL ONCOLOGY, 36, 15, 2018年05月
AMER SOC CLINICAL ONCOLOGY, 英語, 研究発表ペーパー・要旨（国際会議）

ER陽性HER2陰性再発・進行乳癌の治療戦略 HER2陰性進行・再発乳癌に対するベバシズマブとパクリタキセル併用療法の前向き観察研究(JBCRG-C05試験)　　　　　　　　　　　　　　　
唐 宇飛, 山本 豊, 山城 大泰, 近藤 直人, 中村 力也, 柏葉 匡寛, 高橋 將人, 津川 浩一郎, 石川 孝, 中山 貴寛, 大谷 彰一郎, 高野 利実, 藤澤 知巳, 遠山 竜也, 川口 英俊, 増野 浩二郎, 谷野 裕一, 森田 智視, 戸井 雅和, 大野 真司, 日本乳癌学会総会プログラム抄録集, 26回, 276, 276, 2018年05月
(一社)日本乳癌学会, 日本語

BRCA1/2変異陽性乳がん患者に対する適切なマネージメント リスク低減乳房切除術の意義を含め　　　　　　　　　　　　　　　
中村 清吾, 明石 定子, 井手 佳美, 吉田 敦, 澤木 正孝, 津川 浩一郎, 柳田 康弘, 川端 英孝, 山内 清明, 高橋 将人, 武井 寛幸, 菰池 佳史, 遠山 達也, 指宿 睦子, 西村 誠一郎, 土井原 博義, 北田 正博, 新井 正美, 横山 史郎, 三木 義男, 日本外科学会定期学術集会抄録集, 118回, 216, 216, 2018年04月
(一社)日本外科学会, 日本語

「それぞれの癌」難治性癌に対する治療戦略 乳腺 未治療ER+進行乳癌患者におけるpalbociclib第3相試験(PALOMA-2) 日本人subgroup解析　　　　　　　　　　　　　　　
向井 博文, 清水 千佳子, 増田 慎三, 大谷 彰一郎, 大野 真司, 高橋 將人, 山本 豊, 西村 令喜, 佐藤 信昭, 大住 省三, 岩田 広治, 森 優子, 橋垣 学, Lu Dongrui R, 戸井 雅和, 日本癌治療学会学術集会抄録集, 55回, WS13, 1, 2017年10月
(一社)日本癌治療学会, 日本語

BRCA陽性乳がんに対するPARP阻害薬 (特集 乳がんに対する新しい診断法や治療法)
高橋 將人, 腫瘍内科 = Clinical oncology, 20, 3, 199, 204, 2017年09月
科学評論社, 日本語

HER2陽性乳癌に対して術前化学療法が手術に及ぼす影響 Ki67 indexを用いた治療選択研究の外科付随研究　　　　　　　　　　　　　　　
穂積 康夫, 高橋 将人, 藤澤 知巳, 米山 公康, 大住 省三, 赤羽 弘充, 西村 令喜, 高島 勉, 相良 安昭, 井本 滋, 向井 博文, 日本乳癌学会総会プログラム抄録集, 25回, 260, 260, 2017年07月
(一社)日本乳癌学会, 日本語

当科におけるエベロリムスの使用経験
佐藤 雅子, 山本 貢, 富岡 伸元, 渡邊 健一, 高橋 將人, 江戸 美奈子, 秦 浩信, 笠原 里紗, 北海道外科雑誌, 61, 2, 211, 212, 2016年12月
北海道外科学会, 日本語

乳癌骨転移症例における薬剤関連性顎骨壊死(MRONJ)症例の検討
富岡 伸元, 渡邊 健一, 山本 貢, 佐藤 雅子, 高橋 將人, 秦 浩信, 笠原 里紗, 北海道外科雑誌, 61, 2, 220, 221, 2016年12月
北海道外科学会, 日本語

Safety and efficacy of eribulin and trastuzumab in anti-HER2 therapy pretreated patients with HER2-positive metastatic breast cancer: A Japanese multicenter phase 2 study (SBP-04 study)
T. Shien, M. Ikeda, S. Ohtani, F. Hara, M. Takahashi, H. Tuji, S. Yoshitomi, K. Matsuoka, Y. Ogasawara, N. Taira, H. Doihara, S. Ohsumi, ANNALS OF ONCOLOGY, 27, 2016年12月
OXFORD UNIV PRESS, 英語, 研究発表ペーパー・要旨（国際会議）

