Faculty Profiles - SHIEN Tadahiko

Influences of preoperative metformin on immunological factors in early breast cancer. International journal

Takahiro Tsukioki, Tadahiko Shien, Takehiro Tanaka, Yoko Suzuki, Yukiko Kajihara, Minami Hatono, Kengo Kawada, Mariko Kochi, Takayuki Iwamoto, Hirokuni Ikeda, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

Cancer chemotherapy and pharmacology 86 ( 1 ) 55 - 63 2020.7

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

PURPOSE: Metformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer. METHOD: We evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen. RESULT: There was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08). CONCLUSION: Preoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study.

DOI： 10.1007/s00280-020-04092-2

Omitting surgery for early breast cancer showing clinical complete response to primary systemic therapy. International journal

Hideo Shigematsu, Tomomi Fujisawa, Tadahiko Shien, Hiroji Iwata

Japanese journal of clinical oncology 50 ( 6 ) 629 - 634 2020.6

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

Breast cancer is highly sensitive to systemic therapy. High probability of pathological complete response suggests a clinical question that omitting surgery is an effective alternative to surgery in breast cancer showing clinical complete response to primary systemic therapy. However, the validity of omitting surgery for early breast cancer after primary systemic therapy has not been sufficiently established; thus, even if pathological complete response is expected in patients showing clinical complete response, excision of the primary tumor site remains the standard treatment of breast cancer. Inappropriate omitting surgery increases the incidence of local recurrence, which can be the risk of a subsequent distant metastasis and reduced overall survival. To achieve acceptable local control rate, omitting surgery should be investigated in patients with early breast cancer where a high percentage of pathological complete response, a high concordance rate between clinical complete response and pathological complete response and an acceptable local control rate are expected. This review presents concept and ongoing clinical trials for omitting surgery for patients with breast cancer showing clinical complete response to primary systemic therapy.

DOI： 10.1093/jjco/hyaa055

Evaluation of Therapeutic Target Gene Expression Based on Residual Cancer Burden Classification After Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer. International journal

Yuko Takahashi, Takayuki Iwamoto, Yoko Suzuki, Yukiko Kajiwara, Minami Hatono, Takahiro Tsukioki, Kengo Kawada, Mariko Kochi, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Junji Matsuoka, Hiroyoshi Doihara, Shinichi Toyooka

Clinical breast cancer 20 ( 2 ) 117 - 124 2020.4

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

INTRODUCTION: Patients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy. PATIENTS AND METHODS: We retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III. RESULTS: Among hormone receptor-positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node-positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II. CONCLUSION: In hormone receptor-positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials.

DOI： 10.1016/j.clbc.2019.07.001

Adjuvant and neoadjuvant therapy for breast cancer. International journal

Tadahiko Shien, Hiroji Iwata

Japanese journal of clinical oncology 50 ( 3 ) 225 - 229 2020.3

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

Systemic therapies for operable breast cancer patients have improved outcomes and have thus become standard treatments. Recently, new molecular target drugs and regimens are being developed based on the predicted sensitivity for specific breast cancer histological types. Systemic therapy is selected according to recurrence risk, with the treatment for low-risk patients being de-escalated, while high-risk patients receive aggressive systemic treatment with an adequate dose and duration. Neoadjuvant systemic therapy has a different aim. The efficacy of systemic therapies, based on the sensitivities to drugs, is supported by improvements in the rate of breast-conserving therapy. The response to neoadjuvant systemic therapy is the most important factor for predicting outcomes and selecting the optimal adjuvant therapy. Novel biological markers unique to individual patients allow appropriate targeted therapy, which can achieve optimal efficacy.

DOI： 10.1093/jjco/hyz213

YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers. Reviewed International journal

Tatsuaki Takeda, Hiromasa Yamamoto, Ken Suzawa, Shuta Tomida, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Akihiro Miura, Kei Namba, Kazuhiko Shien, Junichi Soh, Tadahiko Shien, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka

Cancer science 111 ( 3 ) 849 - 856 2020.3

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

Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

DOI： 10.1111/cas.14289

Influence of breast density on breast cancer risk: a case control study in Japanese women.

Keiko Nishiyama, Naruto Taira, Taeko Mizoo, Mariko Kochi, Hirokuni Ikeda, Takayuki Iwamoto, Tadahiko Shien, Hiroyoshi Doihara, Setuko Ishihara, Hiroshi Kawai, Kensuke Kawasaki, Yoichi Ishibe, Yutaka Ogasawara, Shinichi Toyooka

Breast cancer (Tokyo, Japan) 27 ( 2 ) 277 - 283 2020.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

