Data from Genetic Risk of Second Primary Cancer in Breast Cancer Survivors: The Multiethnic Cohort Study

Abstract

<div>Abstract<p>Women who have had breast cancer in the past are at increased risk of developing a second primary cancer (SPC), including second primary breast cancer (SPBC) or a second primary non-breast cancer (SPNBC). In the Multiethnic Cohort (MEC) Study, we conducted a prospective cohort analysis in 3,223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino, and Native Hawaiian) to assess the association of rare pathogenic variants (PV) in 37 known cancer predisposition genes with risk of SPC. A total of 719 (22.3%) women developed SPC, of which, 323 (10.0%) were SPBC. Germline PVs in <i>BRCA1</i> (HR, 2.28; 95% CI, 1.11–4.65) and <i>ERCC2</i> (HR, 3.51; 95% CI, 1.29–9.54) were significantly enriched in women with SPC. In the subtype analysis for SPBC, a significant association of <i>ERCC2</i> PVs (HR, 5.09; 95% CI, 1.58–16.4) and a suggestive association of <i>BRCA2</i> PVs (HR, 2.24; 95% CI, 0.91–5.55) were observed. There was also a higher risk of SPNBC in carriers of <i>BRCA1</i> PVs (HR, 2.98; 95% CI, 1.21–7.36). These results provide evidence that germline PVs in <i>BRCA1</i>, <i>BRCA2</i>, and <i>ERCC2</i> contribute to the development of SPC in breast cancer survivors. These findings also suggest that compromised DNA repair mechanisms could be a predisposition factor for SPC in patients with breast cancer, supporting the need for closer monitoring of SPC in women carrying PVs in these genes.</p>Significance:<p>This multiethnic study links germline pathogenic variants in <i>BRCA1</i>, <i>BRCA2</i>, and <i>ERCC2</i> to the development of second primary cancer in breast cancer survivors, providing biological insights and biomarkers to guide patient monitoring.</p></div>