domingo, 11 de agosto de 2019

Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy. - PubMed - NCBI

2019 Aug 2;12(10):1386-1394. doi: 10.1016/j.tranon.2019.07.013. [Epub ahead of print]

Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy.

Shimomura A1, Yonemori K2, Yoshida M3, Yoshida T4, Yasojima H5, Masuda N5, Aogi K6, Takahashi M7, Naito Y8, Shimizu S9, Nakamura R10, Hamada A11, Michimae H12, Hashimoto J13, Yamamoto H14, Kawachi A2, Shimizu C15, Fujiwara Y2, Tamura K2.

Author information

1: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. Electronic address: ashimomu@ncc.go.jp.
2: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
3: Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.
4: Department of Genetic Medicine, National Cancer Center Hospital, Tokyo, Japan.
5: Department of Breast Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.
6: Department of Breast Surgery, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
7: Department of Breast Surgery, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
8: Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
9: Department of Breast and Endocrine Surgery, Kanagawa, Cancer Center, Yokohama, Japan.
10: Department of Breast Surgery, Chiba, Cancer Center, Chiba, Japan.
11: Department of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan.
12: Department of Biostatistics, Kitasato University School of Pharmacy, Tokyo, Japan.
13: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Medical Oncology, St. Luke's International Hospital, Tokyo, Japan.
14: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Medical Oncology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.
15: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Breast Medical Oncology, National Center for Global Health and Medicine, Tokyo, Japan.

Abstract

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).