Reflex Testing for GermlineBRCA1,BRCA2,PALB2, andATMMutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries

Abstract

Purpose We investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes ( BRCA1, BRCA2, PALB2, and ATM) in consecutive patients with pancreatic adenocarcinoma. Methods 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. Results 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 ( P = .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 ( P < .001). BRCA1, BRCA2, and PALB2 carriers with late-stage (III or IV) disease had an overall survival advantage ( P = .049), particularly if treated with platinum-based chemotherapies ( P = .030). Conclusion 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.

Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma

“…Although our study was not sufficiently powered to detect the prevalence of individual rare genes, the frequency of mutations in genes such as BRCA1/2 was in the range of what has been previously reported for primarily non-Ashkenazi cohorts. 8,12,24 For example, we found that 2.7% of the patients (8 of 298) had mutations in BRCA1/2, whereas 1.8% of the patients (15 of 854) in the Hopkins cohort did, with both studies finding less than a 1% prevalence of mutations in PALB2 (1 of 298 and 2 of 854). Likewise, Lowery et al found that only 1 of 615 patients with pancreatic cancer had a germline mutation in PALB2.…”

“…12,28 In addition, trials evaluating poly(adenosine diphosphate ribose) polymerase inhibitors in PDAC patients with germline mutations in BRCA1/2 or PALB2 are ongoing (National Cancer Institute 8993 and NCT03140670). Other than mutations in BRCA1/2, mutations in ATM and CHEK2 were most common in our cohort.…”

“…Recently, retrospective studies have reported increased survival for PDAC patients with germline mutations in BRCA1/2 or PALB2 who received platinum chemotherapy. 12,28 In addition, trials evaluating poly(adenosine diphosphate ribose) polymerase inhibitors in PDAC patients with germline mutations in BRCA1/2 or PALB2 are ongoing (National Cancer Institute 8993 and NCT03140670). Furthermore, with the recent Food and Drug Administration approval of the use of immune checkpoint inhibitors to treat advanced refractory tumors with microsatellite instability or mismatch repair deficiency, identifying germline mutations in mismatch repair genes may provide additional therapeutic options for patients with PDAC.…”

“…[8][9][10][11][12] These studies have drawn attention to the prevalence of a genetic predisposition to PDAC and to the limitations of current guidelines for genetic testing in patients with PDAC. [8][9][10][11][12] These studies have drawn attention to the prevalence of a genetic predisposition to PDAC and to the limitations of current guidelines for genetic testing in patients with PDAC.…”

“…Recent retrospective studies from registries using multigene panels that included PDAC-associated and other cancer susceptibility genes reported germline mutations in 4% to 25% of patients with PDAC not selected for their family history. [8][9][10][11][12] These studies have drawn attention to the prevalence of a genetic predisposition to PDAC and to the limitations of current guidelines for genetic testing in patients with PDAC. However, differences in panel design and cohort ascertainment confound the determination of the true prevalence of mutations and the relative contributions of individual genes to PDAC susceptibility.…”