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

Sue K Park,Boyoung Park,Wonshik Han,Ku Sang Kim,Ho Kyung Sung,Jong-Han Yu,Aung K Win,Sung-Won Kim,Min Hyuk Lee,Dong-Young Noh,Byung-In Moon,John L Hopper,Eunyoung Kang,Choonghyun Ahn,James G Dowty,Jong Won Lee,Jihyoun Lee

doi:10.18632/oncotarget.22193

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.

Highlights

Germline mutations in the BRCA1 or BRCA2 genes are responsible for about 5% of breast cancer (BC) and are associated with a substantially increased lifetime risk of BC to 70 years old with approximately 65% and 45% of risk, respectively, in Caucasian populations [1, 2].Reproductive factors, including lower number of parity, late parity, early age at menarche, and late menopausal age, are well-established risk factors of female BC in the general population [3, 4]
We evaluated the association between reproductive factors as environmental risk modifiers and BC risk in the hereditary highly susceptible women, such as BRCA1/2 mutation carriers and BRCA1/2 mutation unrelated to high-risk females such as non-carriers with family history (FH) of BC and with early-onset BC
LEEP and later age at menopause decreased BC risk in BRCA1/2 mutation carriers and non-carriers with FH, whereas LEEP rather increased the risk for early-onset BC

Summary

Introduction

Germline mutations in the BRCA1 or BRCA2 genes are responsible for about 5% of breast cancer (BC) and are associated with a substantially increased lifetime risk of BC to 70 years old with approximately 65% and 45% of risk, respectively, in Caucasian populations [1, 2].Reproductive factors, including lower number of parity, late parity, early age at menarche, and late menopausal age, are well-established risk factors of female BC in the general population [3, 4]. The direction in the association of reproductive factors on BC risk in the general population has been hypothesized to be somewhat different from that in mutation carriers and genetically high-risk groups, such as familial BC or early-onset BC patients. Asians have a different distribution of genetic and environmental risk factors, such as lower incidence of BC and mortality rates, different age-specific incidence rate, poor prediction of BC assessment models developed in the Western populations, and higher prevalence of BRCA2 than BRCA1 mutations [18,19,20]. Few studies have focused on the effects of reproductive factors on BC for BRCA1/2 mutation carriers in East-Asian population. The effect of reproductive factors on BC risk in the general population may be different from that in genetically high-risk groups, such as familial BC or early-onset BC; previous studies on BC with family history (FH) or early-onset BC did not exist

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