The association between menopausal hormone therapy and breast cancer remains unsettled

It has been more than 2 decades since the Women’s Health Initiative (WHI; https://www.whi.org/) alarmed clinicians with a report that found that the combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), when administered to postmenopausal women, increased breast cancer risk as well as the risks for coronary heart disease, stroke, and total mortality without improving quality of life. Since then, several researchers have questioned the findings, and the overarching conclusions have been revisited by WHI investigators themselves. Despite this, clinicians and their patients continue to take on a “safer rather than sorry” stance and often decide against taking the menopausal hormone therapy (HT), regardless of what symptoms may be present.

For example, in a study appearing in the journal Menopause: The Journal of The Menopause Society in April 2023 (doi:10.1097/GME.0000000000002154), WHI investigators conceded that HT yielded considerable benefits. However, they continued to assert that the associated increase in the risk of breast cancer with combined HT (CEE and MPA) remained a valid concern.

In response, a review published in the journal sought to rectify the association between breast cancer and HT—both CEE alone and CEE in combination with MPA, a large source of the misinterpretation (doi:10.1097/GME.0000000000002267). One of the authors, Avrum Z. Bluming, MD, an oncologist at the Keck School of Medicine at the University of Southern California in Los Angeles, explains it this way: “According to WHI’s own data, estrogen alone significantly decreases the risk of breast cancer development (by 23%) and the risk of breast cancer death (by 40%)—crucial information for women who have had hysterectomies.” In addition, “when started within 10 years of a woman’s final period (the ‘window of opportunity’), the WHI now agrees,” says Dr Bluming, that “it significantly decreases the risk for coronary heart disease, improves longevity, is the best and safest treatment for menopausal symptoms, and does not increase the risk of stroke. Further, it decreases the risk of osteoporotic hip fracture, colon cancer, and diabetes mellitus.” The sole issue at play is the association between combined HT (CEE plus MPA) and the risk of breast cancer.

In their review, Dr Bluming and his colleagues write that “the association between combined HT and an ‘increased breast cancer risk’ is actually not statistically significant. Further, even if one were to accept that the WHI’s claims of an increased risk were accurate, that increase would amount to one additional case of breast cancer for every 1,000 women treated per year but no increase in the risk of dying from breast cancer.” In addition, they argue that the assertion from WHI investigators that there is an association between the declining incidence of breast cancer and the reduction in HT prescriptions is not supported by several lines of data, including the fact that the decline in breast cancer incidence in the United States actually predated the release of the WHI’s results.

Dr Bluming and his colleagues are concerned that the WHI investigators’ 2023 article, by minimizing and deflecting repeated substantive criticisms, prolongs the worry so deeply felt by women and physicians and the resulting underutilization of HT at the expense of women’s health. “As a new generation of women ponders the benefits and risks of HT,” they conclude, “with breast cancer fear as a driving factor in women’s health choices, it is time to be honest about these findings from WHI.”

“This analysis is provocative,” says Joshua D. Safer, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, New York. “It does not change all the messages we’ve received and believed from WHI, but it does a good job of highlighting that the women treated with estrogen had benefit with regard to breast cancer risk—a key point that has been buried for years.”

“I think this review is important in that it makes us reconsider what the risks and benefits are if you’ve prescribed—or are considered prescribing—systemic hormone replacement therapy for women with menopause,” says Ellie Proussaloglou, MD, an assistant professor of surgery (breast surgical oncology) at Yale University in New Haven, Connecticut. “This review addresses whether we are undertreating women with systemic menopausal symptoms, and what’s the impact of that? This is very important as we responsibly consider what the data actually tells us about cancer risk.

“The advice that I give to my patients, and the advice I give to clinicians I meet is to have a really nuanced conversation about the symptoms their patient is experiencing, what breast cancer risks are factoring into that decision making, such as family history and personal factors, and then to strike a balance,” adds Dr Proussaloglou, who is also the physician lead for high-risk breast care in the Division of Cancer Genetics and Prevention at Smilow Cancer Hospital in New Haven, Connecticut. “Too often, we have patients who are told concretely—by their physicians—that HT therapy is bad—it increases your breast cancer risk; this doesn’t account for all of the other medical benefits of HRT [hormone replacement therapy] and quality-of-life factors that impact women during menopause. It also doesn’t account for differential risk from specific hormone formulations.”

Dr Proussaloglou says that oncologists should think about the use of HT separately for patients who have cancer and patients who have not had cancer. “It is important to distinguish patient groups into people who do not have cancer, for whom I think the existing data in this article and other research indicates that HT is not this terrible option that we thought, and those who do have cancer. Of course, for patients with cancer it’s a different conversation regarding risks of hormone replacement.”

“A takeaway from this study is humility,” says Dr Safer, who is also the executive director of the Mount Sinai Center for Transgender Medicine and Surgery. “Some of what we’ve believed we’ve known regarding the connection between breast cancer and exogenous estrogens may be a connection between breast cancer and exogenous progestogens instead. It’s just that most studies examine both agents together due to concern for cancer risk with unopposed exogenous estrogens. It is interesting to consider that the breast cancer risk may not be higher for women who take estrogen/progestogen combination therapy—the opposite of what many have thought.

“Even if that were not true, it would be still true that estrogen seems to protect against breast cancer in some instances, while progestogens mitigate or completely reverse that benefit. That means perhaps we should be encouraging women who don’t have a uterus, and therefore who can take estrogens without progestogens, to take estrogens as they pass typical menopause age. That could be true for both transgender women and for cisgender women who have had a hysterectomy.”

Dr Bluming says that he is realistic about how his and his colleagues’ critique will be received. “This paper (itself) should generate considerable controversy.” He believes that the takeaway message is best stated in the conclusion of the article:

“If WHI had transparently reported their breast cancer findings in 2002, emphasizing, among other things, a lack of statistical significance in breast cancer risk in the per-protocol adjusted statistic; had quickly followed up by publishing a per-protocol analysis adjusting for baseline breast cancer risk factors; and had reminded the public that its findings did not apply to women initiating HT in perimenopause or early post-menopause, there would have been minimal controversy, no confusion, and women’s health would not have suffered so dramatically over the ensuing decades.”