Faculty Profiles - SHIEN Tadahiko

Papers - SHIEN Tadahiko

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Impact of breast surgery in de novo stage IV breast cancer

Tadahiko Shien

TRANSLATIONAL CANCER RESEARCH 8 S118 - S119 2019.3

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. Reviewed International journal

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 2019.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

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.

DOI： 10.3892/ol.2018.9853

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A marked goiter involved in Marine-Lenhart syndrome.

Kosuke Oka, Miho Yasuda, Tadahiko Shien, Fumio Otsuka

Journal of general and family medicine 20 ( 1 ) 37 - 38 2019.1

The efficacy and feasibility of dose-dense sequential chemotherapy for Japanese patients with breast cancer. Reviewed

Daisuke Takabatake, Yukiko Kajiwara, Shoichiro Ohtani, Yoko Itano, Mari Yamamoto, Shinichiro Kubo, Masahiko Ikeda, Mina Takahashi, Fumikata Hara, Kenjiro Aogi, Shozo Ohsumi, Yutaka Ogasawara, Yoshitaka Nishiyama, Hajime Hikino, Kinya Matsuoka, Yuko Takahashi, Tadahiko Shien, Naruto Taira, Hiroyoshi Doihara

Breast cancer (Tokyo, Japan) 25 ( 6 ) 717 - 722 2018.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Tokyo

BACKGROUND: Perioperative dose-dense chemotherapy (DDCT) with granulocyte-colony stimulating factor (G-CSF) prophylaxis is a standard treatment for patients with high-risk breast cancer. The approval of this approach in Japan led to the widespread adoption of DDCT, despite limited efficacy and safety data among Japanese patients. We evaluated the efficacy and safety of neoadjuvant DDCT for Japanese patients with breast cancer. METHODS: This prospective, multicenter, phase II study evaluated 52 women with operable human epidermal growth factor receptor 2-negative breast cancer and axillary lymph node metastasis. Neoadjuvant DDCT (adriamycin plus cyclophosphamide or epirubicin plus cyclophosphamide followed by paclitaxel) was administrated every 2 weeks with G-CSF support. The study endpoints were the rates of pathological complete response (pCR), febrile neutropenia, treatment completion, toxicities, and the relative dose intensity (RDI). RESULTS: The pCR rate was 21.9% (9/41) and the triple-negative (TN) subtype was significantly associated with a high pCR rate (triple-negative: 53.3% vs. luminal A: 7.7% and luminal B: 0%; p = 0.003). The treatment completion rate was 80.8% (42/52) and the average RDI was 98.9%. Most adverse events were manageable and tolerable. Six patients (11.5%) developed febrile neutropenia. Grade 3-4 adverse events were slightly more common among older patients (57%) with a low protocol completion rate (≥ 65 years: 42.9% vs. <65 years: 86.7%, p = 0.0062). CONCLUSION: The pCR rate for DDCT was similar to that of standard chemotherapy, although it was remarkably effective for the TN subtype. DDCT may be feasible for Japanese patients with breast cancer although caution is needed for older patients.

DOI： 10.1007/s12282-018-0877-1

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Journal Watch: our experts look back and highlight some of the key breast cancer research articles from 2018

Elaine M. Walsh, Tadahiko Shien, Cesar A. Santa-Maria

BREAST CANCER MANAGEMENT 7 ( 4 ) 2018.11

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Reviewed International journal

Hiroki Sato, Hiromasa Yamamoto, Masakiyo Sakaguchi, Kazuhiko Shien, Shuta Tomida, Tadahiko Shien, Hirokuni Ikeda, Minami Hatono, Hidejiro Torigoe, Kei Namba, Takahiro Yoshioka, Eisuke Kurihara, Yusuke Ogoshi, Yuta Takahashi, Junichi Soh, Shinichi Toyooka

Cancer science 109 ( 10 ) 3183 - 3196 2018.10

Language：English Publishing type：Research paper (scientific journal)

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

DOI： 10.1111/cas.13763

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Marine-Lenhart症候群の一例

西村碧フィリーズ, 河内麻里子, 枝園忠彦, 鈴木陽子, 梶原友紀子, 鳩野みなみ, 突沖貴宏, 河田健吾, 高橋侑子, 岩本高行, 池田宏国, 平成人, 土井原博義

日本臨床外科学会雑誌 79 ( 増刊 ) 842 - 842 2018.10

Current status of postmastectomy radiation therapy in T1-2 breast cancer with limited positive lymph nodes in Japan: Japan Clinical Oncology Group Survey. Reviewed

Shinsuke Sasada, Tadahiko Shien, Hiroji Iwata

Breast cancer (Tokyo, Japan) 25 ( 5 ) 626 - 627 2018.9

Thyroid follicular carcinoma in a teenager: A case report. Reviewed

Kosuke Oka, Tadahiko Shien, Fumio Otsuka

Journal of general and family medicine 19 ( 5 ) 170 - 172 2018.9

Hormonal Therapy Resistant Estrogen-receptor Positive Metastatic Breast Cancer Cohort (HORSE-BC) Study : Current Status of Treatment Selection in Japan. Reviewed

