Abstract

Poly ADP-ribose inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations.Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay which evaluates single nucleotide variants and insertion-deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy.Among 828 patients, greater than or equal to 1 deleterious BRCA1/2 mutation was detected in 60 (7.2%) patients, including germline (n=42) and somatic (n=18) mutations. Common co-existing mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%) and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9/42 (21.4%) germline BRCA1/2 mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure which contributed to subsequent resistance to PARPi and platinum therapy.cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical application of these findings to guide precision medicine approaches for advanced malignancies.

View details for DOI 10.1158/1078-0432.CCR-19-2933

View details for PubMedID 32034076