Prostate Cancer Gene Alterations Support Potential Role of PARP inhibitors

BRCA mutations and co-occurring gene alterations in prostate cancer suggest that some patients might benefit from oral poly (ADP-ribose) polymerase (PARP) inhibitors, according to authors of a retrospective database analysis of prostate adenocarcinoma molecular biomarkers. The findings were presented at the 2016 Genitourinary Cancers Symposium, held January 7-9, 2016, in San Francisco.

“[The] BRCA mutation rate is 13% in prostate cancer (11% BRCA2 and 2% BRCA1), with these mutations occurring in slightly younger men than the overall population (59 vs 62),” reported lead author Charles E. Myers, MD, of the American Institute for Diseases of the Prostate in Earlysville, Va, and coauthors, in a poster presentation. “The frequency of somatic BRCA mutations observed in prostate cancer, together with preliminary clinical evidence for the efficacy of targeted therapies for these patients, highlights the potential role of a new class of agents for advanced prostate cancer.”

Just over half of BRCA variants were determined to be pathogenic or tumor-associated, rendering them “potentially targetable with DNA-damaging agents,” the authors noted.

The research team analyzed 118 prostate adenocarcinomas from the commercial Caris Life Sciences biomarker data repository. Patients represented in the database had been tested using gene sequencing with 47- and 600-gene panels, protein expression using immunohistochemical assays, and FISH analyses of gene amplification. Sixty-five percent of specimens analyzed were from patients with metastatic sites such as lymph nodes, bone or liver, the authors noted.

“Alterations that have a tendency to co-occur with BRCA mutations vs BRCA wildtype and that reached statistical significance included overexpression of cMET (10% vs 1%; P = .05) and TOPO1 (92% vs 58%; P = .03),” they reported. “These co-occurring alterations may suggest the utility of cMET-targeted therapy or topoisomerase inhibitors in combination with DNA-damaging agents.”

Gene alterations associated with BRCA-wildtype prostate cancer included low TUB883 expression (80% vs 43%; P = .003), “suggesting taxanes may not be the best combination strategy with PARP inhibitors for BRCA-mutated patients.”

Altered PIK3CA pathway genes, including PTEN loss and mutations in PIK3CA, PTEN, and the serine/threonine-protein kinase STK11 gene, “occurred at a much higher frequency in BRCA-wildtype patients, indicating the PIK3CA pathway may stratify a different molecular subtype of prostate cancer,” the authors noted. “With the exception of ERCC1 protein loss, aberrations in DNA-repair pathway genes occur in a range of 2% to 11%, indicating a new subgroup of molecularly-defined prostate cancer patients that may benefit from DNA-damaging agents like PARP inhibitors.”