BACKGROUND: Mammography is the standard examination for breast cancer screening of woman aged ≥ 40 years. High breast density on mammography indicates that mammary gland parenchyma occupy a high percentage of the breast. The objective of this study was to investigate factors associated with breast density and the risk of high breast density for breast cancer. METHODS: A multicenter case-control study was performed in 530 patients and 1043 controls. Breast density was classified as C1-C4 using the Breast Imaging Reporting and Data System (BI-RADS). Clinical factors were obtained from questionnaires or medical records, and the influence of each factor (breast density, menopausal status, body mass index (BMI), parity, presence or absence of breastfeeding history, age at menarche, age at first birth, and familial history of breast cancer) on breast cancer risk in all patients was calculated as an age-adjusted odds ratio (OR). Multivariate logistic regression analyses were then performed in all patients and in pre- and postmenopausal and BMI-stratified groups using factors with a significant age-adjusted OR as adjustment factors. RESULTS: Age-adjusted ORs for breast cancer were significant for breast density, BMI, parity, and breast feeding, but not for age at menarche, age at first birth, or family history of breast cancer. In multivariate analysis, there was a significant correlation between breast density and breast cancer in postmenopausal women (OR for C1 vs. C2 1.90 [95% CI 1.34-2.70]; C1 vs. C4 2.85 [95% CI 1.10-7.16]). This correlation was also significant in patients in the third BMI quartile (22.3-24.5 kg/m2) (OR for C1 vs. C4 8.76 [95% CI 2.38-42.47]); and fourth BMI quartile (>24.5 kg/m2) (OR for C1 vs. C2 1.92 [95% CI 1.17-3.15]; C1 vs. C4 11.89 [95% CI 1.56-245.17]). CONCLUSION: Breast density on mammography is a risk factor for breast cancer after adjustment for other risk factors. This risk is particularly high in postmenopausal women and those with a high BMI.

DOI： 10.1007/s12282-019-01018-6

Gene expression profiling of breast cancers between high and low Ki-67 after short-term preoperative hormone therapy among hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancers with high Ki-67

Yukiko Kajiwara, Takayuki Iwamoto, Yusuke Otani, Miwa Fujihara, Yoko Suzuki, Minami Hatono, Takahiro Tsukioki, Kengo Kawada, Mariko Kochi, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Hiroyoshi Doihara

CANCER RESEARCH 80 ( 4 ) 2020.2

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 ) 2020.2

Validation study of the Emoji scale in evaluating patient reported outcomes for breast cancer patients

Yoko Suzuki, Naruto Taira, Yukiko Kajiwara, Mariko Kochi, Takayuki Iwamoto, Hirokuni Ikeda, Tadahiko Shien, Hiroyoshi Doihara, Yuichiro Kikawa, Yukari Uemura

CANCER RESEARCH 80 ( 4 ) 2020.2

Recurring radiation-induced angiosarcoma of the breast that was treated with paclitaxel chemotherapy: a case report. International journal

Yoko Suzuki, Kohei Taniguchi, Minami Hatono, Yukiko Kajiwara, Yuko Abe, Kengo Kawada, Takahiro Tsukioki, Mariko Kochi, Keiko Nishiyama, Takayuki Iwamoto, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Masahiro Tabata, Hiroyuki Yanai, Hiroyoshi Doihara

Surgical case reports 6 ( 1 ) 25 - 25 2020.1

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

BACKGROUND: Angiosarcoma of the breast is very rare and can be divided into primary and secondary angiosarcoma. Radiation-induced angiosarcoma (RIAS) is classified as secondary angiosarcoma. Diagnosis of RIAS is difficult due to its rarity, and the interpretation of pathological imaging is complicated. In the National Comprehensive Care Network (NCCN) guidelines, the first choice of treatment is surgery with negative margins. Adjuvant radiotherapy (RT) for close soft tissue margins should be considered. Preoperative or adjuvant chemotherapy of nonmetastatic disease is not recommended for angiosarcoma. We report a case of RIAS, which was impossible to diagnose with core needle biopsy (CNB) but was diagnosed by excisional biopsy. The patient was then administered adjuvant chemotherapy using conjugated paclitaxel (PTX). CASE PRESENTATION: A 62-year-old woman noticed a tumor in her right breast. She had a history of right breast cancer and had undergone breast-conserving surgery, RT, and tamoxifen therapy 8 years previously. CNB, which was performed twice, was inconclusive. The tumor was surgically excised and pathological analysis yielded a diagnosis of angiosarcoma. She then underwent a right mastectomy. One month after she underwent right mastectomy, a nodule reappeared on the skin of her right breast, and excisional biopsy revealed recurrence of angiosarcoma. A few weeks later another nodule reappeared near the post-operative scar and excisional biopsy revealed recurrence of angiosarcoma. We assumed that surgical therapy was insufficient because the patient experienced relapse of angiosarcoma after complete mastectomy. After the second recurrence, we treated her with systemic chemotherapy using PTX. There was no evidence of recurrence 8 months after chemotherapy. CONCLUSION: Although angiosarcoma is difficult to diagnose, many patients have a poor prognosis. Therefore, prompt treatment intervention is desired. Moreover, there is little evidence regarding adjuvant therapy of angiosarcoma since it is a rare disease. We consider that adjuvant therapy helped to effectively prevent recurrence in the patient after complete excision.

