Germline BRCA1/2 Mutations: Are They Good Enough to Determine Who Will Respond to Poly(ADP-Ribose) Polymerase Inhibitor Therapy in Advanced Cancer?

Abstract

monotherapy in advanced cancer patients with a germline BRCA1/2 mutation. Among other cancers, the study includes an ovarian cancer cohort of 193 patients with platinum-resistant or platinum-unsuitable ovarian cancer and a cohort of 62 patients with breast cancer. Patients with ovarian cancer were eligible if they were platinum resistant, or if they were not suitable for further platinum therapy due to hypersensitivity or toxicity as deemed by their primary oncologist. Percentage of patients fitting this unsuitability criterion has not been prospectively collected and reported. Data regarding if or what percentage of ovarian cancer patients had a high-grade serous histology have not been provided. Also, data on the percentage of patients with breast cancer with triple-negative disease is not available. The primary end point of the study was tumor response rate by RECIST criteria for all patients. CA-125 levels have not been provided to correlate for response in ovarian cancer cohort. Among patients with platinum-sensitive relapsed ovarian cancer, olaparib therapy has been shown to improve progression-free survival regardless of the BRCA mutational status. 2 The efficacy of olaparib may depend on platinum sensitivity even among patients with BRCAmutated ovarian cancer suggesting that platinum sensitivity may be more relevant to predict response to poly(ADP–ribose) polymerase (PARP) inhibitors than the mutational status of BRCA1 and BRCA2. 3 Many genes other than BRCA are involved in platinum-induced DNA damage repair and are related to platinum sensitivity. 4-5 Not knowing exactly what percentage of patients in Kaufman et al study were platinum resistant versus platinum unsuitable makes it less clear if more than 30% response rate for ovarian cohort were due to BRCA mutation or platinum sensitivity. In other tumor types response rates according to prior platinum therapy also favored no prior platinum exposure even though it did not reach statistical significance. However, the sample sizes were small and, as stated by Kaufman et al, 1 the CIs overlapped. In the Cancer Genome Atlas project 6 approximately 22% of tumors had a BRCA mutation, which is associated with homologous recombination deficiency (HRD), the hallmark for response to PARP inhibitors. The high grade serous ovarian cancers and triple negative breast cancers may represent histologically and phenotypically defined subgroups associated with HRD. The data regarding the percentage of these patients in these two subgroups in ovarian and breast cancer cohorts would be helpful if available. It remains to be shown what exactly determines the response to PARP inhibitor therapy; Is it germline BRCA1/2 mutations? Is it platinum sensitivity? Is it HRD? Or is it a combination of all? Currently, identification of germline BRCA mutations through a blood test seems to be the only US Food and Drug Administration–approved surrogate marker for HRD. However testing tumor tissue for somatic BRCA mutations as well as for genes associated with HRD may better define the subgroup of patients with cancer who would benefit from a number of PARP inhibitors yet to come into clinical practice. The recent US Food and Drug Administration approval of olaparib for ovarian cancer along with a companion diagnostic blood test of BRACAnalysis CDx (Myriad Genetics Laboratories, Salt Lake City, UT) seems to be just the beginning.