Recently, a 3-biomarker homologous recombination deficiency (HRD) score has been shown to predict response to DNA damaging therapies in patients with HGSOC, where patients with a high HRD score (≥42) and/or BRCA1/2 mutation show improved response. In order to evaluate whether changes in tumor biology can impact the prognostic value of this HRD score, we investigated the characteristics of HRD in paired primary and recurrent HGSOC specimens.
HRD scores were evaluated in paired primary and recurrent specimens of HGSOC from 55 patients treated with adjuvant carboplatin and paclitaxel. BRCA1/2 mutation and BRCA1 methylation (including loss of heterozygosity (LOH) status), and HRD scores were characterized using tumor DNA-based assays.
Here we present the results of the initial analysis performed for the first 25 patients. Data for 19 complete primary-recurrent pairs were available for comparative analysis (7/50 samples failed HRD analysis). BRCA mutations were detected in 12% (3/25) of tumors, all of which occurred in BRCA1 and contained LOH at BRCA1. There was no mutation reversion in recurrent samples. Overall, 9 primary-recurrent pairs had high HRD scores, including all 3 mutant pairs. There was a high degree of correlation for all HRD scores in primary and recurrent samples (Pearson correlation coefficient 0.953). Scores for recurrent tumor samples were somewhat more likely to be higher than in the primary (mean = 2.6), but the difference was not significant (p-value = 0.11). The complete analysis will include data from paired primary and recurrent tumors from an additional 30 patients. This will allow more thorough investigation of how changes in the genomic profile of primary and recurrent tumors may impact the HRD score.
Here we show that the 3-biomarker HRD score was not impacted by changes in the genomic profile of paired primary and recurrent tumor samples. This suggests that that testing recurrent HGSOC tumors will not alter treatment strategies relative to analysis of the primary tumor. Additional analysis will reveal whether the trends observed in this initial analysis are maintained in a larger cohort.
Clinical trial identification
Legal entity responsible for the study
J. Patel: Consultant, BTG; Research Funding, Myriad Genetics; Travel, accommodations. J. Sehouli, S. Darb-Esfahani, M. Ganapathi, R. Ganapathi: Research Funding, Myriad Genetics, Inc. K. Timms, C. Solimeno, J. Reid: Myriad employee, salary and stock options. J. Lanchbury: Employee of Myriad Genetics, Inc. Receives salary and stock options as compensation. I. Braicu: Research Funding, Myriad Genetics, Inc.