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By Jeffrey T. Jensen, MD, MPH
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he is a consultant for and receives grant/research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed; and is a consultant for Teva Pharmaceuticals and Microchips.
Synopsis: Using data from the Two Sister Study, investigators found no association of past combined hormone replacement therapy with young-onset (before age 50) breast cancer, and a protective effect with estrogen-only therapy.
Source: O’Brien KM, et al. Hormone therapy and young-onset breast cancer. Am J Epidemiol 2015;181:799-807.
To evaluate the impact of hormone replacement therapy (HT) on young-onset (< 50 year old) breast cancer, the authors used the Sister Study, a prospective cohort study of 50,884 women without breast cancer who had a full or half sister who had been diagnosed with breast cancer. Sister Study participants were enrolled between 2003 and 2009 and were 35-74 years of age living in the United States or Puerto Rico. A case-control study was performed. Cases were diagnosed with breast cancer within the past 4 years and before 50 years of age, and controls were full sisters of cases. After exclusions (e.g., sisters had to be within 7 years of age), there were 1419 eligible cases and 1665 eligible controls in the Two Sister Study sample. Cases included both invasive and in situ cancers. Participants were asked whether they had ever used any form of HT, and if so, the type of therapy and ages at which they started and stopped. Women who exclusively used creams, suppositories, or gels were considered nonusers. HT users were further subdivided according to duration of use (< 2 years vs ≥ 2 years), age at first use (< 40 years vs ≥ 40 years), and timing of first use relative to menopause. Since cases tended to be younger than controls, the investigators used propensity scores to adjust for differences in the opportunity to use HT. The authors used conditional logistic regression to estimate crude and adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the associations of each type of HT with breast cancer risk, using nonusers as the common reference. The adjusted models included birth order, menopausal status, presence of menopausal symptoms, hysterectomy/oophorectomy status, and length of recall between a woman’s interview age and HT exposure assessment age.
Only 11% of controls and 8% of cases reported any use of HT. Of these, most (7% controls, 4% cases) used estrogen-only therapy (E-HT) with smaller proportions (4%, 2%) using estrogen plus progestin (EP-HT) therapy. As expected, use of HT was associated with early menopause, bilateral oophorectomy, and menopausal symptoms. Overall, the use of EP-HT was not associated with young-onset breast cancer (aOR, 0.80; 95% CI, 0.41-1.59). Adjustment for duration or recency of use and age at first use did not measurably modify the associations. In contrast, E-HT use was associated with protection against young-onset breast cancer (aOR, 0.58; 95% CI, 0.34-0.99). Of interest, the use of progestin-only HT was associated with a statistically nonsignificant increased risk of young-onset breast cancer (aOR, 1.51; 95% CI, 0.76-3.00).
The authors concluded that neither EP-HT nor E-HT increases the risk of young-onset breast cancer and that E-HT might be associated with a reduced risk.
According to the American Cancer Society, approximately 25% of breast cancers are diagnosed in women younger than age 50 years.1 Previous research on whether hormonal therapy increases the risk of early breast cancer has been inconclusive. Shantakumar et al2 found an increased risk with EP-HT (aOR, 3.51; 95% CI, 1.45-8.49) but not E-HT (aOR, 1.17; 95% CI, 0.23-5.88), and Palmer et al3 also reported a nonsignificant increased risk for women younger than 50 years of age who took E-HT for at least 5 years (relative risk [RR], 1.6; 95% CI, 0.3-8.5). In contrast, Nelson et al4 found a reduction in risk in women ages 40-49 years who did not have a uterus and reported HT use (likely E-HT). Results from the O’Brien study add to this literature and are consistent with the main findings in the Women’s Health Initiative EP-HT and E-HT studies.
The finding that HT is not associated with early-onset breast cancer risk is highly relevant to clinical practice. First, let’s put this into perspective. Although E-HT was associated with protection in this study, we should be highly cautious when epidemiologic studies provide risk estimates of less than two-fold (e.g., an elevation of risk of > 2.0 or reduction in risk of < 0.5). Therefore, the finding that E-HT actually protects women against breast cancer should be viewed with suspicion. However, the reduction seen is similar to that noted in the Women’s Health Initiative (WHI) E-HT arm. Anderson et al found that the use of estrogen only for a median of 5.9 years was associated with a significantly lower incidence of invasive breast cancer compared with placebo (hazard ratio [HR], 0.77; 95% CI, 0.62-0.95), with no significant difference in risk reduction in those women diagnosed during the intervention phase (21% decrease) and post-intervention (25% decrease).5 And even more impressively, fewer of the E-HT-treated women died from breast cancer (HR, 0.37; 95% CI, 0.13-0.91) or from any cause. You should also keep in mind that the magnitude of the effect of protection with E-HT (~60%) is actually larger than the magnitude of widely quoted increased risk with EP-HT (~25%)!
The absence of an increase of early breast cancer with EP-HT in the O’Brien study also provides reassurance. Most epidemiologic studies of this type suffer from recall bias that tends to push the risk estimate in the direction of harm, as women who are “cases” may be more likely to remember exposure than controls. Although the hazard ratio for breast cancer was significantly elevated in the WHI EP-HT arm (HR, 1.24; CI, 1.01-1.54), the magnitude of the increase is small, and statistical significance is lost in most of the subanalyses.6 Another finding of great interest in the O’Brien study is the nonsignificant elevation of odds of early breast cancer seen in women prescribed EP-HT. The most likely indication would be abnormal uterine bleeding, and the most commonly prescribed drug would be medroxyprogesterone acetate (MPA), the same progestin used in Prempro™, the combination therapy of the WHI. Taken together, these data provide additional evidence against the use of MPA for HT. I recommend oral micronized progesterone or the levonorgestrel intrauterine system (off label) for my postmenopausal patients with a uterus.
So what did you hear from the media about this study? Probably crickets. Even the authors of this study seemed disappointed not to report an elevation of risk; the results section of the abstract stated “unopposed estrogen use was inversely associated with the risk of young-onset breast cancer” rather than stating the effect was protective. Good news continues to be no news. But this is information you can use in the clinic tomorrow counseling young women faced with the decision of starting HT for premature menopause: Breast cancer risk concern should not be the deciding factor for the use of postmenopausal HT. In particular, for women who undergo surgical menopause at a young age, the results are directly applicable and highly reassuring, particularly if hysterectomy is also planned.