北海道がんセンターにおけるがん診療医科歯科前連携システム構築の取り組み　　　　　　　　　　　　　　　
秦 浩信, 加藤 秀則, 菊地 久美子, 江戸 美奈子, 吉川 和人, 國井 信彦, 今待 賢治, 鎌口 真由美, 渡邊 健一, 高橋 將人, 永森 聡, 近藤 啓史, 国立病院総合医学会講演抄録集, 70回, P4, 5, 2016年11月
国立病院総合医学会, 日本語

乳腺 その他 乳癌骨転移症例における薬剤関連性顎骨壊死(MRONJ)症例の検討　　　　　　　　　　　　　　　
富岡 伸元, 秦 浩信, 渡邊 健一, 山本 貢, 佐藤 雅子, 高橋 將人, 日本癌治療学会学術集会抄録集, 54回, WS20, 6, 2016年10月
(一社)日本癌治療学会, 日本語

癌に対するプレシジョンメディシン Ki-67 indexを用いたHER2陽性乳癌に対する治療選択研究　　　　　　　　　　　　　　　
向井 博文, 山口 雄, 高橋 將人, 穂積 康夫, 藤澤 知巳, 大住 省三, 赤羽 弘充, 西村 令喜, 高島 勉, 朴 英進, 相良 安昭, 遠山 竜也, 井本 滋, 水野 聡朗, 上村 夕香理, 日本癌治療学会学術集会抄録集, 54回, S8, 3, 2016年10月
(一社)日本癌治療学会, 日本語

PRECIOUS: A randomized, open-label phase III trial of pertuzumab retreatment in HER2-positive locally advanced/metastatic breast cancer patients who were previously treated with pertuzumab, trastuzumab, and chemotherapy.
Yutaka Yamamoto, Hiroji Iwata, Takayuki Ueno, Masahiro Kashiwaba, Naruto Taira, Masato Takahashi, Hiroshi Tada, Koichiro Tsugawa, Tatsuya Toyama, Naoki Niikura, Fumikata Hara, Tomomi Fujisawa, Tetsuhiro Yoshinami, Shigehira Saji, Toshimi Takano, Norikazu Masuda, Satoshi Morita, Masakazu Toi, Shinji Ohno, JOURNAL OF CLINICAL ONCOLOGY, 34, 15, 2016年05月
AMER SOC CLINICAL ONCOLOGY, 英語, 研究発表ペーパー・要旨（国際会議）

Prospective observational cohort study of bevacizumab combined with paclitaxel as the first-or second-line chemotherapy for locally advanced or metastatic breast cancer (Study JBCRG-C05: B-SHARE)
N. Kondo, Y. Yamamoto, H. Yamashiro, M. Kashiwaba, R. Nakamura, M. Takahashi, U. Toh, K. Tsugawa, K. Narui, K. Tamaki, T. Yoshinami, S. Ohtani, Y. Kai, T. Takano, Y. Yanagita, S. Morita, M. Toi, S. Ohno, EUROPEAN JOURNAL OF CANCER, 57, S92, S92, 2016年04月
ELSEVIER SCI LTD, 英語, 研究発表ペーパー・要旨（国際会議）

Prognostic value of aldehyde dehydrogenase 1 (ALDH1) and tumor infiltrating lymphocytes (TIL) to predict the late recurrence in ER positive, HER2 negative breast cancer
Y. Miyoshi, T. Shien, A. Ogiya, N. Ishida, K. Yamazaki, R. Horii, Y. Horimoto, N. Masuda, H. Yasojima, T. Inao, T. Osako, M. Takahashi, N. Tomioka, K. Hagio, Y. Endo, M. Hosoda, H. Yamashita, CANCER RESEARCH, 76, 2016年02月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

Anti-HER2 therapy for HER2-positive metastatic breast cancer: regimens and treatment outcomes
Kenichi Watanabe, Kanako Hagio, Motoi Baba, Mayuko Ikarashi, Masako Sato, Nobumoto Tomioka, Masato Takahashi, ANNALS OF ONCOLOGY, 26, 143, 143, 2015年11月
OXFORD UNIV PRESS, 英語, 研究発表ペーパー・要旨（国際会議）

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients (vol 20, pg 709, 2015)
Hiroyasu Yamshiro, Hiroji Iwata, Norikazu Masuda, Naohito Yamamoto, Reiki Nishimura, Shoichiro Ohtani, Nobuaki Sato, Masato Takahashi, Takako Kamio, Kosuke Yamazaki, Tsuyoshi Saito, Makoto Kato, Tecchuu Lee, Shinji Ohno, Katsumasa Kuroi, Toshimi Takano, Masahiro Takada, Shinji Yasuno, Satoshi Morita, Masakazu Toi, INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 20, 4, 723, 724, 2015年08月
SPRINGER JAPAN KK, 英語, その他

