December 13, 2019
Two different types of menopausal hormone therapy — estrogen alone and estrogen plus progestin — have opposite effects on breast cancer incidence that persist long after stopping treatment, according to over 19 years of follow-up of the landmark Women's Health Initiative (WHI) released today.
The data indicate that use of conjugated equine estrogens (CEE) alone significantly decreases breast cancer incidence and deaths from breast cancer, while CEE plus medroxyprogesterone acetate (MPA) significantly increases the risk of developing the disease. In both instances, these effects linger for decades after discontinuation.
The data are "remarkable," said lead investigator Rowan T. Chlebowski, MD, PhD, Harbor-UCLA Medical Center, Torrance, California. To date, "no one has been able to reconcile these findings," he acknowledged.
Asked whether these data should influence current guidelines on menopausal hormone therapy, Chlebowski said, "Yes, I would hope so. Women considering estrogen alone should know it's safer and there may be a breast cancer benefit associated with its use," he said.
Women considering estrogen plus progestin have "a little more difficult dilemma because they have to be willing to accept a 20-year and maybe lifetime increased breast cancer risk [although] the absolute risk is very small," he said.
50 Years of Controversy, Lingering Questions
After a half-century, hormone therapy's influence on breast cancer "still remains controversial" with discordant findings from observational studies compared with randomized controlled trials, Chlebowski noted.
Most recently, in a meta-analysis of 58 observational studies, estrogen plus progestin and estrogen alone were both associated with a significantly increased risk of breast cancer. And in the Million Women Study, both estrogen plus progestin as well as estrogen alone were associated with a significantly increased risk of dying from breast cancer.
Against this backdrop, Chlebowski provided an update today on breast cancer findings from the WHI randomized controlled trials with more than 19 years of follow-up. The WHI is funded by the National Institutes of Health (NIH).
From 1993 to 1998, more than 27,000 postmenopausal women aged 50 to 79 years with no prior breast cancer enrolled in one of two randomized, placebo-controlled WHI trials implemented at 40 US centers, with follow-up through September 2016.
Women with an intact uterus received CEE (0.625 mg/day) plus MPA (2.5 mg/day) or placebo (n = 8102) for a median of 5.6 years. Women with prior hysterectomy received CEE alone (n = 5310) or placebo (n = 5429) for a median of 7.2 years.
After about 19 years of follow-up, CEE alone resulted in a significant 23% reduction in breast cancer incidence (hazard ratio [HR], 0.77; P = .005), whereas CEE+MPA resulted in a significant 29% increased risk of breast cancer (HR, 1.29; P < .001).
"A woman takes estrogen/progestin for 5 years and she is exposed to a 20-year risk of increasing breast cancer risk ... and one could speculate that it will be a lifetime risk for short-term use," said Chlebowski.
In terms of deaths from breast cancer, there was 45% increase (borderline significance) with CEE+MPA (HR, 1.45; P = .06) and a significant 44% reduction with CEE alone (HR, 0.56; P = .02).
Chlebowski said it should be noted that "none of the approved agents for breast cancer risk reduction ... have been able to demonstrate a reduction in deaths from breast cancer so this is a very unique finding." Chlebowski has been a consultant for AstraZeneca, Novartis, Amgen, Genentech, Pfizer, Puma, Immunomedics, and has received NIH grant funding.
Commenting on the new data for Medscape Medical News, Charles L. Shapiro, MD, professor of medicine, hematology and medical oncology, Icahn School of Medicine at Mount Sinai in New York City, said it's clear that the risk — "both positive and negative" — continues beyond using hormone therapy for at least 10 years.
"Women should be reassured if they had short-term estrogen exposure they are not at increased risk — in fact, the data suggest there is decreased risk," he said.
"Women who had conjugated estrogen and MPA in the past should be aware that their risk may be slightly higher and get their mammograms. Whether that should merit special screening, or more frequent screenings, I don't think we know that," added Shapiro.