Gene Alteration In Triple Negative Breast Cancer Patients In A Phase I/Ii Study Of Combination Therapy With Eribulin And Olaparib

Background: Olaparib (Lynparza®) shows efficacy in patients with triple negative breast cancer (TNBC). Eribulin is one of the standard therapies for metastatic breast cancer. A phase I/II study of combination therapy with eribulin and olaparib capsule (EO study) was conducted on patients with TNBC. We investigated the correlation between response to combination therapy and homologous recombination deficiency (HRD). Methods: Tissue samples were collected from patients who participated in the EO study. Archival tissue samples were examined for gene alterations using the Foundation Medicine, Inc. (FMI) gene panel. Pathogenic or likely pathogenic gene alterations were extracted from all detected gene alterations using the FMI data dictionary. This dictionary uses the COSMIC database, relevant literature, and internal evidence to determine the reportable status of an alteration. HRD-related genes were defined as previously described (Konstantinopoulos PA, et al. Cancer Discovery, 2015). Correlation between presence of HRD and response to combination therapy was tested using chi-square test. Results: A total of 32 tissue samples were collected. Nineteen samples were collected from the phase I and 13 samples from the phase II. Seventeen patients were treated at the recommended dose. Thirty-three gene mutations were detected. The most frequent gene mutations were TP53 (n = 27, 84.4%), PIK3CA (n = 7, 21.9%), BRCA1 (n = 5, 15.6%), MLL3 (n = 5, 15.6%), and AKT1 (n = 4, 12.5%). We detected 32 gene amplifications, with MYC being the most common (n = 6, 18.8%). Eight homozygous deletions were detected, and the most frequent was loss of PTEN (n = 4, 12.5%). We detected 10 gene rearrangements. HRD, including BRCA1/2 mutations, was observed in nine patients. The overall response rate (RR) and clinical benefit rate (CBR) were 31.3% and 78.1%, respectively. The RRs in patients with HRD and without HRD were 44.4% and 26.1%, respectively (p=.4072). The CBRs for the HRD and non-HRD groups were 66.7% and 82.6%, respectively (p =.3702). Conclusions: Eighty-three gene alterations were detected in TNBC pts receiving combination olaparib/eribulin therapy. Patients with HRD had numerically higher response rate. Clinical trial identification: UMIN000018721 Legal entity responsible for the study: Japan Funding: Japan Agency for Medical Research and Development, AstraZeneca Disclosure: A. Shimomura: Research fund from AstraZeneca, Inc. K. Yonemori: Lecture fee from Eisai. N. Masuda: Research Funds from Chugai, Eisai. Honorarium from Chugai, AstraZeneca. K. Aogi: Honoraria from Chugai, Eisai, Sanofi, SRL, AstraZeneca, Taiho, Novartis, Daiichi Sankyo, Mochida Pharmaceutical, Ono Pharmaceutical, Otsuka Pharmaceutical, Nihon Medi-Physics and Eli Lilly. M. Takahashi: Lecture fee from Eisai, AstraZeneca, Chugai. Y. Naito: Honoraria from Eisai, Chugai, Taiho, Novartis, Eli Lilly, Meiji Seika, Bayer Yakuhin, Roche Diagnostics. Research funds from Merck Serono, AstraZeneca, Eli Lilly, Nippon Kayaku. C. Shimizu: Research funds from Chugai, Pfizer, Eli lilly, MSD. K. Tamura: Research funds from AstraZeneca, Daiichi Sankyo, Pfizer, MSD. Y. Fujiwara: Lecture fee from AstraZeneca, Eisai, Daiichi Sankyo, Taiho, Chugai, Eli Lilly, Yakut. Research funds from Taiho, Takeda, Chugai, Eli Lilly, Nippon Kayaku. All other authors have declared no conflicts of interest.