Breastfeeding and breast cancer risk by receptor status--a systematic review and meta-analysis

Abstract

Background: Breastfeeding is inversely associated with overall risk of breast cancer. This association may differ in breast cancer subtypes defined by receptor status, as they may reflect different mechanisms of carcinogenesis. We conducted a systematic review and meta-analysis of case-control and prospective cohort studies to investigate the association between breastfeeding and breast cancer by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status.

Design: We searched the PubMed and Scopus databases and bibliographies of pertinent articles to identify relevant articles and used random-effects models to calculate summary odds ratios (ORs) and 95% confidence intervals (CIs).

Results: This meta-analysis represents 27 distinct studies (8 cohort and 19 case-control), with a total of 36 881 breast cancer cases. Among parous women, the risk estimates for the association between ever (versus never) breastfeeding and the breast cancers negative for both ER and PR were similar in three cohort and three case-control studies when results were adjusted for several factors, including the number of full-term pregnancies (combined OR 0.90; 95% CI 0.82-0.99), with little heterogeneity and no indication of publication bias. In a subset of three adjusted studies that included ER, PR, and HER2 status, ever breastfeeding showed a stronger inverse association with triple-negative breast cancer (OR 0.78; 95% CI 0.66-0.91) among parous women. Overall, cohort studies showed no significant association between breastfeeding and ER+/PR+ or ER+ and/or PR+ breast cancers, although one and two studies (out of four and seven studies, respectively) showed an inverse association.

Conclusions: This meta-analysis showed a protective effect of ever breastfeeding against hormone receptor-negative breast cancers, which are more common in younger women and generally have a poorer prognosis than other subtypes of breast cancer. The association between breastfeeding and receptor-positive breast cancers needs more investigation.

Keywords: HER2 receptor; breast cancer; breastfeeding; estrogen receptor; meta-analysis; progesterone receptor.

Figure 1.

Flowchart of selection of studies. *When articles were indexed in both databases, only one was considered for further review. **Four studies were excluded because results were only reported by increments of breastfeeding duration or by average number of children breastfed; another study was excluded because the reference group was not those with the lowest duration of breastfeeding.

Figure 2.

Association between ever breastfeeding and the breast cancers that are negative for both estrogen and progesterone receptors. Adj, adjusted for at least age, body mass index, parity, and family history of breast cancer; Menop, menopausal status of study participants (‘Pre’ and ‘Post’ indicate that participants were premenopausal or postmenopausal women, respectively); NR, not-reported; Pub. year, publication year.

Figure 3.

Funnel plot for the association between breastfeeding and the breast cancers that are negative for both estrogen and progesterone receptors. (A) All studies. P value for publication bias—Egger's method: 0.16; Begg's method: 0.12. (B) Studies adjusted for at least age, body mass index, parity, and family history of breast cancer. P value for publication bias—Egger's method: 0.47; Begg's method: 0.32.

Figure 4.

Association between ever breastfeeding and the breast cancers that were positive for both estrogen and progesterone receptors. Adj, adjusted for at least age, body mass index, parity, and family history of breast cancer; Menop, menopausal status of study participants (‘Pre’ and ‘Post’ indicate that participants were premenopausal or postmenopausal women, respectively); Pub. year, publication year.