Faculty Profiles - SHIEN Tadahiko

Papers - SHIEN Tadahiko

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Significance of primary lesion resection in Stage IV breast cancer. Reviewed International journal

Tadahiko Shien, Hiroji Iwata

Japanese journal of clinical oncology 47 ( 5 ) 381 - 384 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Systemic treatment with drugs is administered to prolong survival and palliate symptoms in Stage IV breast cancer patients who have distant metastases at diagnosis. Surgical procedures for the primary tumor are not actively recommended in guidelines due to lack of evidence indicating prognostic benefit. Recently, several retrospective studies have shown primary tumor resection to prolong overall survival in patients with Stage IV breast cancer. Prospective randomized trials began enrolling patients to examine this possibility and two have already reported results. However, the results of these two trials were discordant. The first trial, conducted in India, reported negative effects of primary tumor resection after primary systemic therapy. A Turkish trial then obtained a positive effect of surgery as primary treatment. Several questions regarding the effects, timing, methods and eligibility for primary surgery have yet to be answered. Robust evidence, which is anticipated from other ongoing trials examining surgery for metastatic breast cancer, is eagerly awaited.

DOI： 10.1093/jjco/hyx027

Trends in axillary treatment for breast cancer patients undergoing sentinel lymph node biopsy as determined by a questionnaire from the Japanese Breast Cancer Society. Reviewed

Shigeru Imoto, Chikako Yamauchi, Yoshifumi Komoike, Koichiro Tsugawa, Daisuke Yotsumoto, Noriaki Wada, Takayuki Ueno, Mari S Oba, Tadahiko Shien, Sadatoshi Sugae, Hitoshi Tsuda, Kimiyasu Yoneyama

Breast cancer (Tokyo, Japan) 24 ( 3 ) 427 - 432 2017.5

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

BACKGROUND: Sentinel lymph node biopsy (SLNB) alone has been compared with SLNB followed by axillary lymph node dissection (ALND) in sentinel lymph node (SLN)-positive breast cancer patients in randomized phase III trials: the addition of ALND did not further improve the patient's outcome. However, there is still some controversy, regarding the clinical application of SLNB alone. To identify the optimal axillary treatment in the era of SLNB, the Japanese Breast Cancer Society conducted a group study of SLNB in 2014. METHODS: A questionnaire on axillary surgery and radiation therapy was sent to 432 Japanese institutes in December 2014, and 309 (72 %) completed the questionnaire. RESULTS: SLNB was performed at 98 % of the institutes, and 77 % offered irradiation for cancer treatment. Regarding breast-conserving surgery (BCS), SLNB alone was indicated at 41 % of the institutes in the cases of SLN with micrometastases. However, in the cases of SLN with macrometastases, ALND was performed at 64 %. The proportion of ALND seemed to be higher in total mastectomy than in BCS regardless of the SLN-positive status. In the cases of SLN with micrometastases, the radiation field was localized in the conserved breast at about half of the institutes. On the other hand, in the cases of SLN with macrometastases, it was extended to axillary and/or supraclavicular lesions beyond the conserved breast at about 70 % of the institutes. CONCLUSIONS: Japanese breast physicians were conservative with respect to the omission of ALND in SLN-positive breast cancer, especially in the cases of SLN with macrometastases.

DOI： 10.1007/s12282-016-0721-4

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 ( 3 ) 473 - 482 2017.5

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

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.

DOI： 10.1007/s12282-016-0730-3

Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers. Reviewed International journal

Takayuki Iwamoto, Toyomasa Katagiri, Naoki Niikura, Yuichiro Miyoshi, Mariko Kochi, Tomohiro Nogami, Tadahiko Shien, Takayuki Motoki, Naruto Taira, Masako Omori, Yutaka Tokuda, Toshiyoshi Fujiwara, Hiroyoshi Doihara, Balazs Gyorffy, Junji Matsuoka

Oncotarget 8 ( 16 ) 26122 - 26128 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：IMPACT JOURNALS LLC

BACKGROUND: The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers. RESULTS: Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P < 0.001). Post-Ki67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P < 0.001 and 0.041, respectively). MATERIALS AND METHODS: Core needle biopsy specimens of primary breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre- and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed. CONCLUSIONS: IHC based post-Ki67 levels may have distinct predictive power compared with the naïve IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

