Gulhan, Doga

Mutations in BRCA1 and BRCA2 genes, whether inherited or somatically acquired, cause homologous recombination deficiency (HRD) in tumor cells. The timing of HRD onset in the emerging tumor lineage is unknown. Here, we present HRDTimer, an algorithm to infer the onset of HRD-driven mutagenesis prior to cancer diagnosis. We estimate that HRD arises at 34% of SBS1-based molecular time---corresponding to a median of 8.3 years (IQR 7.1--10.4) prior to diagnosis in triple-negative breast cancers, and 15.0 years (IQR 12.0--20.6) in ER-positive breast cancers. Bulk sequencing reveals accelerated SBS1 accumulation following neoplastic transformation compared to normal tissue, influencing the estimated age of HRD onset. Single-cell duplex sequencing confirms SBS1 acceleration in tumors and further shows that non-tumor cells largely lack the HRD signature, indicating that HRD is rare in pre-malignant cells, even in BRCA1/2 mutation carriers. Together, our analysis pinpoints the onset of HRD before diagnosis, defining a window for detection and potential interception.

PURPOSE The multicenter, open-label, randomized phase 2 NCI-9944 study ( NCT02595892 ) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.