エリブリン隔週投与法の有効性と安全性の検討 JUST-STUDY　　　　　　　　　　　　　　　
渡邊 健一, 吉波 哲大, 原 文堅, 相良 安昭, 川口 英俊, 松並 展輝, 長谷川 善枝, 岩本 充彦, 四元 大輔, 高橋 將人, 水谷 麻紀子, 増田 慎三, 中山 貴寛, 大谷 彰一郎, 日本乳癌学会総会プログラム抄録集, 23回, 408, 408, 2015年07月
(一社)日本乳癌学会, 日本語

Low body mass index (BMI) is associated with poor survival in Japanese patients with early breast cancer; an exploratory analysis of prospective randomized phase Ill trials N-SAS BC02 and 03
Yoichi Naito, Yasuo Ohashi, Isao Yokota, Toru Watanabe, Hiroji Iwata, Shozo Ohsumi, Shinji Ohno, Yasuo Hozumi, Seiichiro Yamamoto, Masato Takahashi, Tomohiko Aihara, Hirofumi Mukai, CANCER RESEARCH, 75, 2015年05月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

Impact of BMI on survival and toxicity in early breast cancer: An exploratory analysis of prospective randomized phase III study N-SAS BC02 and 03.
Yoichi Naito, Yasuo Ohashi, Isao Yokota, Toru Watanabe, Hiroji Iwata, Shozo Ohsumi, Shinji Ohno, Yasuo Hozumi, Seiichiro Yamamoto, Masato Takahashi, Tomohiko Aihara, Hirofumi Mukai, JOURNAL OF CLINICAL ONCOLOGY, 33, 15, 2015年05月
AMER SOC CLINICAL ONCOLOGY, 英語, 研究発表ペーパー・要旨（国際会議）

乳癌外科治療の個別化に向けての取り組み 乳腺・内分泌 新しい乳がん局所療法としてのラジオ波焼灼療法(RFA)多施設共同研究　　　　　　　　　　　　　　　
木下 貴之, 山本 尚人, 高橋 将人, 土井原 博義, 藤澤 知巳, 和田 徳昭, 高橋 三奈, 大谷 彰一郎, 佐藤 信昭, 黒井 克昌, 麻賀 創太, 日本外科学会定期学術集会抄録集, 115回, PD, 7, 2015年04月
(一社)日本外科学会, 日本語

臨床と研究 乳癌再発診断における腫瘍マーカーNCC-ST-439の有用性に関する検討
市川 伸樹, 渡邊 健一, 上徳 ひろみ, 佐藤 雅子, 高橋 將人, 外科, 76, 4, 408, 412, 2014年04月
手術乳癌患者で、2005〜2006年に再発が確認された71例(27〜81歳、中央値54歳)において(二次癌を含む)、NCC-ST-439の感度および発見契機、他腫瘍マーカー上昇の有無、再発形式、ER/HER2発現との関係について検討した。また、2009年10月〜2010年9月の乳癌術後経過観察において、1回以上NCC-ST-439が測定された1826例について、2011年10月までの観察期間内での陽性的中率について検討した。NCC-ST-439の感度は35.2%で、CEAとCA15-3に対し大きな差を認めなかった。また、CEAまたはCA15-3いずれかの感度は62.0%とやや高めであったが、NCC-ST-439による感度の上乗せ効果は9.9%であった。NCC-ST-439上昇と再発確認部位の関係については骨、肝転移での上昇が有意に多い結果であった。ER陽性例、HER2陰性例での上昇が多く、新規上昇例の陽性的中率は32.3%とやや高く、NCC-ST-439単独陽性例に限ると、陽性的中率は20.7%であった。, (株)南江堂, 日本語

Randomized phase II study of preoperative docetaxel and cyclophosphamide-containing chemotherapy for luminal-type breast cancer
N. Sato, N. Masuda, K. Higaki, T. Morimoto, Y. Yanagita, M. Mizutani, S. Ohtani, K. Kaneko, T. Fujisawa, M. Takahashi, T. Kadoya, N. Matsunami, Y. Yamamoto, S. Ohno, T. Takano, S. Morita, S. Tanaka, M. Toi, CANCER RESEARCH, 73, 2013年12月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