DOI： 10.18632/oncotarget.15385

Evaluation of ALDH1 expression in ipsilateral breast cancer recurrence. Reviewed International journal

Tadahiko Shien, Takehiro Tanaka, Masahiko Tanabe, Yasuhiro Okumura, Norikazu Masuda, Atsushi Yoshida, Nobuyuki Arima, Yoshifumi Komoike, Satoru Tanaka, Takuji Iwase, Tetsuya Taguchi, Katsuhiko Nakatsukasa, Hideo Inaji, Makoto Ishitobi

Oncology letters 13 ( 3 ) 1071 - 1077 2017.3

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

Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem cell (CSC) marker that is easily evaluable. The expression and clinical significance of ALDH1 in ipsilateral breast tumor recurrence (IBTR) has yet to be investigated. In the present study, the expression profile of ALDH1 and its correlation with prognosis in IBTR tissues was examined. Patients with IBTR from eight institutions were retrospectively enrolled in the study. Immunohistochemistry was used to examine ALDH1 expression patterns in the tissue specimens of primary cancers and IBTRs. ALDH1 expression levels were investigated in 182 IBTR tumors, which included cases of invasive carcinoma selected from 271 consecutive patients with IBTR. ALDH1 was expressed in 23% of the IBTR tissue samples. The rate of concordant expression between primary cancer and IBTR tissues was 68%. There was no significant association between disease-free survival (DFS) and ALDH1 expression levels in IBTR. IBTRs that expressed ALDH1 and Ki-67 had a poorer prognosis and this expression pattern was significantly associated with DFS (P=0.0073). The percentages of ALDH1 positive expression in each tissue subtype were as follows: Luminal A, 20%; luminal B, 24%; human epidermal growth factor 2 (HER2), 35%; triple-negative, 21%. There was a significant correlation between DFS and ALDH1 expression levels in HER2-type IBTR tissue specimens (P=0.034). In conclusion, it is possible that ALDH1 and Ki-67 expression levels may be useful for predicting prognosis in patients with HER2-type tumors.

DOI： 10.3892/ol.2016.5538

Development of a Japanese version of the BREAST-Q and the traditional psychometric test of the mastectomy module for the assessment of HRQOL and patient satisfaction following breast surgery. Reviewed

Miho Saiga, Naruto Taira, Yoshihiro Kimata, Satoko Watanabe, Yuko Mukai, Kojiro Shimozuma, Taeko Mizoo, Tomohiro Nogami, Takayuki Iwamoto, Takayuki Motoki, Tadahiko Shien, Junji Matsuoka, Hiroyoshi Doihara

Breast cancer (Tokyo, Japan) 24 ( 2 ) 288 - 298 2017.3

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

BACKGROUND: An understanding of health-related quality of life (HRQOL) is of utmost importance in both oncological and esthetic breast surgery. The BREAST-Q is a patient-reported outcome (PRO) measure that investigates HRQOL and patient satisfaction before and after breast surgery. The aim of this study was to develop a Japanese version of the BREAST-Q including the mastectomy module, the reconstruction module, the augmentation module and the reduction/mastopexy module, and to assess the psychometric properties of the mastectomy module among Japanese women. METHODS: The Japanese version of the BREAST-Q was developed through forward translation, backward translation and patient testing. Traditional psychometric testing of the mastectomy module was administered to 45 post-mastectomy patients. RESULTS: The mastectomy, reconstruction, augmentation and reduction/mastopexy modules were formally developed into Japanese. Despite cultural difference between Japanese women and original target population, the contents were considered to be valid among Japanese woman. With the exception of the sexual well-being subscale, good reliability and validity were evident for the mastectomy module (Test-retest reliability 0.76-0.95, Chronbach's alpha coefficient 0.77-0.98). CONCLUSIONS: The BREAST-Q Japanese version is a useful PRO measure for investigating the impact of breast surgery on HRQOL and patient satisfaction. Further validation in younger Japanese women is needed to determine the usefulness of the sexual well-being subscale.

