Reflex Testing for Germline BRCA1, BRCA2, PALB2, and ATM Mutations in Pancreatic Cancer: Mutation Prevalence and
Alyssa L Smith1, Cavin Wong1, Adeline Cuggia1
1Alyssa L. Smith, Cavin Wong, Adeline Cuggia, Anita Hall, Claire Bascuñana, and George Zogopoulos, Goodman Cancer Research Centre, McGill University; Alyssa L. Smith, Cavin Wong, Adeline Cuggia, Anita Hall, Claire Bascuñana, Peter Metrakos, William D. Foulkes, and George Zogopoulos, Research Institute of the McGill University Health Centre; Jamil Asselah, Nathaniel Bouganim, Khashayar Rafatzand, Prosanto Chaudhury, Jeffrey Barkun, Peter Metrakos, Victoria Marcus, Atilla Omeroglu, William D. Foulkes, and George Zogopoulos, McGill University Health Centre; George Chong and William D. Foulkes, Jewish General Hospital, Montreal, Canada; Ayelet Borgida, Spring Holter, Ashton A. Connor, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, New York, NY; Mohammad R. Akbari, Women's College Hospital, Toronto; Véronique Poulin, Jacques Jolivet, and Petro Vafiadis, Centre de Santé et de Services Sociaux de Saint-Jérôme, Saint-Jérôme; Philippe Le, Centre de Santé et de Services Sociaux du Suroît, Suroît; Frédéric Lemay and Annie Beaudoin, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke; and Guillaume Martel, The Ottawa Hospital, Ottawa, Canada.
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.