Prevalence and differentiation of hereditary breast and ovarian cancer in Japan.
Seigo Nakamura, Takuji Iwase, Seiichiro Nishimura, Hideko Yamauchi, Tadashi Nomizu, Shozo Ohsumi, Masato Takahashi, Shinichi Baba, Tadao Shimizu, JOURNAL OF CLINICAL ONCOLOGY, 31, 15, 2013年05月
AMER SOC CLINICAL ONCOLOGY, 英語, 研究発表ペーパー・要旨（国際会議）

A prospective multicenter randomized phase II neo-adjuvant study of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) followed by docetaxel, cyclophosphamide and trastuzumab (TCH) versus TCH followed by FEC versus TCH alone, in patients (pts) with operable HER2 positive breast cancer: JBCRG-10 study
N. Masuda, N. Sato, K. Higaki, M. Kashiwaba, N. Matsunami, T. Takano, J. Yamamura, K. Kaneko, M. Takahashi, S. Ohno, T. Fujisawa, S. Tsuyuki, Y. Miyoshi, S. Ohtani, Y. Yamamoto, H. Bando, T. Onoda, H. Kawabata, S. Morita, T. Ueno, M. Toi, CANCER RESEARCH, 72, 2012年12月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

長軸法による超音波ガイド下腋窩静脈穿刺による中心静脈リザーバー留置術の検討
柴崎 晋, 市川 伸樹, 上徳 ひろみ, 佐藤 雅子, 渡邊 健一, 高橋 將人, 外科, 74, 9, 981, 985, 2012年09月
2010年7月〜2012年2月の間に女性乳癌患者89例(平均年齢57.6±11.6歳、右側47例、左側42例)に対して、超音波(US)ガイド下腋窩静脈穿刺法とX線透視を併用して中心静脈(CV)リザーバーを留置した。その結果、本法による穿刺成功率は98.9%、カテーテル挿入成功率は97.8%であり、平均穿刺回数は1.19±0.4回、挿入時間は38.1±12.9分であった。合併症では動脈誤穿刺を1例で認められたが血腫形成は認めず、気胸も血胸も起さなかった。また、ポート感染が2例で発生したが挿入時期や患者の全身状態に問題があったと考えられた。以上より、USガイド下腋窩静脈穿刺法によるCVリザーバー留置術は安全に施行できる手技と考えられた。, (株)南江堂, 日本語

迷入性縦隔内甲状腺腫の1例
大畑 多嘉宣, 細田 充主, 高橋 將人, 北海道外科雑誌, 57, 1, 40, 43, 2012年06月
北海道外科学会, 日本語

Radiofrequency ablation (RFA) of breast cancer: A multicenter retrospective analysis
Toshikazu Ito, Shoji Oura, Naohito Yamamoto, Shinji Nagamine, Masato Takahashi, Hirokazu Tanino, Noboru Yamamichi, Mitsuharu Earashi, Hiroyoshi Doihara, Shigeru Imoto, Shoshu Mitsuyama, Hiroshi Sonoo, Kohei Akazawa, JOURNAL OF CLINICAL ONCOLOGY, 30, 15, 2012年05月
AMER SOC CLINICAL ONCOLOGY, 英語, 研究発表ペーパー・要旨（国際会議）

2010年度日本乳癌学会班研究課題最終報告 「我が国における遺伝性乳癌・卵巣癌(BRCA陽性患者)及び未発症陽性者のデータベース構築及び対策に関する研究」　　　　　　　　　　　　　　　
中村 清吾, 高橋 將人, 戸崎 光宏, 中山 貴寛, 野水 整, 三木 義男, 村上 茂, 村上 好恵, 青木 大輔, 新井 正美, 有賀 智之, 岩瀬 拓士, 大住 省三, 繁永 礼奈, 清水 忠夫, 西村 誠一郎, 馬場 信一, 阪埜 浩司, 平沢 晃, 藤森 実, 森 美樹, 山内 英子, 四元 淳子, 日本乳癌学会総会プログラム抄録集, 20回, 232, 232, 2012年05月
(一社)日本乳癌学会, 日本語

Pattern of ipsilateral breast tumor recurrence after breast conservation therapy
R. Kinoshita, S. Shimizu, K. Tsuchiya, N. Kato, H. Shirato, H. Taguchi, M. Takahashi, H. Takahashi, Japanese Journal of Clinical Radiology, 56, 13, 1813, 1818, 2011年12月10日
Between 1988 and 2008, 489 patients received breast conservation therapy at Hokkaido University. Among them, we identified and analyzed 20 ipsilateral breast tumor recurrences.75% of recurrence was occurred in the same quadrant of the primary tumor. Twelve patients received mastectomy, seven patients received local tumor excision.17 of 20 patients are alive without disease. Salvage breast-conserving therapy may be feasible for certain condition., 金原出版, 日本語

