Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion Mutations among Patients with Advanced Solid Tumors.

Purpose: PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) mutations. Acquired reversions can restore function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of mutations.

Experimental Design: Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion-deletion mutations (indels) in , and distinguishes somatic/reversion from germline mutations with high accuracy.

Results: Among 828 patients, one or more deleterious mutations were detected in 60 (7.2%) patients, including germline ( = 42) and somatic ( = 18) mutations. Common coexisting mutations included (61.6%), (30%), (26.6%), (15%), and (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.

Conclusions: cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.