Exogenous Hormones: Oral Contraceptives and Hormone Replacement Therapy/Hormone Therapy (HRT/HT)
Oral contraceptives have been associated with a small increased risk of breast cancer in current users that diminishes over time. A well-conducted case-control study did not observe an association between breast cancer risk and oral contraceptive use for every use, duration of use, or recency of use.
Another case-control study found no increased risk of breast cancer associated with the use of injectable or implantable progestin-only contraceptives in women aged 35 to 64 years.
Exogenous hormone therapy (HT) after menopause is associated with increased breast cancer risk. The Women’s Health Initiative (WHI) investigated the effect of hormones and dietary interventions on breast cancer risk. Women with intact uteri aged 50 to 79 years were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). Breast cancer risk was increased with HT with a hazard ratio (HR) of 1.24 (95% confidence interval [CI], 1.02–1.50), resulting in early termination of the HT arm of the trial. The excess risk was observed for invasive but not in situ breast cancer. The HT-related cancers were larger than those related to placebo, though grade and histology were similar. HT was also associated with a higher percentage of abnormal mammograms.
Another trial, the Heart and Estrogen/progestin Replacement Trial,  included an open-label follow-up of a randomized controlled trial of estrogen and progestin therapy in 2,763 women (mean age of 67 years) with coronary heart disease. Breast cancer incidence was increased after a mean follow-up of 6.8 years (relative risk [RR] = 1.27; 95% CI, 0.84–1.94; absolute risk increase 4.7–5.9 cases/1,000 person-years). Though not statistically significant, the RR estimate is consistent with the much larger WHI study.
The risk of breast cancer associated with estrogen-only HT therapy is lower than the risk for combined HT.[8,9,10,11] In a case-control study of women aged 65 years and older, estrogen-only HT, even for more than 25 years' duration, was not associated with risk of invasive breast cancer. The estrogen-only WHI found a nearly statistically significant reduction in
breast cancer incidence in the estrogen-only arm compared with placebo (HR = 0.77; 95% CI, 0.59–1.01; absolute risk reduction from 33–26 breast cancers/10,000 person-years). It is not clear whether this finding is a real effect of estrogen only or is due to chance.
Ionizing Radiation Exposure
A well-established relationship exists between exposure to ionizing radiation
and the risk of developing breast cancer. Excess breast cancer risk is
consistently observed in association with a variety of exposures such as
fluoroscopy for tuberculosis and radiation treatments for acne, tinea, thymic
enlargement, postpartum mastitis, or Hodgkin’s lymphoma. Although risk is
inversely associated with age at radiation exposure, the manifestation of
breast cancer risk occurs according to the usual age-related pattern. An
estimate of the risk of breast cancer associated with medical radiology puts
the figure at less than 1% of the total. However, it has been theorized that
certain populations, such as AT (ataxia telangiectasia) heterozygotes, are at
increased risk of breast cancer from radiation exposure. A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer still further (RR = 1.54; 95% CI, 1.1–2.1), especially for women who were x-rayed before the age of 20.