Abstract P1-09-02: Prevalence of genetic mutations in patients with second primary breast cancers
Authors: Yao K , Clifford J , Li S , LaDuca H , Hulick PJ , Xu J , Gutierrez S , Black MH 
Published: May 2019

Background: Women newly diagnosed with primary breast cancer (PBC) often undergo multi-gene panel testing to determine their contralateral breast cancer (BC) risk and whether a contralateral prophylactic mastectomy is warranted. However, with the exception of BRCA1/2, gene-specific associations with contralateral or second PBC (SPBC) have not been established. Methods: The study sample was comprised of 83,278 women with BC referred to a single diagnostic laboratory for multi-gene panel testing. The frequency of pathogenic/likely pathogenic variants in clinically-actionable genes (CAG), including highly penetrant genes (HPG: BRCA1, BRCA2, TP53, PTEN) and moderately penetrant genes (MPG: ATM, CHEK2, PALB2, CDH1, NBN, NF1) was compared between women with a PBC and SPBC. Women with a SPBC &lt;1 year from their first diagnosis were excluded. Logistic regression burden tests were used to test for associations between mutated genes and SPBC adjusting for age at diagnosis of first BC, histology, presence of first- or second-degree relative with BC, and race/ethnicity. Results: The study included 75,550 women with PBC and 7,728 with SPBC. The median (IQR) time between primaries for the SPBC group was 11 (6,17) years . Women with SPBC were slightly more likely to be Caucasian (67.8% vs. 63.4%; p&lt;0.001), older when referred for genetic testing (mean difference 9.7 years, p&lt;0.001), slightly younger at first BC diagnosis (mean difference 2.1 years, p&lt;0.001) and slightly more likely to have &gt;1 first or second degree relative with BC (62.2% vs. 60.8%; p=0.004) than PBC. Among women tested for all CAGs, 4,883 (8.1%) were carriers of pathogenic/likely pathogenic variants (11.1% SPBC vs. 7.8% PBC). CHEK2 was the most frequently mutated gene (3.4% SPBC vs. 2.3% PBC), followed by BRCA1 (2.7% SPBC vs.1.6% PBC), BRCA2 (2.2% SPBC vs. 1.8% PBC), and PALB2 (1.4% SPBC vs. 0.9% PBC). In fully adjusted models, women with SPBC were 1.38 times as likely (p=&lt;0.0001) as women with PBC to test positive for a CAG (OR=1.35 for HPG and 1.34 for MPG). BRCA1 (OR=1.49; p&lt;0.0001), followed by CHEK2 (OR=1.36; p&lt;0.0001) and PALB2 (OR=1.53; p&lt;0.001) were most significantly associated with SPBC. TP53, BARD1, ATM and BRCA2 were marginally associated with SPBC (p=0.01 to 0.06). When results were stratified by race/ethnicity, ORs among Caucasians were similar to those observed overall. Among African Americans, women with SPBC were 1.76 times as likely to carry a CAG (p&lt;0.001) than their PBC counterparts. PALB2 (OR=2.69; p=0.002), BRCA2 (OR=1.85; p=.004), and TP53 (OR=3.88; p=.009) were most significantly associated with SPBC followed by BRCA1 (OR=1.63; p=.002). Analysis of gene associations for other racial/ethnic groups was limited by small sample size. Conclusions: There is a significantly higher prevalence of CAG mutations among women with SPBC, even after adjusting for age at diagnosis and family history. These findings support SPBC as a standalone indication for multigene panel testing. Additional studies aimed to assess cumulative risk of SPBC for CAG beyond BRCA1/2 are needed to help guide clinical management decisions for mutation carriers.

Citation Format: Yao K, Clifford J, Li S, LaDuca H, Hulick PJ, Xu J, Gutierrez S, Black MH. Prevalence of genetic mutations in patients with second primary breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-02.