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 (PVs) 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 BRCA1 (HR=2.28, 95% CI=1.11-4.65) and ERCC2 (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 ERCC2 PVs (HR=5.09, 95% CI=1.58-16.4) and a suggestive association of BRCA2 PVs (HR=2.24, 95% CI= 0.91-5.55) were observed. There was also a higher risk of SPNBC in carriers of BRCA1 PVs (HR=2.98, 95% CI=1.21-7.36). These results provide evidence that germline PVs in BRCA1, BRCA2, and ERCC2 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 breast cancer patients, supporting the need for closer monitoring of SPC in women carrying PVs in these genes.

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