Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).

Abstract

5072 Background: A small proportion of metastatic PC exhibit outlier somatic mutation (mut) rates exceeding the average of 4.4 mut/Mb. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing from a panel of PC genes using plasma cell-free DNA samples collected from metastatic castration-resistant prostate cancer (mCRPC) pts and calculated somatic mutation burden. HM samples were additionally subjected to whole exome sequencing to determine trinucleotide mutational signatures and microsatellite instability (MSI). Clinical data was retrospectively collected and compared to a control cohort of 199 mCRPC pts. Results: 671 samples from 434 pts had ctDNA > 2% and were evaluable. 32 samples from 24 pts had > 11 mut/Mb and fell above the 95th percentile for mutation burden with a median mutation burden of 34 mut/Mb. 11 pts had deleterious mutations or homozygous deletions in mismatch repair (MMR) genes and 4 further pts had evidence of MMR deficiency (MMRd) from mutational signatures and MSI status. The remaining 9 pts had either BRCA2 mutations (n = 4), Kataegis (localized hypermutation, n = 3), or undefined causes for HM (n = 2). The incidence of MMRd was 3.5% (15/434), and germline MMRd was 0.2% (1/434). For MMRd pts with available clinical data (10/15) at diagnosis, the median age was 73.6 y, 70% had Gleason score ≥8, and 50% presented with M1 disease. Comparing the MMRd with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9–11.4) vs. 18.2 m (95% CI 15.1–21.3), p = 0.001; median time from CRPC to death was 13.1 m (95% CI 0.3–25.9) vs. 40.1 m (95% CI 32.4–47.8), p < 0.001. Conclusions: HM and MMRd can be identified using liquid biopsy and could help to select pts for immunotherapy.