DOI： 10.1007/s12282-016-0703-6

N-acetyltransferase 2 polymorphism and breast cancer risk with smoking: a case control study in Japanese women. Reviewed

Akio Hara, Naruto Taira, Taeko Mizoo, Keiko Nishiyama, Tomohiro Nogami, Takayuki Iwamoto, Takayuki Motoki, Tadahiko Shien, Junji Matsuoka, Hiroyoshi Doihara, Setsuko Ishihara, Hiroshi Kawai, Kensuke Kawasaki, Youichi Ishibe, Yutaka Ogasawara, Shinichiro Miyoshi

Breast cancer (Tokyo, Japan) 24 ( 2 ) 254 - 262 2017.3

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

BACKGROUND: Recent studies have suggested that the association between smoking and breast cancer risk might be modified by polymorphisms in the N-acetyltransferase 2 gene (NAT2). Most of these studies were conducted in Western countries, with few reports from East Asia. METHODS: We conducted a case-control study of 511 breast cancer cases and 527 unmatched healthy controls from December 2010 to November 2011 in Japan. Unconditional logistic regression was used to analyze the association of smoking with breast cancer risk stratified by NAT2 phenotype. RESULTS: In this population, 11 % of the cases and 10 % of the controls were classified as a slow acetylator phenotype. Compared to never smokers, current smokers had an increased breast cancer risk in multivariate analysis [odds ratio (OR) = 2.27, 95 % confidence interval (95 %CI) = 1.38-3.82]. Subgroup analyses of menopausal status indicated the same tendency. Subgroup analyses of NAT2 phenotype, the ORs in both of rapid and slow acetylator phenotype subgroups were comparable, and no interactions were observed between smoking status and NAT2 phenotype (p = 0.97). A dose-dependent effect of smoking on breast cancer risk was seen for the rapid acetylator phenotype, but not for the slow acetylator phenotype. CONCLUSION: Given the high frequency of the rapid acetylator phenotype, these results show that smoking is a risk factor for breast cancer among most Japanese women. It may be of little significance to identify the NAT2 phenotype in the Japanese population.

DOI： 10.1007/s12282-016-0696-1

Clinicopathological factors predicting early and late distant recurrence in estrogen receptor-positive, HER2-negative breast cancer. Reviewed

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 2016.11

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

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.

DOI： 10.1007/s12282-015-0649-0

A Phase I Trial of 100 mg/m2 Docetaxel in Patients with Advanced or Recurrent Breast Cancer. Reviewed

Tomoki Tamura, Taizo Hirata, Masahiro Tabata, Shiro Hinotsu, Akinobu Hamada, Takayuki Motoki, Takayuki Iwamoto, Taeko Mizoo, Tomohiro Nogami, Tadahiko Shien, Naruto Taira, Junji Matsuoka, Hiroyoshi Doihara

Acta medica Okayama 70 ( 5 ) 425 - 427 2016.10

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

Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m2. Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m2 were 22.1% , 23.3% , and 36.0% , respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m2, and Japanese guidelines also recommend a dose of 100 mg/m2. However, the approved dose in Japan is up to 75 mg/m2. We have launched a phase I trial evaluating 100 mg/m2 docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age 20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m2 docetaxel. This study will clarify whether 100mg/m2 docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer.

DOI： 10.18926/AMO/54607

Study about the Efficacy of Metformin to Immune Function in Cancer Patients. Reviewed

Mototsugu Watanabe, Hiromasa Yamamoto, Shingo Eikawa, Kazuhiko Shien, Tadahiko Shien, Junichi Soh, Katsuyuki Hotta, Jun Wada, Shiro Hinotsu, Toshiyoshi Fujiwara, Katsuyuki Kiura, Hiroyoshi Doihara, Shinichiro Miyoshi, Heiichiro Udono, Shinichi Toyooka

Acta medica Okayama 70 ( 4 ) 327 - 30 2016.8

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

A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8＋ T cells, which produce multiple cytokines.

