Prevalence and spectrum of pathogenic variants among patients with multiple primary cancers.

Abstract

10595 Background: Multiple primary cancers (MPCs) are a hallmark of cancer predisposition syndromes. We aim to characterize the frequency of germline pathogenic/likely pathogenic variants (PVs) among patients with MPCs. Herein we report the frequency of PVs by sex, number of cancers and age at diagnosis among a laboratory-based cohort of patients with MPCs. Methods: Patients with MPCs who underwent germline genetic testing with Ambry Genetics from 3/2012 to 12/2016 were included in our cohort. Eligible individuals had multigene panel testing, which included 21 genes, at minimum: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. Clinical factors including age at diagnosis, age at testing and cancer type were obtained from test requisition forms and clinical notes. Patients with > 1 PVs were excluded from the analysis. Using Rv.3.3.3., the frequencies of PVs by sex, number of cancers and age at diagnosis were compared using two-sided χ2 tests or Fisher’s exact test when the number was < 10. Results: Of the 9820 patients with MPCs tested for the 21 genes above, 104 (1.1%) had multiple PVs and were excluded. Among the remaining 9716 patients in the analytic cohort, most were female (91.1%) and white (71.0%). The median age at testing was 63 years (IQR: 16) and the median ages of first and second cancer diagnosis were 49 (IQR: 18) and 58 (IQR: 17) years, respectively. Overall, 1406 (14.5%) were found to have PVs: 14.3% of females and 16.2% of males. The prevalence of PVs increased with the number of primary cancers (PCs) as follows, 2 PCs: 13.1% (95% CI:12.4-13.8%), 3 PCs: 15.9% (95% CI:14.0-18.0%), >4 PCs: 18.0% (95% CI:13.7-23.3%), (p < 0.01). Among patients with 2 PCs (n = 8145), differences in the prevalence of PVs by age at diagnosis were significant: 2 PCs diagnosed at an age < 50 (13.5%, 95% CI:12.0-15.1%), 1 PC diagnosed at an age < 50 (14.8%, 95% CI:13.4-16.5%), 2 PCs diagnosed at age >50 years (12.1%, 95% CI: 11.1-13.2%), (p = 0.01). PVs were most frequently identified in: BRCA2 (2.2%) BRCA1 (2.0%), CHEK2 (1.9%) and ATM (1.5%). There were also significant differences in the frequencies of PVs in BRCA1, BRCA2 and MLH1 by sex (p < 0.05). Conclusions: These data demonstrate a high frequency of germline PVs among both males and females with MPC. The frequency of PVs was higher among patients with a higher number of PCs. Differences in the prevalence of PVs by age at cancer diagnosis while significant, were not meaningful as 12.1% of individuals with 2 PCs diagnosed at age >50 years had germline PVs. Limitations include the homogenous testing population (predominately female and white) and small numbers in some patient categories. These data may aid in counseling patients with MPCs and their families as well as encourage less restrictive genetic testing of this population. Further analysis of PV frequencies by specific cancer combinations was conducted and will follow.