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Reproductive factors as risk modifiers of breast cancer in BRCA mutation carriers and high-risk non-carriers.

ABSTRACT: This study was conducted to identify the role of reproductive factors as environmental modifiers for breast cancer (BC) risk in clinic-based, East-Asian BRCA1 and BRCA2 mutation carriers and non-carriers with high-risk criteria of BRCA mutations (family history (FH) of BC, early-onset BC (aged ≤40 years)). A total of 581 women who were BRCA carriers (222 BRCA1 and 359 BRCA2), 1,083 non-carriers with FH, and 886 non-carriers with early-onset BC were enrolled and interviewed to examine the reproductive factors, from 2007 to 2014. The hazard ratio (HR) and its 95% confidence interval (CI) in the weighted Cox regression model were used to calculate the BC risk based on the reproductive factors. Earlier menarche increased BC risk by 3.49-fold in BRCA2 mutation carriers (95%CI=2.03-6.00) and 3.30-fold in non-carriers with FH (95%CI=1.73-6.34), but was insignificantly associated with BRCA1 carriers and non-carriers for early-onset BC (P-heterogeneity=0.047). Higher parity decreased BC risk in BRCA carriers and non-carriers with FH, especially in BRCA1 carriers (HR=0.27, 95% CI=0.09-0.83 for two parity; and HR=0.23, 95%CI=0.05-1.00 for ≥3 parity), but increased the early-onset BC risk (HR=4.63, 95%CI=2.56-8.51 for >3 parity, p-heterogeneity=0.045). Oral contraceptive (OC) use and longer estrogen exposure periods (≥30 years) were associated with an increased risk of early-onset BC (HR=3.99, 95%CI=1.65-9.67; HR=7.69, 95%CI=1.96-25.01), while OC use was not associated with BC risk in other groups and longer estrogen exposure had rather decreased risk for BC risk (both p-heterogeneity<0.001). Several reproductive factors as risk modifiers could heterogeneously be associated with BC among BRCA1/2 mutation carriers, non-carriers with FH, and early-onset BC non-carriers.

SUBMITTER: Park B

PROVIDER: S-EPMC5731939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Differences in genomic profiling and immunity-associated parameters between germline BRCA and non-BRCA carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets. Methods: The study cohort included 21 consecutive TNBC cases with germline BRCA1/2 mutations and 54 non-BRCA carriers with a tumor size ≥ 2 cm and/or ≥1 affected lymph nodes. Differences in clinicopathological characteristics and genomic profiles were analyzed through next-generation sequencing. Univariate Kaplan-Meier analysis and Cox regression model were applied to survival analysis. Immunohistochemistry was used to confirm the consistency between CCNE1 amplification and cyclin E1 protein overexpression. Results: The cohort included 16 and five patients with germline BRCA1 and BRCA2 mutations, respectively. Patients with germline BRCA1/2 mutations were diagnosed at a significantly younger age and were more likely to have a family history of breast and/or ovarian cancer. Six non-BRCA carriers (11.11%) carried germline mutations in other cancer susceptibility genes, including five mutations in five homologous recombination repair (HRR) pathway genes (9.26%) and one mutation in MSH3 (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non-BRCA and BRCA carriers, respectively. PIK3CA missense mutation (p = 0.046) and CCNE1 amplification (p = 0.2) were found only in the non-BRCA carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). BRCA status did not affect disease-free survival (DFS, p = 0.15) or overall survival (OS, p = 0.52). CCNE1 amplification was an independent risk factor for DFS in non-BRCA carriers with TNBC (HR 13.07, 95% CI 2.47-69.24, p = 0.003). Consistency between CCNE1 amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity. Conclusions: We found differences in genetic alterations between germline BRCA and non-BRCA carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, CCNE1 amplification is a novel potential prognostic marker and therapeutic target for non-BRCA carriers with TNBC. Cyclin E1 may be used instead of CCNE1 to improve clinical applicability.

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Reproductive factors as risk modifiers of breast cancer in BRCA mutation carriers and high-risk non-carriers.

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