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 2018.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/56172

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Current Multidisciplinary Approach to Fertility Preservation for Breast Cancer Patients. Reviewed

Yuko Takahashi, Tadahiko Shien, Ai Sakamoto, Yuko Tsuyumu, Ryo Yoshioka, Maya Uno, Minami Hatono, Mariko Kochi, Kengo Kawada, Takahiro Tsukioki, Takayuki Iwamoto, Hirokuni Ikeda, Naruto Taira, Junji Matsuoka, Mikiya Nakatsuka, Hiroyoshi Doihara

Acta medica Okayama 72 ( 2 ) 137 - 142 2018.4

Language：English Publishing type：Research paper (scientific journal)

Adverse effects on fertility are a significant problem for premenopausal breast cancer patients. Since April 2009, we have been referring young patients for fertility counseling provided by a multidisciplinary team. Here we evaluated the efficacy and safety of our current fertility preservation approach. We retrospectively analyzed the cases of 277 patients < 45 years old at diagnosis, which was made between 2009 and 2016. Seventy-two (26%) patients received fertility counseling. Seventeen (6%) of the 277 patients decided to preserve their fertility before starting adjuvant systemic therapy. Six (35%) patients underwent oocyte cryopreservation, and 11 (65%) married patients opted for embryo cryopreservation. There were no pregnancies among the patients undergoing oocyte cryopreservation, whereas 3 (27%) of the patients who opted for embryo cryopreservation became pregnant. Two (12%) patients stopped endocrine therapy after 2 years in an effort to become pregnant, but their breast cancers recurred. Though the problem of fertility loss for breast cancer patients is important and we should assess the infertility risk for all patients, we should also consider the prognosis. In June 2016, we launched a prospective multicenter cohort study to evaluate the efficacy and safety of fertility preservation in greater detail.

DOI： 10.18926/AMO/55854

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Open-label Phase II study of everolimus plus endocrine therapy in postmenopausal women with ER-positive and HER2-negative metastatic breast cancer (Chloe trial)

Tatsunori Shimoi, Akihiko Shimomura, Tadahiko Shien, Yukari Uemura, Hiroaki Kato, Masahiro Kitada, Tatsuya Toyama, Tomohiko Aihara, Hirofumi Mukai

Open Access Journal of Clinical Trials 10 13 - 18 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：DOVE MEDICAL PRESS LTD

? 2018 Shimoi et al. Background: This is a randomized, multicenter, open-label, Phase II study designed to evaluate the efficacy of everolimus added to continuous aromatase inhibitor (AI) administration in patients who had maintained stable disease or a better response for at least 5 months. Patients and methods: Patients will be randomized to everolimus and standard therapy groups (1:1 ratio). In the everolimus group, patients will receive everolimus in addition to the AI agent. The standard therapy group will continue AI alone treatment. The primary endpoint is progression-free survival. Target accrual is 130 patients with a two-sided type I error rate of 10% and 80% power to detect 35% risk reduction. Conclusion: The Chloe trial will provide important information about the efficacy and safety of adding everolimus to AI in patients with estrogen receptor-positive and human epidermal growth factor 2-negative metastatic breast cancer.

DOI： 10.2147/OAJCT.S155706

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Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study. Reviewed International journal

Tadahiko Shien, Hiroyoshi Doihara, Nobuaki Sato, Keisei Anan, Kansei Komaki, Keisuke Miyauchi, Yasuhiro Yanagita, Tomomi Fujisawa, Shoshu Mitsuyama, Chizuko Kanbayashi, Mikihiro Kusama, Morihiko Kimura, Hiromitsu Jinno, Muneaki Sano, Tadashi Ikeda

Cancer chemotherapy and pharmacology 81 ( 2 ) 269 - 275 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Verlag

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1-2, node metastases (n = 0-3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.

DOI： 10.1007/s00280-017-3491-6

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Tumour-infiltrating lymphocytes (TILs)-related genomic signature predicts chemotherapy response in breast cancer. Reviewed International journal

Mariko Kochi, Takayuki Iwamoto, Naoki Niikura, Giampaolo Bianchini, Shinobu Masuda, Taeko Mizoo, Tomohiro Nogami, Tadahiko Shien, Takayuki Motoki, Naruto Taira, Yutaka Tokuda, Hiroyoshi Doihara, Junji Matsuoka, Toshiyoshi Fujiwara

Breast cancer research and treatment 167 ( 1 ) 39 - 47 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer New York LLC

PURPOSE: The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes. METHODS: We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies. RESULTS: Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P < 0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30-3.14, P = 0.025). CONCLUSIONS: TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes.