DOI： 10.1186/s40792-020-0790-7

The Japanese Breast Cancer Society clinical practice guidelines for surgical treatment of breast cancer, 2018 edition. Reviewed

Masafumi Inokuchi, Goro Kutomi, Yuko Kijima, Takehiko Sakai, Masataka Sawaki, Tadahiko Shien, Noriko Hanamura, Kenji Yano, Noriaki Wada, Shigehira Saji, Hiroji Iwata

Breast cancer (Tokyo, Japan) 27 ( 1 ) 4 - 8 2020.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

We have prepared the Japanese Breast Cancer Society clinical practice guidelines (CPGs) for surgical treatment of breast cancer, 2018 update after a systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. The CPG committee for surgical treatment of breast cancer, composed of breast surgeons and plastic surgeons treating breast cancer, has developed the CPGs. Eight clinical questions (CQs) were selected and divided roughly into the following five categories: (1) breast surgery in initial therapy (CQs 1-3); (2) axillary surgery in initial therapy (CQs 4-5); (3) breast reconstruction in initial therapy (CQ 6); (4) surgical treatment for recurrent and metastatic breast cancer (CQs 7-8); and (5) others. Recommendations for these CQs were decided by the GRADE grid method. In addition, 4 outlines, 14 background questions (BQs), and 12 future research questions (FQs) were also selected. Statements for these BQs and FQs are provided. We developed the updated CPGs for surgical treatment of breast cancer, 2018, which include 8 CQs and recommendations. As a decision-making tool for the understanding and treatment of breast cancer, these guidelines will help surgical oncologists dealing with breast cancer, medical staff, and patients, along with their family members.

DOI： 10.1007/s12282-019-01030-w

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 2019.11

Distinct gene expression profiles between primary breast cancers and brain metastases from pair-matched samples. International journal

Takayuki Iwamoto, Naoki Niikura, Rin Ogiya, Hiroyuki Yasojima, Ken-Ichi Watanabe, Chizuko Kanbayashi, Michiko Tsuneizumi, Akira Matsui, Tomomi Fujisawa, Tsutomu Iwasa, Tadahiko Shien, Shigehira Saji, Norikazu Masuda, Hiroji Iwata

Scientific reports 9 ( 1 ) 13343 - 13343 2019.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.

DOI： 10.1038/s41598-019-50099-y

非小細胞肺癌におけるモネンシン併用療法によるEMT関連薬剤耐性の克服(Overcoming EMT-mediated drug resistance with Monensin-based combined therapy in non-small cell lung cancer)

大智宏祐, 諏澤憲, 冨田秀太, 荒木恒太, 宮内俊策, 三浦章博, 武田達明, 難波圭, 枝園和彦, 山本寛斉, 岡崎幹生, 枝園忠彦, 豊岡伸一

日本癌学会総会記事 78回 P - 1139 2019.9

The influences of preoperative metformin on immunological factors in early breast cancer.

Takahiro Takahiro, Tadahiko Shien, Naruto Taira, Mariko Kochi, Takayuki Iwamoto, Hiroyoshi Doihara, Heiichiro Udono, Shinichi Toyooka

JOURNAL OF CLINICAL ONCOLOGY 37 ( 15 ) 2019.5

The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA).

Chizuko Kanbayashi, Alastair Mark Thompson, Eun-Sil Shelley Hwang, Ann H. Partridge, Daniel William Rea, Jelle Wesseling, Tadahiko Shien, Tomonori Mizutani, Taro Shibata, Hiroji Iwata

JOURNAL OF CLINICAL ONCOLOGY 37 ( 15 ) 2019.5

Ganetespib in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer. Reviewed International journal

Eisuke Kurihara, Kazuhiko Shien, Hidejiro Torigoe, Tatsuaki Takeda, Yuta Takahashi, Yusuke Ogoshi, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Mikio Okazaki, Tadahiko Shien, Shuta Tomida, Shinichi Toyooka

Anticancer research 39 ( 4 ) 1767 - 1775 2019.4

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

BACKGROUND: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types. MATERIALS AND METHODS: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition. RESULTS: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M. CONCLUSION: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.

DOI： 10.21873/anticanres.13283

TNM classification of malignant tumors (Breast Cancer Study Group). Reviewed International journal

Masataka Sawaki, Tadahiko Shien, Hiroji Iwata

Japanese journal of clinical oncology 49 ( 3 ) 228 - 231 2019.3

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

The eighth editions of the primary tumor, lymph node and metastasis classifications for breast cancer issued by the American Joint Commission of Cancer and the Union for International Cancer Control were revised in 2017. The major change made by the American Joint Commission of Cancer is to incorporate biological factors such as estrogen and progesterone receptor, human epidermal growth factor receptor 2, histological grade and multigene prognostic assays, into the staging system. Tumor biomarkers and low recurrence scores confirmed by multigene prognostic assays change the staging. Minor changes are to add the post-neoadjuvant therapy clinical and pathological classification and to define the size of tumor, lymph node and metastasis components more precisely. Little has changed in the Union for International Cancer Control. We have identified key points of change in both eighth editions of the tumor, lymph node and metastasis classifications and we discuss possible problems which may arise when they are adopted in Japanese practice, as well as future directions.

DOI： 10.1093/jjco/hyy182