乳房温存療法後局所再発症例の検討　　　　　　　　　　　　　　　
木下 留美子, 清水 伸一, 土屋 和彦, 加藤 徳雄, 田口 大志, 高橋 將人, 高橋 弘昌, 白土 博樹, 臨床放射線, 56, 13, 1813, 1818, 2011年12月
乳房温存術および温存乳房に対する術後放射線治療を施行した489例のうち、局所再発を認めた20例(中央値46歳)について報告した。手術は乳房扇状部分切除9例、乳房円状部分切除11例、リンパ節郭清17例で、化学療法を7例に、術後ホルモン療法を5例に行った。照射線量は45Gy/18frが10例、50Gy/20frが10例であった。病理学的分類はStage 0が6例、IAが8例、IIAが4例、IIBが1例、化学療法後のStage yIIAが1例であった。局所再発までの期間は8〜180ヵ月(中央値40ヵ月)で、15例は初発時と同一領域、5例は異なる領域に認め、照射野内18例、照射野辺縁2例であった。再発に対する治療は12例で乳房切除術を施行し、うち1例は手術前後に化学療法を行った。7例は腫瘤切除を行い、うち5例は術後放射線照射を行った。手術を拒否した1例でホルモン療法を行った。再発後最長193ヵ月の経過観察で、無病生存が17例、担癌生存3例であった。, 金原出版(株), 日本語

VW-1-7 乳癌ラジオ波治療の実際とその課題(VW1 ビデオワークショップ(1)乳癌に対するOncoplastic Surgery : 根治性と整容性を追究した乳癌手術の実際,第111回日本外科学会定期学術集会)
高橋 將人, 細田 充主, 高橋 弘昌, 柴崎 晋, 上徳 ひろみ, 渡邊 健一, 藤堂 省, 日本外科学会雑誌, 112, 1, 303, 303, 2011年05月25日
一般社団法人日本外科学会, 日本語

乳癌のsubtypeからみた乳癌術後補助化学療法の考え方　　　　　　　　　　　　　　　
佐伯 俊昭, 伊藤 良則, 高橋 將人, 中山 貴寛, 山本 豊, 乳癌の臨床, 26, 1, 58, 65, 2011年04月
(株)篠原出版新社, 日本語

乳房温存療法後局所再発症例の検討　　　　　　　　　　　　　　　
木下 留美子, 清水 伸一, 土屋 和彦, 加藤 徳雄, 田口 大志, 高橋 将人, 高橋 弘昌, 白土 博樹, 日本医学放射線学会秋季臨床大会抄録集, 46回, S506, S506, 2010年08月
(公社)日本医学放射線学会, 日本語

VD-011-3 乳癌RFA治療 : 安全な治療適応決定のために(乳腺,一般ビデオ,第110回日本外科学会定期学術集会)
高橋 将人, 細田 充主, 高橋 弘昌, 松野 吉宏, 藤堂 省, 日本外科学会雑誌, 111, 2, 281, 281, 2010年03月05日
一般社団法人日本外科学会, 日本語

Evidence based Case Management(EB-CM)in Breast Cancer エビデンスに基づくケースマネジメント 閉経後乳癌の場合　　　　　　　　　　　　　　　
渡辺 亨, 相原 智彦, 相良 安昭, 高橋 將人, 名郷 直樹, 向井 博文, 乳癌の臨床, 25, 1, 65, 75, 2010年02月
(株)篠原出版新社, 日本語

7.小児甲状腺びまん性硬化型乳頭癌の2例(第35回北海道小児がん研究会)
小野 仁, 細田 充主, 高橋 將人, 高橋 弘昌, 藤堂 省, 岡田 忠雄, 佐々木 文章, 小児がん : 小児悪性腫瘍研究会記録, 47, 2, 350, 350, 2010年
がんの子供を守る会, 日本語

乳房温存手術後接線照射における被照射腋窩リンパ節領域の検討　　　　　　　　　　　　　　　
田口 大志, 清水 伸一, 木下 留美子, 白土 博樹, 高橋 弘昌, 高橋 將人, 細田 充主, 藤堂 省, 北海道外科雑誌, 54, 2, 188, 188, 2009年12月
北海道外科学会, 日本語

