Sex Hormones, Risk Factors, and Risk of Estrogen Receptor–Positive Breast Cancer in Older Women: A Long-term Prospective Study

Objective: Antiestrogens reduce the risk of estrogen receptor–positive (ER+) but not ER-negative (ER−) breast cancer. Women at high risk of ER+ cancer would be the most likely to benefit from these treatments, but the best approach to predicting ER+ cancer is uncertain. Methods: We prospectively assessed putative risk factors for breast cancer and archived serum at −190°C from a community-based cohort of 7,676 women ages ≥65 years who had no history of breast cancer. Follow-up for breast cancer over 10.5 years was 99% complete. Using a case-cohort design, we measured baseline levels of estradiol and testosterone in 196 cases of invasive ER+ cancer and 378 randomly selected controls. Results: Women whose testosterone level in highest two quintiles had a 4-fold increased risk of ER+ breast cancer ( P < 0.0001). High estradiol concentration also indicated an increased risk but was not a significant predictor after adjustment for testosterone. Women with >16 years of education had a 2.1 times increased risk ( P = 0.03) of ER+ cancer, but no other risk factors were significantly related to an increased risk of ER+ cancer. Women with a family history of breast cancer had a 2.9-fold increased risk of ER− cancer ( P = 0.002) but no increased risk of ER+ cancer (relative hazard = 1.2, 0.8-1.8). Conclusions: High serum testosterone and advanced education predicted ER+ breast cancer. If confirmed, high testosterone level may be more accurate than family history of breast cancer and other conventional risk factors for identifying older women who are most likely to benefit from antiestrogen chemoprevention.