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Oncotarget. 2017 Oct 31;8(60):102110-102118. doi: 10.18632/oncotarget.22193. eCollection 2017 Nov 24.

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

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Department of Cancer Control and Population Health, National Cancer Center Graduate School of Cancer Science and Policy, Gyeonggi-Do, Korea.
National Cancer Control Institute, National Cancer Center, Gyeonggi-Do, Korea.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
Cancer Research Institute, Seoul National University, Seoul, Korea.
Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea.
Department of Surgery, Daerim-Sungmo Hospital, Seoul, Korea.
Department of Surgery, College of Medicine, Soonchunhyang University, Seoul, Korea.
Department of Surgery, College of Medicine, University of Ulsan and Asan Medical Center, Seoul, Korea.
Department of Surgery, Breast and Endocrine Service, Seoul National University Bundang Hospital, Gyeonggi-Do, Korea.
Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Breast-Thyroid Center, Ulsan City Hospital, Ulsan City Hospital Group, Ulsan, Korea.
Department of Surgery, Ewha Womans University Hospital, Seoul, Korea.
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.


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.


BRCA1/2 mutation carriers; breast neoplasm; early onset breast cancer; familial breast cancer; reproductive factors

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