アレイCGHを用いた肝細胞癌の予後に関するゲノム異常領域の検討 既存の臨床病理学的因子との比較(Analysis of genomic abnormaity concerning with prognosis of hepatocellular carcinoma by array CGH)　　　　　　　　　　　　　　　
中西 一彰, 森田 桂子, 富岡 伸元, 神山 俊哉, 横尾 英樹, 高橋 将人, 尾崎 倫孝, 平野 隆, 藤堂 省, 日本癌学会総会記事, 68回, 313, 313, 2009年08月
日本癌学会, 英語

HP-046-2 高感度アレイCGHを用いた肝細胞癌の生物学的悪性度および予後に関するゲノム異常領域の検討(肝臓(肝がん基礎研究1),ハイブリッドポスター,第109回日本外科学会定期学術集会)
中西 一彰, 森田 佳子, 多田 光宏, 富岡 伸元, 神山 俊哉, 横尾 英樹, 高橋 将人, 尾崎 倫孝, 松下 通明, 藤堂 省, 平野 隆, 日本外科学会雑誌, 110, 2, 473, 473, 2009年02月25日
一般社団法人日本外科学会, 日本語

HP-228-3 ステレオガイドマンモトーム生検442症例の検討(乳がん(画像診断2),ハイブリッドポスター,第109回日本外科学会定期学術集会)
高橋 將人, 細田 充主, 高橋 弘昌, 藤堂 省, 日本外科学会雑誌, 110, 2, 770, 770, 2009年02月25日
一般社団法人日本外科学会, 日本語

乳腺mucocele-like tumorの2例
坂谷 慈, 長津 明久, 蔵谷 大輔, 細田 充主, 高橋 将人, 高橋 弘昌, 藤堂 省, 北海道外科雑誌, 53, 1, 111, 111, 2008年06月
北海道外科学会, 日本語

DP-110-3 早期乳癌に対するラジオ波熱凝固療法(RFA)(第108回日本外科学会定期学術集会)
高橋 將人, 細田 充主, 高橋 弘昌, 伊藤 智雄, 藤堂 省, 日本外科学会雑誌, 109, 2, 564, 564, 2008年04月25日
一般社団法人日本外科学会, 日本語

扁平上皮化生を伴った橋本病の1例　　　　　　　　　　　　　　　
宮城 久之, 中木村 繁, 細田 充生, 高橋 將人, 高橋 弘昌, 伊藤 智雄, 藤堂 省, 日本臨床外科学会雑誌, 69, 3, 718, 718, 2008年03月
日本臨床外科学会, 日本語

無痛性甲状腺炎を契機に発見された甲状腺被包型乳頭癌の1例
島田 慎吾, 細田 充主, 高橋 將人, 高橋 弘昌, 伊藤 智雄, 藤堂 省, 北海道外科雑誌, 52, 2, 148, 152, 2007年12月, ［査読有り］
症例は63歳の男性。健康診断で体重減少と甲状腺機能亢進を指摘され前医を受診。甲状腺左葉上極に直径1.7cmの境界不明瞭・内部不均一な腫瘤が認められ穿刺吸引細胞診で甲状腺乳頭癌と診断された。また左葉下極にも、直径1.3cmの境界明瞭・内部均一な充実性腫瘤が認められ、画像的には良性結節が示唆された。このため、甲状腺左葉・峡部切除施行した。病理組織上、左葉上極の腫瘤は被膜を有さない甲状腺乳頭癌、左葉下極の腫瘤は被包型乳頭癌の診断で、甲状腺機能亢進は血液検査所見と合わせて無痛性甲状腺炎のためと考えられた。甲状腺被包型乳頭癌は比較的まれであり、画像診断上は濾胞腺腫などの良性結節と鑑別が困難である。以上を踏まえ、良性結節が示唆されても悪性を否定しきれないとき、特にその鑑別によっては術式が変わる可能性があるときは本症を疑って積極的に細胞診や術中迅速病理診断などを施行していくべきであると考えられた。(著者抄録), 北海道外科学会, 日本語

緊急手術を要した巨大乳腺扁平上皮癌の1例
渡辺 正明, 細田 充主, 高橋 將人, 北海道外科雑誌, 52, 1, 32, 36, 2007年06月
北海道外科学会, 日本語

DP-015-3 早期乳癌に対するラジオ波熱凝固療法(RFA)の有用性を確認するための臨床研究(第107回日本外科学会定期学術集会)
高橋 將人, 細田 充主, 高橋 弘昌, 伊藤 智雄, 藤堂 省, 日本外科学会雑誌, 108, 2, 362, 362, 2007年03月10日
一般社団法人日本外科学会, 日本語

