Association between common risk factors and molecular subtypes in breast cancer patients.

Background: Breast cancer is the most commonly diagnosed cancer in women worldwide and characterized its by molecular and clinical heterogeneity. Gene expression profiling studies have classified breast cancers into five subtypes: luminal A, luminal B, HER-2 overexpressing, basal-like, and normal breast-like. Although clinical differences between subtypes have been well described in the literature, etiologic heterogeneity have not been fully studied. The aim of this study was to assess the associations between several hormonal and nonhormonal risk factors and molecular subtypes of breast cancer.

Methods: This cross-sectional study consisted of 1884 invasive breast cancer cases. Variables studied included family history, age at first full-term pregnancy, number of children, duration of lactation, menstruation history, menopausal status, blood type, smoking, obesity, oral contraceptive use, hormone replacement therapy and in vitro fertilization. The odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariate logistic regression analysis.

Results: Thousand two-hundred and forty nine patients had luminal A, 234 had luminal B, 169 had HER-2 overexpressing and 232 had triple negative breast cancer. The age of ≥40 years was found to be a risk factor for luminal A (OR 1.41 95% CI 1.15-1.74; p=0.001) and HER-2 overexpressing subtype (OR: 1.51, 95% CI: 1.01-2.25; p=0.04). Women who were nulliparous (OR 1.48, 95% CI 1.03-2.13; p=0.03) or who had their first full-term pregnancy at age 30 years or older (OR 1.25 95% CI 0.83-1.88; p=0.04) were at increased risk of luminal breast cancer, whereas women with more than two children had a decreased risk (OR 0.68, 95% CI 0.47-0.97; p=0.03). Breast-feeding was also a protective factor for luminal subtype (OR 0.74, 95% CI 0.53-1.04; p=0.04) when compared to non-luminal breast cancer. We found increased risks for postmenopausal women with HER-2 overexpressing (OR 2.20, 95% CI 0.93-5.17; p=0.04) and luminal A (OR 1.87, 95% CI 0.93-3.90, p=0.02) breast cancers, who used hormone replacement therapy for 5 years or more. Overweight and obesity significantly increased the risk of triple negative subtype (OR 1.89 95% CI 1.06-3.37; p=0.04 and OR 1.90 95% CI 1.00-3.61; p=0.03), on the contrary, decreased the risk of luminal breast cancer (OR 0.63 95% CI 0.43-0.95; p=0.02 and OR 0.50 95% CI 0.32-0.76; p=0.002, respectively) in premenopausal women. There were no significant differences between risk of breast cancer subtypes and early menarche, late menopause, family history, postmenopausal obesity, oral contraseptive use, smoking, in vitro fertilization, blood groups and use of hands.

Conclusions: Reproductive and hormonal characteristics (breastfeeding, parity, age at first full-term birth, hormone replacement therapy) were associated with luminal subtype, compared to non-luminal breast cancer, as consistent with previous studies. Obesity and overweight increased the risk of triple negative subtype, particularly in premenopausal women. Older age and use of hormone replacement therapy were related to the risk of HER-2 overexpressing breast cancer. Our data suggest a significant heterogeneity in association of traditional breast cancer risk factors and tumor subtypes.