Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy
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 a...
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Format: | Article |
Language: | English |
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Elsevier
2019-10-01
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Series: | Translational Oncology |
Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523319302037 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy Translational Oncology |
author_facet |
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 |
author_sort |
Akihiko Shimomura |
title |
Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy |
title_short |
Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy |
title_full |
Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy |
title_fullStr |
Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy |
title_full_unstemmed |
Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy |
title_sort |
gene alterations in triple-negative breast cancer patients in a phase i/ii study of eribulin and olaparib combination therapy |
publisher |
Elsevier |
series |
Translational Oncology |
issn |
1936-5233 |
publishDate |
2019-10-01 |
description |
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). |
url |
http://www.sciencedirect.com/science/article/pii/S1936523319302037 |
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doaj-dcf6a662f48a4a31ae6c491fcbcde18e2020-11-25T01:43:59ZengElsevierTranslational Oncology1936-52332019-10-01121013861394Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination TherapyAkihiko Shimomura0Kan Yonemori1Masayuki Yoshida2Teruhiko Yoshida3Hiroyuki Yasojima4Norikazu Masuda5Kenjiro Aogi6Masato Takahashi7Yoichi Naito8Satoru Shimizu9Rikiya Nakamura10Akinobu Hamada11Hirofumi Michimae12Jun Hashimoto13Harukaze Yamamoto14Asuka Kawachi15Chikako Shimizu16Yasuhiro Fujiwara17Kenji Tamura18Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Address all correspondence to: Akihiko Shimomura, MD, PhD, Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, JapanDepartment of Pathology, National Cancer Center Hospital, Tokyo, JapanDepartment of Genetic Medicine, National Cancer Center Hospital, Tokyo, JapanDepartment of Breast Surgery, National Hospital Organization Osaka National Hospital, Osaka, JapanDepartment of Breast Surgery, National Hospital Organization Osaka National Hospital, Osaka, JapanDepartment of Breast Surgery, National Hospital Organization Shikoku Cancer Center, Matsuyama, JapanDepartment of Breast Surgery, National Hospital Organization Hokkaido Cancer Center, Sapporo, JapanDepartment of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Breast and Endocrine Surgery, Kanagawa, Cancer Center, Yokohama, JapanDepartment of Breast Surgery, Chiba, Cancer Center, Chiba, JapanDepartment of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, JapanDepartment of Biostatistics, Kitasato University School of Pharmacy, Tokyo, JapanDepartment of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Medical Oncology, St. Luke’s International Hospital, Tokyo, JapanDepartment of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Medical Oncology, National Hospital Organization Kumamoto Medical Center, Kumamoto, JapanDepartment of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, JapanDepartment of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Breast Medical Oncology, National Center for Global Health and Medicine, Tokyo, JapanDepartment of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, JapanDepartment of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, JapanBACKGROUND: 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).http://www.sciencedirect.com/science/article/pii/S1936523319302037 |