Reproductive risk factors in relation to molecular subtypes of breast cancer: Results from the nurses' health studies

Abstract

Several intrinsic breast cancer subtypes, possibly representing unique etiologic processes, have been identified by gene expression profiles. Evidence suggests that associations with reproductive risk factors may vary by breast cancer subtype. In the Nurses' Health Studies, we prospectively examined associations of reproductive factors with breast cancer subtypes defined using immunohistochemical staining of tissue microarrays. Multivariate-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Over follow-up, we identified 2,063 luminal A, 1,008 luminal B, 209 HER2-enriched, 378 basal-like and 110 unclassified tumors. Many factors appeared associated with luminal A tumors, including ages at menarche (Pheterogeneity=0.65) and menopause (Pheterogeneity=0.05), and current HT use (Pheterogeneity=0.33). Increasing parity was not associated with any subtype (Pheterogeneity=0.76), though age at first birth was associated with luminal A tumors only (per 1-year increase HR=1.03 95%CI (1.02, 1.05), Pheterogeneity=0.04). Though heterogeneity was not observed, duration of lactation was inversely associated with risk of basal-like tumors only (7+ months vs. never HR=0.65 95%CI (0.49, 0.87), Ptrend=0.02), Pheterogeneity=0.27). Years between menarche and first birth was strongly positively associated with luminal A and non-luminal subtypes (e.g. 22-year interval vs. nulliparous HR=1.80, 95%CI (1.08, 3.00) for basal-like tumors; Pheterogeneity=0.003), and evidence of effect modification by breastfeeding was observed. In summary, many reproductive risk factors for breast cancer appeared most strongly associated with the luminal A subtype. Our results support previous reports that lactation is protective against basal-like tumors, representing a potential modifiable risk factor for this aggressive subtype.

Breast cancer risk prediction: an update to the Rosner–Colditz breast cancer incidence model

“…In addition, vegetable intake and breastfeeding duration also significantly contributed to improving the model for ER−/PR− breast cancer, but not ER+ models, consistent with prior research [17,18,19]. The age-adjusted AUC for the final model for all invasive breast cancer was 0.636.…”

“…[17] Longer duration of breastfeeding has also been associated with lower risk of ER− tumors. [18, 19] Whether these risk factors improve breast cancer risk prediction above and beyond the risk factors in the current Rosner-Colditz model is unknown. Percent mammographic density (MD), which reflects the proportion of the breast which is dense (radiographically light) on a mammogram, is consistently one of the strongest independent predictors of breast cancer risk.…”

Parity, hormones and breast cancer subtypes - results from a large nested case-control study in a national screening program

“…In contrast, in the systematic review of 38 studies [47] they used a wider definition of luminal A (ER+ and/or PR+ and HER2-), and only one luminal B subtype (ER+ and/or PR+ HER2+). Some studies have also added on Ki67 to the definition of luminal B [40, 48, 49], which may give a more precise definition of luminal B, although Ki67 is notoriously difficult to assess [55]. Although our luminal A results were much in line with previous studies, there were some slight differences between our study and previous studies of luminal B, as discussed below.…”

“…There is less evidence of a protective effect of parity on luminal B-like and HER2-positive cancers and parity has consistently been found not to protect against triple-negative disease [7, 47–50]. There is some, albeit inconsistent, evidence that older age at menarche and breastfeeding may protect against all subtypes [7, 8, 47, 49–52] suggesting that these protective effects may work through non-hormonal mechanisms. The use of menopausal hormone therapy has been consistently associated with an increased risk of luminal A-like breast cancer, but the evidence is less clear for risk of luminal B-like, HER2-positive and triple-negative breast cancer [10, 47, 49].…”

Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes

“…Understanding similarities and differences in epidemiologic, pathological, molecular, and clinical features by biologically relevant subtypes is essential in order to reduce morbidity and mortality from EOC, as has been achieved with breast cancer [9,10]. For breast cancer, subtype-specific risk factors have been described [11–14], targeted treatments are effective in improving clinical outcomes [15,16], and differences in the incidence and mortality of subtypes [17,18] has set the stage to identify causes of racial, ethnic and socioeconomic disparities [19]. Similar research in EOC is in its infancy partially because it is a rare cancer (incidence 11.9 per 100,000) [20] but also because the recent major paradigm shifts in the understanding of EOC point to the need to approach EOC research in new ways.…”