Reflex Testing for Germline <i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, and <i>ATM</i> Mutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries.

Abstract

We investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes (<i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, and <i>ATM</i>) in consecutive patients with pancreatic adenocarcinoma. One hundred fifty patients with French-Canadian (FC) ancestry were evaluated for founder mutations, and 114 patients were subsequently assessed by full gene sequencing and multiplex ligation-dependent probe amplification for nonfounder mutations. Two hundred thirty-six patients unselected for ancestry were also assessed for mutations by full gene sequencing. The FC founder mutation prevalence among the 150 patients was 5.3% (95% CI, 2.6% to 10.3%), and the nonfounder mutation prevalence across the four genes among the 114 patients tested was 2.6% (95% CI, 0.6% to 7.8%). In the case series unselected for ancestry, 10.0% (95% CI, 2.7% to 26.4%) of patients reporting Ashkenazi Jewish (AJ) ancestry carried an AJ founder mutation, with no nonfounder mutations identified. The mutation prevalence among patients without FC/AJ ancestry was 4.9% (95% CI, 2.6% to 8.8%). Mutations were more frequent in patients diagnosed at ≤ 50 years of age (<i>P</i> = .03) and in patients with either two or more first- or second-degree relatives with pancreas, breast, ovarian or prostate cancer, or one such relative and a second primary of one of these cancer types (<i>P</i> < .001). <i>BRCA1</i>, <i>BRCA2</i>, and <i>PALB2</i> carriers with late-stage (III or IV) disease had an overall survival advantage (<i>P</i> = .049), particularly if treated with platinum-based chemotherapies (<i>P</i> = .030). Considering these results, we recommend reflex founder mutation testing of patients with FC/AJ ancestry and full gene sequencing of patients who are ≤ 50 years or meet the identified family history criteria. Reflex testing of all incident patients for these four genes may become justified as full gene sequencing costs decline.