DOI： 10.18926/AMO/54514

A phase 1, dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer. Reviewed International journal

Seiji Yoshitomi, Naruto Taira, Hiroyoshi Doihara, Taeko Mizoo, Tomohiro Nogami, Takayuki Iwamoto, Takayuki Motoki, Tadahiko Shien, Yutaka Ogasawara, Junji Matsuoka, Hisashi Tsuji, Toshiharu Mitsuhashi

Cancer chemotherapy and pharmacology 78 ( 2 ) 289 - 94 2016.8

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

PURPOSE: Gemcitabine (Gem) with paclitaxel (Pac) is used for patients with metastatic breast cancer who require cytoreduction with manageable toxicities. Nanoparticle albumin-bound (nab)-Pac exhibits better efficacy and reduces the risk of hypersensitivity reactions associated with solvent-based Pac. Therefore, Gem plus nab-Pac (GA) therapy may be effective for metastatic breast cancer. The purpose of this study was to determine the maximum tolerated dose for GA therapy. METHODS: The subjects were patients with metastatic breast cancer with performance status 0 or 1 and normal hepatic, renal and marrow function. Leukopenia, neutropenia or thrombocytopenia of grade 4, neutropenic fever, or non-hematological toxicity of grade 3 or higher during the 1st cycle, and chemotherapy-induced peripheral neurotoxicity of grade 2 or higher at the end of the 1st cycle were defined as dose-limiting toxicities (DLTs). Gem (1250 mg/m(2)) was administered on days 1 and 8. nab-Pac was administered at a starting dose of 180 mg/m(2) (cohort 1) and escalated to 220 mg/m(2) (cohort 2) and 260 mg/m(2) (cohort 3) on day 1 of the 21-day cycle, using a 3 + 3 design. RESULTS: Nine patients (n = 3, 3, and 3 in cohorts 1, 2, and 3, respectively) were included in the study (median age 56 years; range 43-75 years). DLTs did not occur in any cohorts. CONCLUSIONS: The initial recommend dose in GA therapy is 1250 mg/m(2) Gem and 260 mg/m(2) nab-Pac. It is well known that nab-Pac has cumulative toxicities, and thus the efficacy and safety of GA therapy require validation in a phase 2 study.

DOI： 10.1007/s00280-016-3091-x

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. 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 Endo, Mitsuchika Hosoda, Hiroyoshi Doihara, Shinichiro Miyoshi, Hiroko Yamashita

Breast cancer research : BCR 18 ( 1 ) 73 - 73 2016.7

Language：English Publishing type：Research paper (scientific journal) Publisher：BioMed Central Ltd.

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.

DOI： 10.1186/s13058-016-0731-3

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 Reviewed

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 18 2016.7

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

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.

DOI： 10.1186/s13058-016-0731-3

Local recurrence risk after previous salvage mastectomy. Reviewed International journal

M Tanabe, T Iwase, Y Okumura, A Yoshida, N Masuda, K Nakatsukasa, T Shien, S Tanaka, Y Komoike, T Taguchi, N Arima, R Nishimura, H Inaji, M Ishitobi

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 42 ( 7 ) 980 - 5 2016.7

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

INTRODUCTION: Breast-conserving surgery is a standard treatment for early breast cancer. For ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery, salvage mastectomy is the current standard surgical procedure. However, it is not rare for patients with IBTR who have received salvage mastectomy to develop local recurrence. In this study, we examined the risk factors of local recurrence after salvage mastectomy for IBTR. PATIENTS AND METHODS: A total of 118 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent salvage mastectomy without irradiation for IBTR between 1989 and 2008 were included from eight institutions in Japan. The risk factors of local recurrence were assessed. RESULTS: The median follow-up period from salvage mastectomy for IBTR was 4.6 years. Patients with pN2 or higher on diagnosis of the primary tumor showed significantly poorer local recurrence-free survival than those with pN0 or pN1 at primary tumor (p < 0.001). Multivariate analysis showed that the lymph node status of the primary tumor was a significantly independent predictive factor of local recurrence-free survival (p = 0.02). CONCLUSION: The lymph node status of the primary tumor might be a predictive factor of local recurrence-free survival after salvage mastectomy for IBTR. Further research and validation studies are needed. (UMIN-CTR number UMIN000008136).

