Year of Publication



Public Health

Date Available


Degree Name

Master of Public Health (M.P.H.)

Committee Chair

Dr. Tomi Akinyemiju

Committee Member

Dr. Tisha Johnson

Committee Member

Dr. Chunyan He


Introduction: Hormone-related reproductive factors have been reported to be associated with breast cancer subtypes. However, the direction and magnitude of these associations were inconsistent. Additionally, for breast cancer defined by estrogen receptor (ER) and progesterone receptor (PR): ER+PR+, ER+PR-, ER-PR+, and ER-PR- subtypes, no meta-analysis was available for ER+PR-and ER-PR+ subtypes. For ER+PR+ and ER-PR- subtypes, only a few reproductive risk factors have been examined in meta-analyses.

Methods: Primary studies published from 2011 to 2017 were retrieved from PubMed, Embase, and Scopus. Following PRISMA guidelines, a total of 98 eligible studies investigated the association between reproductive factors and breast cancer subtypes. Among these 98 studies, 27 were included in the meta-analysis regarding the association between reproductive factors and ERPR subtypes. Odds ratios (OR), relative risks (RR), and hazard ratios (HR) were extracted for reproductive factors, including age at menarche, age at menopause, menopausal status, pregnancy, age at first birth, parity, breastfeeding, years since last birth, OC use, and HRT. OR and HR were converted to RR to ensure consistency. A meta-analysis with a random effect model was separately conducted for each combination of a reproductive factor and a BC subtype defined by ERPR status. Heterogeneity across studies was examined by I2-statistic, publication bias was examined utilizing Egger and Begg’s test.

Results: This meta-analysis observed that late age at menarche was associated with a reduced risk for ER+PR+ (RR:0.79, 95% CI: 0.72, 0.85), ER+PR- (RR:0.75, 95% CI:0.58, 0.92), ER-PR+ (RR: 0.79, 95% CI:0.63, 0.95), and ER-PR- subtypes (RR:0.85, 95% CI: 0.79, 0.91). Ever versus never pregnancy was associated with a statistically significant reduced risk of ER+PR+ (RR: 0.62, 95% CI: 0.47, 0.78), ER+PR- (RR: 0.70, 95% CI: 0.57, 0.83), and ER-PR+ subtypes (RR: 0.68, 95% CI: 0.49, 0.87). Ever versus never breastfeeding was associated with a statistically significant reduced risk of ER+PR+ (RR: 0.87, 95% CI: 0.79, 0.96), ER+PR- (RR: 0.67, 95% CI: 0.52, 0.83), and ER-PR- subtypes (RR: 0.81, 95% CI: 0.69, 0.93). No significant results were observed for years since last birth and oral contraceptive use. Additionally, results were relatively less consistent for age at menopause, menopausal status, age at first birth, parity, and hormone replacement therapy. There was no evidence of publication bias for pregnancy and parity. For the rest reproductive factors, there is some evidence of publication bias.

Conclusion: The patterns of reproductive factors differ by ERPR status. Most significant associations were observed for ER+PR+ and ER+PR- subtypes. Moreover, strongest associations were mostly observed in ER+PR- subtype. Thus, breast cancer preventive guideline regarding reproductive factors probably should be revised by subtypes. Moreover, ever breastfeeding and pregnancy could probably be added to breast cancer risk calculation model, although more prospective studies with a large sample size are needed to confirm the findings.

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