Research Papers:

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

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

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Oncotarget. 2017; 8:102110-102118. https://doi.org/10.18632/oncotarget.22193

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Boyoung Park1,2, John L. Hopper3, Aung K. Win3, James G. Dowty3, Ho Kyung Sung4,5, Choonghyun Ahn4,5,6, Sung-Won Kim7, Min Hyuk Lee8, Jihyoun Lee8, Jong Won Lee9, Eunyoung Kang10, Jong-Han Yu11, Ku Sang Kim12, Byung-In Moon13, Wonshik Han14, Dong-Young Noh14 Sue K. Park4,5,6 and KOHBRA Study Group

1Department of Cancer Control and Population Health, National Cancer Center Graduate School of Cancer Science and Policy, Gyeonggi-Do, Korea

2National Cancer Control Institute, National Cancer Center, Gyeonggi-Do, Korea

3Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia

4Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea

5Cancer Research Institute, Seoul National University, Seoul, Korea

6Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea

7Department of Surgery, Daerim-Sungmo Hospital, Seoul, Korea

8Department of Surgery, College of Medicine, Soonchunhyang University, Seoul, Korea

9Department of Surgery, College of Medicine, University of Ulsan and Asan Medical Center, Seoul, Korea

10Department of Surgery, Breast and Endocrine Service, Seoul National University Bundang Hospital, Gyeonggi-Do, Korea

11Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

12Breast-Thyroid Center, Ulsan City Hospital, Ulsan City Hospital Group, Ulsan, Korea

13Department of Surgery, Ewha Womans University Hospital, Seoul, Korea

14Department of Surgery, Seoul National University College of Medicine, Seoul, Korea

Correspondence to:

Sue K. Park, email: [email protected]

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

Received: June 20, 2017    Accepted: September 21, 2017    Published: October 31, 2017


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.

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