DOI： 10.1016/j.ejso.2016.03.008

Other Link： http://orcid.org/0000-0001-5536-132X

Evaluation of aldehyde dehydrogenase 1 and transcription factors in both primary breast cancer and axillary lymph node metastases as a prognostic factor. Reviewed

Maiko Ito, Tadahiko Shien, Masako Omori, Taeko Mizoo, Takayuki Iwamoto, Tomohiro Nogami, Takayuki Motoki, Naruto Taira, Hiroyoshi Doihara, Shinichiro Miyoshi

Breast cancer (Tokyo, Japan) 23 ( 3 ) 437 - 44 2016.5

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

BACKGROUND: Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells, and the expression of ALDH1 may be a prognostic factor of poor clinical outcome. The epithelial-mesenchymal transition may produce cells with stem-cell-like properties promoted by transcription factors. We investigated the expression of ALDH1 and transcription factors in both primary and metastatic lesions, and prognostic value of them in breast cancer patients with axillary lymph node metastasis (ALNM). METHOD: Forty-seven breast cancer patients with ALNM who underwent surgery at Okayama University Hospital from 2002 to 2008 were enrolled. We retrospectively evaluated the levels of ALDH1 and transcription factors, such as Snail, Slug and Twist, in both primary and metastatic lesions by immunohistochemistry. RESULTS: In primary lesions, the positive rate of ALDH1, Snail, Slug and Twist was 19, 49, 40 and 26%, respectively. In lymph nodes, that of ALDH1, Snail, Slug and Twist was 21, 32, 13 and 23%, respectively. The expression of ALDH1 or transcription factors alone was not significantly associated with a poor prognosis. However, co-expression of ALDH1 and Slug in primary lesions was associated with a shorter DFS (P = 0.009). CONCLUSIONS: The evaluation of the co-expression of ALDH1 and transcription factors in primary lesions may be useful in prognosis of node-positive breast cancers.

DOI： 10.1007/s12282-015-0583-1

Relative Prognostic and Predictive Value of Gene Signature and Histologic Grade in Estrogen Receptor-Positive, HER2-Negative Breast Cancer. Reviewed International journal

Takayuki Iwamoto, Catherine Kelly, Taeko Mizoo, Tomohiro Nogami, Takayuki Motoki, Tadahiko Shien, Naruto Taira, Naoki Hayashi, Naoki Niikura, Toshiyoshi Fujiwara, Hiroyoshi Doihara, Junji Matsuoka

Clinical breast cancer 16 ( 2 ) 95 - 100 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

BACKGROUND: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, first-generation genomic signatures serve predominately as prognostic biomarkers and secondarily as predictors of response to chemotherapy. We compared both the prognostic and predictive value of histologic grades and genomic markers. METHODS: We retrieved publicly available cDNA microarray data from 1373 primary ER(+)/HER2(-) breast cancers and developed a genomic signature simulated from Recurrence Online (http://www.recurrenceonline.com/) to calculate the recurrence score and risk using predefined sets of genes in the cDNA microarray. We then compared the prognostic and predictive information provided by histologic grade and genomic signature. RESULTS: Based on genomic signatures, 55%, 28%, and 17% of breast cancers were classified as low, intermediate, and high risk, respectively, whereas the histologic grades were I, II, and III in 22%, 59%, and 19% of breast cancers, respectively. Univariate analysis in the untreated cohort revealed that both histologic grade (overall P = .007) and genomic signature (P < .001) could predict prognosis. Results were similar using the genomic signature, with pathologic complete response rates of 4.6%, 5.7%, and 16.5% for low-, intermediate-, and high-risk cancers, respectively. Neither biomarker was statistically significant in multivariate analysis for predictive response to neoadjuvant chemotherapy (NAC). CONCLUSION: Genomic signature was better at identifying low-risk cases compared to histologic grade alone, but both markers had similar predictive values for NAC response. Better predictive biomarkers for NAC response are still needed.

DOI： 10.1016/j.clbc.2015.10.004

Prognosis after mastectomy versus repeat lumpectomy in patients with ipsilateral breast cancer recurrence: A propensity score analysis. Reviewed International journal

A Yoshida, O Takahashi, Y Okumura, N Arima, K Nakatsukasa, M Tanabe, T Shien, N Masuda, S Tanaka, Y Komoike, T Taguchi, T Iwase, R Nishimura, H Inaji, H Yamauchi, M Ishitobi

