Hormone Therapy and Young-Onset Breast Cancer

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Hormone Therapy and Young-Onset Breast Cancer

Abstract and Introduction


Estrogen plus progestin hormone therapy (HT) is associated with an increased risk of postmenopausal breast cancer, but few studies have examined the impact of HT use on the risk of breast cancer in younger women. We assessed the association between estrogen plus progestin HT or unopposed estrogen HT and young-onset breast cancer using data from the Two Sister Study (2008–2010), a sister-matched study of 1,419 cases diagnosed with breast cancer before the age of 50 years and 1,665 controls. We assessed exposures up to a family-specific index age to ensure comparable opportunities for exposures and used propensity scores to control for birth cohort effects on HT use. Ever HT use was uncommon (7% and 11% in cases and controls, respectively). Use of estrogen plus progestin was not associated with an increased risk of young-onset breast cancer (odds ratio = 0.80, 95% confidence interval: 0.41, 1.59). Unopposed estrogen use was inversely associated with the risk of young-onset breast cancer (odds ratio = 0.58, 95% confidence interval: 0.34, 0.99). Duration of use, age at first use, and recency of use did not modify these associations.


Breast cancer is the leading contributor to cancer incidence in women in the United States, with an estimated 232,340 new invasive and 64,640 new in situ breast cancer cases in 2013. Although incidence increases with age, approximately 25% of diagnoses occur before the age of 50 years.

There are some etiologic and clinical differences between young-onset and older-onset breast cancer. For example, obesity is associated with reduced risk before but not after menopause, and later age at menarche might be a stronger risk factor for premenopausal breast cancer than for postmenopausal breast cancer. Younger cases tend to present with a higher histological grade and more advanced stage than later-onset cases and are more likely to have triple-negative or human epidermal growth factor receptor-2–positive cancer.

Hormone therapy (HT) comprises estrogen and/or progestin/progesterone usually taken in the form of pills or patches. Women take HT for a range of indications, including but not limited to relief of menopausal symptoms, replacement of hormone levels after oophorectomy, migraine prevention, or osteoporosis prevention. Although most users are peri- or postmenopausal, there is some use among young or premenopausal women.

In many observational studies and randomized controlled trials, it has been reported that postmenopausal women treated with combined estrogen and progestin HT (EP-HT) experience an increased risk of breast cancer. In particular, in the Women's Health Initiative (WHI), investigators found that postmenopausal women randomized to EP-HT had a hazard ratio of 1.26 (95% confidence interval (CI): 1.00, 1.59) for breast cancer relative to placebo users. Longer durations of EP-HT may further increase risk, although these associations seem to dissipate once treatment ends.

The effects of unopposed estrogen therapy (E-HT), which is contraindicated in women with intact uteri because of the risk of endometrial cancer, are less clear. In a second WHI trial restricted to women who were 50–79 years of age with no uterus, those randomized to E-HT were less likely to develop breast cancer than were controls who took placebos (hazard ratio = 0.77, 95% CI: 0.62, 0.95). Few studies have examined progestin alone (P-HT), but some have suggested an increased risk.

The association between HT and breast cancer in young women has been examined in several studies, but only 2 studies differentiated between types of HT. Shantakumar et al. found odds ratios of 3.51 (95% CI: 1.45, 8.49) and 1.17 (95% CI: 0.23, 5.88) for the associations of premenopausal breast cancer with use of EP-HT and E-HT, respectively. Palmer et al. found weak evidence that women under 50 years of age who took E-HT for at least 5 years had increased risk of breast cancer (relative risk = 1.6, 95% CI: 0.3, 8.5). We used data from the Two Sister Study, a sister-matched case-control study, to examine whether use of HT (EP-HT, E-HT, and P-HT) is a risk factor for young-onset breast cancer.

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