The association between germline BRCA2 variants and sensitivity to platinum‐based chemotherapy among men with metastatic prostate cancer

Abstract

Background BRCA2-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment. Methods Retrospective analysis of a single-institution cohort of men with castration-resistant metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001-2015, 8,081 adult men with prostate cancer seen in consultation and/or treated at Dana-Farber Cancer Institute provided blood samples and consented to analysis of biological material and clinical records. A subgroup of 141 received at least two doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These subjects were categorized according to absence or presence of pathogenic germline mutations in BRCA2, based on DNA sequencing from whole blood. Primary outcome was response rate to carboplatin/docetaxel chemotherapy as defined by decline in prostate-specific antigen exceeding 50% within 12 weeks of initiating this regimen. Association between BRCA2 mutation status and response to carboplatin-based chemotherapy was tested, using Fisher’s exact test, with a two-sided p-value of <0.05 as threshold for significance. Results Pathogenic germline BRCA2 variants were observed in 8/141 (5.7%; 95% CI=2.5%-10.9%) participants. Six of eight (75%) BRCA2 carriers experienced prostate-specific antigen decline >50% within 12 weeks, compared to 23 of 133 (17%) non-carriers (absolute difference 58%; 95% CI=27%-88%; P<0.001). Prostate cancer cell lines functionally corroborate these clinical findings. Conclusions BRCA2-associated castration-resistant prostate cancer is associated with higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2 associated prostate cancer.

Coming of Age in Canada: A Study of Population-Based Genetic Testing for Breast and Ovarian Cancer

“…Mutations are associated with lifetime risks of 80% for breast cancer and 15%-40% for cancer of the ovary or fallopian tube for BRCA2 and BRCA1 respectively 3 . BRCA2 is the most frequently mutated gene in both prostate cancer 4,5 and pancreatic cancer [6][7][8] , and patients with BRCA2 mutations can benefit from novel therapies such as cis-platinum 9 . Annually, about 8500 cases of prostate cancer and 2150 cases of pancreatic cancer are diagnosed in Ontario, but very few of those patients are being tested for BRCA2.…”

Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

“…Personalized therapy of advanced metastatic prostate cancer has entered a new phase since the demonstration of the clinical efficacy of PARP inhibitors and platinum in cases with germline mutations in the DNA repair pathway, especially homologous recombination [4,24]. However, some of the DNA damage checkpoint gene germline mutants do not benefit from PARP inhibitor therapy [25] and some cases without such germline mutations are sensitive to platinum-based therapy [24,26]. Therefore, optimal use of these therapeutic approaches will require more accurate identification of HR deficient cases.…”

Exploiting DNA damage without repair: The activity of platinum chemotherapy in BRCA‐mutated prostate cancers

“…To date, there have been scattered case reports of men with mCRPC harboring BRCA2 mutations who had dramatic responses to platinum chemotherapy . In this issue of Cancer , Pomerantz and colleagues describe the largest cohort of men to date with identified BRCA2 mutations who received treatment with carboplatin. On a prospective, institutional review board‐approved protocol at Dana Farber Cancer Institute, this team identified 141 men with mCRPC who had blood samples available for DNA extraction (almost all of whom had failed prior docetaxel monotherapy) and received had treatment with combined carboplatin and docetaxel.…”