24年間の経過をたどり巨大嚢胞を形成した甲状腺乳頭癌の1例
野口 卓郎, 高橋 弘昌, 高橋 将人, 細田 充主, 佐々木 彩実, 藤堂 省, 日本臨床外科学会雑誌 = The journal of the Japan Surgical Association, 68, 1, 27, 30, 2007年01月25日
日本語

頚部リンパ節転移で発見された甲状腺オカルト癌の1例
寺崎 康展, 細田 充主, 高橋 將人, 北海道外科雑誌, 51, 2, 30, 34, 2006年12月
北海道外科学会, 日本語

N-glycans correlate 5-FU resistance in colon 26 and derived cell lines
Jun Hamaguchi, Hiroaki Nakagawa, Masato Takahashi, Takeaki Kudo, Naoya Kamiyama, Bailong Sun, Yuji Sato, Kisaburo Deguchi, Satoru Todo, Shin-Ichiro Nishimura, GLYCOBIOLOGY, 16, 11, 1151, 1151, 2006年11月
OXFORD UNIV PRESS INC, 英語, 研究発表ペーパー・要旨（国際会議）

Alterations in N-glycans seen in drug-resistant human hepatocellular carcinoma
Takeaki Kudo, Hiroaki Nakagawa, Masato Takahashi, Jun Hamaguchi, Naoya Kamiyama, Hideki Yokoo, Kazuaki Nakanishi, Takahito Nakagawa, Toshiya Kamiyama, Kisaburo Deguchi, Satoru Todo, Shin-Ichiro Nishimura, GLYCOBIOLOGY, 16, 11, 1151, 1151, 2006年11月
OXFORD UNIV PRESS INC, 英語, 研究発表ペーパー・要旨（国際会議）

抗癌剤耐性ヒト肝癌細胞株におけるN-結合型糖鎖の構造変化　　　　　　　　　　　　　　　
工藤 岳秋, 中川 裕章, 高橋 將人, 神山 直也, 濱口 純, 横尾 英樹, 中西 一彰, 中川 隆公, 尾崎 倫孝, 神山 俊哉, 出口 喜三郎, 西村 紳一郎, 藤堂 省, 日本癌学会総会記事, 65回, 100, 100, 2006年09月
日本癌学会, 日本語

大腸癌手術症例における定量的RT‐PCR法による骨髄微小転移検索
前田好章, 高橋将人, 本間重紀, 正村裕樹, 近藤正男, 佐藤裕二, 藤堂省, 日本大腸こう門病学会雑誌, 58, 5, 275, 275, 2005年05月
(一社)日本大腸肛門病学会, 日本語

乳腺葉状腫瘍の3例-特に診断所見の検討について（共著）
藤好 真人, 高橋 將人, 田口 和典, 高橋 弘昌, 伊藤 智雄, 藤堂 省, 日本臨床外科学会雑誌, 65(8):2077-2082, 8, 2077, 2082, 2004年
葉状腫瘍は線維上皮性腫瘍であり,その増殖性の違いから良性,境界型,悪性に分類される.病型分類は治療方針決定において重要であるが,その術前診断は困難である.
われわれは1990年より2003年9月末までに乳腺葉状腫瘍を3例経験しており,病型は2例が悪性, 1例が良性であった.術前画像診断ではMMGとUSで病型診断は困難であり, Dynamic MRIのtime intensity curveでは,悪性例で漸増型,良性例で急増型を示し,通常の浸潤性乳管癌の増強パターンとは一致しなかった.悪性例の1例では術前にマンモトーム生検にて病型分類が可能であった.手術は悪性例2例には単純乳房切除術を施行し,良性例には腫瘍摘出術のみを施行した.免疫染色では, Ki-67およびp53が,良性例に比し,悪性例において,多数の細胞で陽性であり,病型分類に有用であった. CEAは3例とも陽性であった.
術後は補助療法を行わず経過観察をしているが現在まで再発を認めていない., Japan Surgical Association, 日本語

乳癌におけるPEA3/E1AF発現の意義 HER2発現との関連性
田口 和典, 高橋 将人, 秦 浩信, 進藤 正信, 高橋 弘昌, 佐々木 文章, 吉田 幸一, 藤堂 省, 日本外科学会雑誌, 104, 臨増, 703, 703, 2003年04月
(一社)日本外科学会, 日本語

