New Data Supports Link Between Menopausal Hormone Tx and Breast Cancer

Up until 2002 many women routinely took menopausal hormone therapy (MHT) for symptoms of menopause as well as to prevent osteoporosis and heart disease. That changed, however, with the findings from the Women's Health Initiative (WHI) trial of estrogen plus progestin (combination therapy).
A 2013 overview of WHI hormone therapy trials reported that during the WHI combination therapy trial, breast cancer risk progressively increased to 24% overall. For every 10,000 women taking the combination hormone therapy for 1 year, there were nine additional cases of breast cancer, and the risk remained elevated during the post-intervention follow-up period.
This link between hormone therapy and an increased risk of breast cancer changed clinical practice, and led to a dramatic reduction in the use of MHT.
Now, a meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer of 58 studies, including 24 prospective cohort studies, essentially strengthens the evidence of a link between MHT -- particularly the increased risk of breast cancer associated with combination therapy -- and suggests the risks may be greater than previously thought.
In the study, published online in The Lancet, the authors' analysis took into account the age when MHT was first used, duration of use, and the amount of time since the last use. The mean age of when the participants started menopause was 50, as was the mean age at which they started using MHT.
The researchers found that women who used MHT had a significantly higher risk of developing invasive breast cancer than women who never used MHT, and calculated that for women of average weight in developed countries, 5 years of MHT starting at age 50 would increase breast cancer incidence at ages 50-69 by about the following:

• One in every 50 users of estrogen plus daily progestogen preparations

• One in every 70 users of estrogen plus intermittent progestogen preparations

• One in every 200 users of estrogen-only preparations

"The corresponding excesses from 10 years of MHT would be about twice as great," the collaborative group added.
The author of an accompanying commentary, Joanne Kotsopoulos, PhD, of Women's College Research Institute in Toronto, wrote: "This was a very comprehensive study, with strong evidence showing a causal relationship between hormone therapy and breast cancer risk, and is a very important contribution to the literature. The take-home message is that there was a significantly increased risk of invasive breast cancer in women who used menopausal hormone therapy versus women who never used it, The effect was stronger if current or past users, and was also stronger with increasing duration of use. What was also reiterated was that [the combined therapy] had a stronger effect than estrogen alone."
One of the authors of the 2013 review, WHI investigator Rowan Chlebowski, MD, PhD, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, noted that the study results about the association between breast cancer and combined hormone therapy "are really identical in many ways to the [WHI] randomized clinical trial data suggesting an increase in breast cancer incidence and an increase in deaths from breast cancer, which is sustained even years after you stop."
The study's findings regarding estrogen alone "will be a matter of discussion," he added.
While the WHI estrogen-plus-progestin trial breast cancer risk showed a progressively increased risk of breast cancer, the investigators in the estrogen-alone trial observed a reduced risk of breast cancer among women assigned to estrogen compared with placebo.
As noted in the overview of the WHI randomized trials, the WHI investigators found that for every 10,000 women taking estrogen-alone for 1 year, there were seven fewer cases of breast cancer. This effect was present but not statistically significant during the intervention phase, but it persisted after stopping, and there was a significantly reduced risk of breast cancer (21%) over a 13-year follow-up.
The authors of The Lancet study suggested that since the average age at randomization was 64 in the estrogen-only trial, it is possible that starting estrogen-only therapy well after menopause might not have the same effect on breast cancer risk as starting at about the time that menopause begins. They also suggested that the protective effect of hormone treatment seen in the estrogen-only trial possibly "arose mainly by the play of chance, perhaps augmented by changes in breast density somewhat reducing the sensitivity of mammographic screening."
While The Lancet study provides important information about the long-term effects of combination therapy on breast cancer risk, the conflicting conclusions regarding estrogen-only therapy and breast cancer risk represents a challenge going forward, said Chlebowski: "Is it possible that 58 observational studies can give a different answer than a $300 million randomized trial, and both be right when they are done in the same time frame, with pretty much the same medications? The discordance between findings of these full-scale observational studies and a full-scale randomized trial with respect to estrogen alone on breast cancer incidence and mortality remains a question."
As for the impact that The Lancet study results may have, Kotsopoulos said clinicians and patients must have a "personalized, frank discussion" about the circumstances for each woman.
"A woman who is presenting with severe menopausal symptoms with quality of life severely diminished and who has no other contraindications may be a candidate for hormone-replacement therapy," Kotsopoulos added. "And women who are candidates for hormone therapy based on discussion with clinicians should use it for the minimal amount of time they need it, and those who are initiating hormone therapy should make sure it is actually mitigating their symptoms."
"In the past a lot of women were put on hormone therapy and they were just taking it for decades and it wasn't really helping their symptoms. Now that we know there is an increase in breast cancer risk, candidates should use it for the shortest amount of time," she continued.
She said that obviously, it's a stronger risk with the combined therapy, but it is necessary for women who still have their uterus intact, and have not had a hysterectomy. "For women who've had a hysterectomy, it's a little easier because they can be put on estrogen alone, where we see a smaller increase in risk."