Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies

Abstract

Background: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.

Methods: We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.

Results: In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.

Conclusions: This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

Figure 1

Breast tumor subtypes defined by expression of estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratins 5 or 5/6 (CK5 or CK5/6), and epidermal growth factor receptor (EGFR) in 34 studies participating in the Breast Cancer Association Consortium. The number of case patients for each tumor subtype was pooled across all studies with data on the particular subtype.

Figure 2

Risk factors and differential associations with the risk of estrogen receptor (ER)–positive and ER-negative tumor subtypes based on case–control comparisons in 12 population-based studies. Case–control comparisons were stratified by mutually exclusive categories of ER status. The analysis included 14 795 case patients (10 900 for ER⁺ and 3895 for ER⁻) and 17 399 control subjects pooled across 12 studies. The black diamonds and the horizontal lines represent odds ratios (ORs) and corresponding 95% confidence intervals (CIs), respectively. Odds ratios were obtained from unconditional logistic regression models with case–control status (case patients were stratified by ER status) as outcome variables and age, study, and each risk factor separately as independent variables. The associations between body mass index (BMI) in women older than 50 years and family history in first-degree relatives are not shown because they were not statistically significantly modified by ER status in case–case comparisons.Ref = referent category. Odds ratio are presented on the log scale.