一卵性双生児に同時期に発症した甲状腺乳頭癌症例（共著）
下國 達志, 高橋 将人, 田口 和典, 高橋 弘昌, 佐々木 文章, 藤堂 省, 日本臨床外科学会雑誌, 64(6)1331-1336, 6, 1331, 1336, 2003年
2003 June, Japan Surgical Association, 日本語

Weekly Trastuzumab-Paclitaxel療法が著効を示した乳房温存手術後炎症性乳癌型皮膚再発の１例（共著）
植木 伸也, 高橋 弘昌, 高橋 将人, 田口 和典, 伊藤 智雄, 藤堂 省, 日本臨床外科学会雑誌, 64(3):598-602, 3, 598, 602, 2003年
2003 March, Japan Surgical Association, 日本語

p73αカルボキシル末端領域結合蛋白質の機能解析
渡邊 健一, 尾崎 俊文, 中川 隆公, 高橋 将人, 林 俊治, 細田 充主, 宮崎 耕, 中川原 章, 藤堂 省, 日本外科学会雑誌, 103, 188, 188, 2002年03月10日
一般社団法人日本外科学会, 日本語

Functional characterization of naturally occurring mutants (P405R and P425L) of p73α and p73β found in neuroblastoma and lung cancer
Masahiko Naka, Toshinori Ozaki, Naoyuki Takada, Masato Takahashi, Tomotane Shishikura, Shigeru Sakiyama, Mitsuhiro Tada, Satoru Todo, Akira Nakagawara, Oncogene, 20, 27, 3568, 3572, 2001年06月14日
The novel candidate tumor suppressor p73, a structural and functional homolog of p53, activates various p53 responsive promoters and induces tumor cell apoptosis. Although p73 is infrequently mutated in human cancers, we have previously found two types of p73 mutation with amino acid substitution (P405R and P425L) in primary neuroblastoma and lung cancer. Here we report generations of the p73 mutants with either P405R or P425L substitution and functional analysis of these naturally occurring mutants. Indirect immunofluorescence staining revealed that nuclear accumulation of p73α or p73β was not affected by these mutations. The P425L substitution reduced the ability of p73α to transactivate various p53 responsive promoters (p21Waf1, Mdm2, and Bax). Moreover, this down-regulation was correlated with the reduced capability of p73α(P425L) to suppress cell growth in p53-deficient SAOS-2 cells. In contrast, p73β(P425L) was as effective as wild-type p73β in transactivation and growth inhibition. On the other hand, the P405R substitution had no significant effect on both the transcriptional activity and the growth-suppressive ability of p73α or p73β. These results suggested that, at least, one of the naturally occurring p73 mutants, p73α(P425L), was a functionally defective mutant of p73., 英語

Survival-associated histologic spreading modes of operable intrahepatic, peripheral-type cholangiocarcinomas.
T Namieno, K Koito, M Takahashi, Y Une, K Yamashita, T Shimamura, World journal of surgery, 25, 5, 572, 7, 2001年05月, ［国際誌］
We investigated survival-associated histologic and metastatic spreading modes of intrahepatic, peripheral-type cholangiocarcinomas resected to contribute to surgical control of the tumor. Previous results have been mostly obtained from autopsies, reflecting the terminal status of patients. We clinicopathologically reviewed the resected 20 intrahepatic, peripheral-type cholangiocarcinomas and investigated the histologic findings of resected specimens and medical records to assess spreading modes along with patients' survival. The carcinoma cells superficially spread in the ductal epithelium in 75%, infiltrated along Glisson's system and migrated multidirectionally in 100%, and permeated the vascular network in 80%. The cumulative survival rate significantly related to vascular permeation, extrahepatic metastases, and lymphatic, neural, and nodal involvement but not to ductal spread, tumor size (cutoff size 5 cm), or intrahepatic metastases by the log-rank test, The patients with lymphatic, neural, or nodal involvement died early after surgery, Practically, only vascular permeation was identified as a significant independent variable for survival using multivariate analysis. Peripheral cholangio-carcinomas spread mainly in three modes: ductal spread, infiltration along Glisson's system, and vascular permeation. In the practically operable cases, vascular permeation is closely related to survival, and intrahepatic metastasis may be surgically controlled to some degree., SPRINGER-VERLAG, 英語

乳腺外科　　　　　　　　　　　　　　　
北海道大学病院
2022年01月 - 現在

1994年04月 - 現在
日本乳癌学会　　　　　　　　　　　　　　　

1991年06月 - 現在
日本外科学会　　　　　　　　　　　　　　　

乳癌の悪性度診断　　　　　　　　　　　　　　　
その他の研究制度
競争的資金