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 42 ( 4 ) 474 - 80 2016.4

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

INTRODUCTION: Mastectomy is the current standard surgical procedure for ipsilateral breast tumor recurrence (IBTR). However, there is little evidence about the prognostic impact of the surgical procedure (mastectomy versus repeat lumpectomy) for IBTR. PATIENTS AND METHODS: A total of 271 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent definitive surgery for IBTR between 1989 and 2008 were included from eight institutions in Japan. The impact of the surgical procedure for IBTR on distant disease-free survival (DDFS) and overall survival (OS) was evaluated using and multivariable proportional hazards regression and propensity score matching methods. RESULTS: Of the 271 patients, 149 patients (55%) underwent repeat lumpectomy and 122 patients (45%) underwent mastectomy after IBTR. The median follow-up period from definitive surgery for IBTR was 55 months. There was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR, adjusted for various clinical and tumor characteristics. In addition, for the matched patient cohort, no difference in DDFS and OS was seen between the 2 groups. CONCLUSION: In our study, both multivariate analysis and the propensity score matching method demonstrated that there was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR. Further studies are warranted (UMIN-CTR number UMIN000008136).

DOI： 10.1016/j.ejso.2016.01.011

Other Link： http://orcid.org/0000-0001-5536-132X

Metastatic Cutaneous Apocrine Adenocarcinoma Treated With a Combination of Pertuzumab-Based Targeted Therapy and Taxane Chemotherapy: A Case Report. Reviewed International journal

Masaki Otsuka, Osamu Yamasaki, Tatsuya Kaji, Tadahiko Shien, Keiji Iwatsuki

JAMA dermatology 152 ( 1 ) 111 - 3 2016.1

Breast Cancer Metastasis to the Stomach That Was Diagnosed after Endoscopic Submucosal Dissection. Reviewed International journal

Masahide Kita, Masashi Furukawa, Masaya Iwamuro, Keisuke Hori, Yoshiro Kawahara, Naruto Taira, Tomohiro Nogami, Tadahiko Shien, Takehiro Tanaka, Hiroyoshi Doihara, Hiroyuki Okada

Case reports in gastrointestinal medicine 2016 2085452 - 2085452 2016

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

A 52-year-old woman presented with stage IIB primary breast cancer (cT2N1M0), which was treated using neoadjuvant chemotherapy (epirubicin, cyclophosphamide, and paclitaxel). However, the tumor persisted in patchy areas; therefore, we performed modified radical mastectomy and axillary lymph node dissection. Routine endoscopy at 8 months revealed a depressed lesion on the gastric angle's greater curvature, and histology revealed signet ring cell proliferation. We performed endoscopic submucosal dissection for gastric cancer, although immunohistochemistry revealed that the tumor was positive for estrogen receptor, mammaglobin, and gross cystic disease fluid protein-15 (E-cadherin-negative). Therefore, we revised the diagnosis to gastric metastasis from the breast cancer.

DOI： 10.1155/2016/2085452

Kampo medicine in perioperative care for cancer patients Reviewed

Koji Nishijima, Genichi Nishimura, Toshiaki Saeki, Chikako Shimizu, Hiroyoshi Doihara, Tadahiko Shien

Japanese Journal of Cancer and Chemotherapy 42 ( 13 ) 2430 - 2446 2015.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

Operative stress causes various changes in the body, and immunological hypofunction and malnutrition increase complications and adversely affect long-term prognosis. Therefore, reducing operative stress as much as possible, minimizing complications after surgery, and aiming for a satisfactory postoperative course are important. However, difficult and unresolvable situations often arise when only the conventional Western medicine approach is used because the situation and condition varies for each patient. We believe that Kampo medicine is very useful in diverse situations. Particularly, Kampo medicine has been used more frequently in recent years, with the expectation of numerous effects, because the effectiveness of Kampo medicine on various disease states has been proven and the pharmacological ingredients and the mechanisms by which Kampo medicine exerts its effects have been better clarified scientifically. Kampo medicine will have an effect in various situations, and we think that Kampo medicine occupies an important position in team-based medical care with multiple specialists. Kampo medicine compounds have been reported to be useful for the following conditions: Hochuekkito and Juzentaihoto for improving immunocompetence after operative stress, Daikenchuto and Rikkunshito for improving postoperative gastrointestinal motility, Shakuyakukanzoto for postoperative wound pain control, Yokukansan for postoperative delirium, and Inchinkoto for postoperative liver dysfunction. The availability of numerous treatment choices that work well in specific situations would be useful for cancer patients during the perioperative period.

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