Menopausal hormone therapy regimens have opposite lasting effects on breast cancer incidence
SAN ANTONIO — Two common hormone therapy regimens had opposite long-term effects on breast cancer incidence among postmenopausal women, according to results from two large randomized controlled Women’s Health Initiative trials presented at San Antonio Breast Cancer Symposium.
Consistent with prior observational studies, use of estrogen plus progestin appeared associated with increased breast cancer incidence.
However, contrary to prior studies, use of estrogen alone appeared associated with reduced risk for breast cancer and death. This discordance is difficult to reconcile, according to Rowan T. Chlebowski, MD, PhD, chief of the division of medical oncology and hematology at Harbor-UCLA Medical Center and investigator at The Lundquist Institute.
“We were monitoring the estrogen-only group for harm from breast cancer, but we saw just the opposite,” Chlebowski told Healio. “It turns out women in their 50s who want to take estrogen alone are likely to derive an overall benefit. I think there is still a risk associated with estrogen plus progestin, and that risk persists after discontinuation of use, but the absolute risk remains small and that needs to be taken into account.”
Millions of women worldwide receive menopausal hormone therapy. Those with an intact uterus receive estrogen plus progestin, whereas those who underwent prior hysterectomy receive estrogen alone.
“After a half century, however, the effects of estrogen alone or estrogen plus progestin alone on breast cancer remain controversial,” Chlebowski said.
The most recent observational studies — a meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer that included 58 studies, and the Million Women Study — reported estrogen alone or with progestin significant increased risk for breast cancer incidence and mortality.
Chlebowski presented updated findings from two randomized Women’s Health Initiative trials conducted at 40 U.S. centers from 1993 to 1998.
The trials included a combined 27,347 postmenopausal women aged 50 to 79 years with no prior breast cancer.
Women with an intact uterus received conjugated equine estrogen dosed at 0.625 mg daily plus medroxyprogesterone acetate dosed at 2.5 mg daily (n = 8,506) or placebo (n = 8,102) for a median 5.6 years.
Women who had undergone hysterectomy received conjugated equine estrogen alone at the 0.625 mg/day dose (n = 5,310) or placebo (n = 5,429) for a median 7.2 years.
Researchers evaluated the impact each regimen had on breast cancer incidence and mortality.
Study protocol mandated annual mammography. Investigators verified breast cancers by central medical record and pathology report review, and they used central death certificate and medical record review enhanced by National Death Index queries to verify deaths.
In the first trial, after 18.3 years of cumulative follow-up, researchers identified 1,003 incidence breast cancers.
Women who received estrogen plus progestin appeared 29% more likely than those assigned placebo to receive a breast cancer diagnosis (HR = 1.29; 95% CI, 1.14-1.47). Those assigned estrogen and progestin also exhibited an increased risk for breast cancer death (HR = 1.45), but this difference did not reach statistical significance.
The results appeared consistent regardless of disease histology, receptor status and other categories.
In the second trial, after 16.1 years of cumulative follow-up, researchers identified 520 incident breast cancers.
Women who received conjugated equine estrogens alone appeared 23% less likely to receive a breast cancer diagnosis (HR = 0.77; 95% CI, 0.65-0.92) and 44% less likely to die of breast cancer (HR = 0.56; 95% CI, 0.34-0.92) than those assigned placebo.
Subgroup analysis showed estrogen alone conferred a statistically significant 55% reduction in frequency of ER-positive, PR-negative breast cancers, a subtype associated with poor risk.
The findings from this trial are reassuring that women who have undergone hysterectomy can use estrogen alone. However, no one has been able to reconcile the findings from this trial with results from prior observational studies, Chlebowski said.
“Our population was older than women normally starting postmenopausal hormone therapy, though we saw no interaction by age,” Chlebowski said. “It looked like time from menopause was an important factor, as a woman had to be further from menopause to have the greatest effect. We saw a significant interaction with that during the intervention years but it went away, so it looks like something else is going on.”
In both trials, the effect of therapy on breast cancer incidence and mortality persisted for more than a decade after discontinuation.
“That was totally unexpected,” Chlebowski told Healio. “It wasn’t clear at all that both of these effects would be so long-lasting.”
Researchers acknowledged study limitations. Even though death due to breast cancer is the most clinically relevant breast cancer outcome, the fact breast cancer mortality analyses were not protocol-specified. Also, the trials evaluated one dose and schedule of each hormone therapy regimen, so findings may not apply to other preparations, doses or schedules.
However, the findings — in conjunction with other hormone therapy effects on clinical outcomes — should inform clinical decision-making and could even have implications for guidelines, Chlebowski said.
“I would hope so,” he said. “One of the issues is, how do you interpret [findings from a meta-analysis of] 58 observational studies against a 10,800-patient randomized trial with 20 years of follow-up? Women who are considering estrogen alone should know it is safer and their may be a breast cancer benefit associated with its use. Women considering estrogen plus progestin have a little more difficult dilemma because they have to accept a 20-year — or maybe even a lifetime — increased breast cancer risk ... keeping in mind that the absolute risks are very small.” – by Mark Leiser
Chlebowski RT. Abstract GS5-00. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: The Women’s Health Initiative program is supported by NHLBI, NIH, DHS and NCI. Chlebowski reports honoraria from AstraZeneca, Genentech and Novartis, and consultant fees from AstraZeneca, Genentech, Immunomedics, Novartis, Pfizer and Puma Biotechnology. Please see the abstract for all other authors’ relevant financial disclosures.