HRT Doubles Recurrence Risk in Breast Cancer Survivors

By Charles Bankhead
LONDON, March 25 -- Breast cancer survivors treated with hormone replacement therapy had a more than two-fold increased risk of recurrence or a contralateral malignancy, according to long-term follow-up data from a randomized clinical trial.
Those randomized to HRT had five-year breast cancer rates of 22.2% compared with 8% in women who received best patient care for menopausal symptoms without hormone therapy, Lars Holmberg, M.D., Ph.D., of King's College London, and colleagues, reported in the April 2 issue of the Journal of the National Cancer Institute.
"The results of the HABITS [Hormonal Replacement after Breast Cancer -- Is It Safe?] trial indicate a substantial risk a new breast cancer event among breast cancer survivors using hormone therapy," the authors concluded.
"Our results further suggest that hormone therapy not only induces and promotes breast cancer but may also stimulate the growth of tumor microdeposits in breast cancer survivors," they added.
Despite the statistically significant impact of hormone therapy on breast cancer risk, the authors said more data from randomized studies are needed to define the risk and to clear up inconsistencies in prior studies.
However, Kathleen Pritchard, M.D., a breast cancer specialist at Sunnybrook Odette Cancer Center in Toronto, said in an accompanying editorial that the study "suggests quite definitively that there is a statistically significantly increased risk of recurrence in women given HRT following diagnosis of breast cancer."
Persistent questions about the potential risks and benefits of HRT in breast cancer survivors provided impetus for several observational studies and analyses of case series. More recently, data from the Women's Health Initiative and the Million Women Study provided additional compelling evidence of an increased risk of breast cancer among HRT users, the King's College authors said.
However, data from randomized clinical trials had been lacking. Among the few randomized trials, HABITS had been stopped early after a preliminary analysis showed more than a three-fold increased risk of breast cancer in HRT users after two years.
In the current study, Dr. Holmberg and colleagues reported four-year median follow-up data. The report encompassed 442 of the original 447 breast cancer survivors included in the study.
HABITS was a noninferiority trial with 80% statistical power to detect a 36% increase in the risk of a new breast cancer event after HRT. Participants were previously treated patients with stage 0 to 2 breast cancer, and were recurrence free without signs of active disease at enrollment. They and were randomly assigned to HRT for menopausal symptoms and compared with women treated with best symptomatic treatment without hormones.
After the median follow-up of four years, 39 women randomized to HRT had a new breast cancer event compared with 17 in the group that did not receive HRT. The difference translated into a hazard ratio of 2.4 (95% CI 1.3 to 4.2).
HRT had no apparent effect on the risk of distant metastasis (six versus four) or breast cancer death (six versus five).
In reviewing potential limitations of the study, the authors noted that they could not account for possible effects of certain patient characteristics and types of hormonal therapy on breast cancer risk at the time HABITS was stopped. Additionally, the study did not have a placebo control, and judgments about disease recurrence might have been subjective.
The authors concluded that physicians and their patients should continue to weigh the risks and benefits of HRT in postmenopausal breast cancer survivors.
In her editorial commentary, Dr. Pritchard characterized the HABITS data more definitively: "It seems that the harmful side effects of HRT have finally been clearly demonstrated. . . . Why did we wait so long?"
"It seems ridiculous to continue to impute effects from observational studies when the conduct of a relatively small randomized controlled clinical study could clearly provide a definitive answer to the question under study," she added.
Neither Dr. Holmberg and colleagues nor Dr. Pritchard reported disclosures.
Primary source: Journal of the National Cancer InstituteSource reference:Holmberg L, et al "Increased risk of recurrence after hormone replacement therapy in breast cancer survivors" J Natl Cancer Inst 2008; 100: 475-482. Additional source: Journal of the National Cancer InstituteSource reference: Pritchard KI "Should observational studies be a thing of the past?" J Natl Cancer Inst 2008; 100: 451-453.