DOI： 10.1007/s10549-017-4502-3

Durable complete response in HER2-positive breast cancer: a multicenter retrospective analysis. International journal

Naoki Niikura, Akihiko Shimomura, Yumi Fukatsu, Masataka Sawaki, Rin Ogiya, Hiroyuki Yasojima, Tomomi Fujisawa, Mitsugu Yamamoto, Michiko Tsuneizumi, Akira Kitani, Junichiro Watanabe, Akira Matsui, Yuko Takahashi, Seiki Takashima, Tadatoshi Shien, Kenji Tamura, Shigehira Saji, Norikazu Masuda, Yutaka Tokuda, Hhiroji Iwata

Breast cancer research and treatment 167 ( 1 ) 81 - 87 2018.1

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Though advanced and metastatic epidermal growth factor receptor 2 (HER2)-positive disease is not curable, a small proportion of patients with HER2-positive metastatic breast cancer remain in prolonged complete remission with anti-HER2 treatment. We hypothesized that some cases of HER2-positive metastatic breast cancer may be curable. In this large, multicenter retrospective study, we aimed to assess the long-term outcomes for patients with a durable response to trastuzumab. METHODS: We retrospectively evaluated the data of patients diagnosed with HER2-positive metastatic breast cancer who received trastuzumab for more than 2 years as the first-line treatment. Patients diagnosed between April 1, 2001 and December 31, 2014 at 19 institutions in Japan were included in the analysis. From 124 potential subjects, 16 were excluded and 108 were evaluated. RESULTS: The median follow-up length was 7.7 years. Disease progression occurred in 44/108 (40.7%) patients and 13/108 (12%) patients died. The median progression-free survival was 11.2 years, and as more than 80% of patients were alive 10 years after metastatic breast cancer diagnosis. Of the 108 patients, 57 achieved a clinical complete response. Trastuzumab therapy was interrupted for 27 (47.4%) of these patients (based on the doctor's recommendation for 19 patients, owing to adverse events for 4 patients, owing to unknown reasons for 3 patients, and at the request of 1 patient). Disease progression occurred in 4 of the 27 patients after the interruption of trastuzumab treatment. The median duration of trastuzumab therapy for all 27 patients was 5.1 years (0.9-9.3 years). CONCLUSION: We found that some patients showed no evidence of disease after the interruption of trastuzumab therapy. Discontinuation of maintenance trastuzumab in this patient population after a limited time should be explored cautiously while awaiting a global collaborative effort for a randomized trial.

DOI： 10.1007/s10549-017-4489-9

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The eligibility of primary tumor resection for de novo stage IV breast cancer patients Reviewed

Tadahiko Shien

Translational Cancer Research 7 S604 - S607 2018

The sexual lives of breast cancer patients: Coping with changes associated with treatment

Ayumi Yoshikawa, Shinya Saito, Makiko Kondo, Yuko Tsuyumu, Naruto Taira, Tadahiko Shien, Hiroyoshi Doihara

Clinical Nursing Studies 6 ( 1 ) 61 - 61 2017.11

Publishing type：Research paper (scientific journal) Publisher：Sciedu Press

Objective: To clarify how breast cancer patients undergoing post-surgical hormone therapy cope with changes in their sexual lives and support themselves and their partners during these changes.Methods: Participants were 37 breast cancer patients undergoing post-surgical hormone therapy and attending mammary outpatient clinics. In-depth interviews and grounded theory were used to collect and analyze data, respectively.Results: First, sexual life was divided into four groups: “No complaint” regarding sexual activity, “Slight discord”, “Handicapped in meeting a life partner” and “Uninterested” in sexual activity. Sexual life during surgical-hormone therapy did not change significantly from sexual life before breast cancer. Second, meanings of sexual activity for breast cancer patients were divided into five, “Regaining femininity”, “Confirming love”, “Sharing pleasure”, “Response to partner’s higher desire” and “Procreation”. They differed by group. Third, coping strategies were divided into six, “Virtuous cycle to confirm love and regain lost femininity”, “Struggle to avoid relationship crisis”, “Reconfirmation of partner’s affection by his abstinence”, “Attempt to recover the sexual activity they hope for”, “Pursuing children or assuaging partner’s desire by other means” and “Difficulty making a partner continue to have sexual activity”.Conclusions: Nurses should screen breast cancer patients for changes in their sexual lives and to ascertain what sexual activity means to patients, and support them in selecting appropriate coping methods.

DOI： 10.5430/cns.v6n1p61

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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 Reviewed

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 2017.10

Erratum to: Post-relapse survival in patients with the early and late distant recurrence in estrogen receptor-positive HER2-negative breast cancer. Reviewed

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 2017.7

Metformin improves immune function of exhausted peripheral CD8(+) T cells derived from cancer patients

Mototsugu Watanabe, Shingo Eikawa, Kazuhiko Shien, Hiromasa Yamamoto, Tadahiko Shien, Junichi Soh, Hiroyoshi Doihara, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono

CANCER RESEARCH 77 2017.7

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