Experts debate new analysis concerning breast cancer risk with menopausal HT
A recent meta-analysis of nearly 60 epidemiologic studies suggests that women who initiated systemic hormone therapy around the time of menopause were at greater risk for invasive breast cancer than similar never-users, with some excess risk persisting more than a decade after stopping therapy. The analysis, which evaluated findings from large observational studies, also suggests that increased risk for breast cancer doubles for women who used hormone therapy for 10 years vs. 5 years.
“The totality of the worldwide evidence shows that breast cancer risk is increased while women use menopausal hormone therapy and also after they stop taking it,” Valerie Beral, DBE, FRS, FRCOG, FMedSci, professor of epidemiology and co-director of the cancer epidemiology unit at the University of Oxford in England, told Endocrine Today. “This means that the absolute risk is greater than previously thought. For example, 5 years of menopausal HT, starting at age 50 years, would increase breast cancer incidence from ages 50 to 69 years by about one additional case in every 50 users of estrogen plus daily progestogen HT, one in every 70 users of estrogen plus intermittent progestogen HT, and one in every 200 users of estrogen-only HT.
The findings, published in August in The Lancet, are a cause for concern among some menopause clinicians, who worry women who might benefit from HT will unnecessarily avoid it.
“The presentation of the findings is problematic, because the results are likely to be taken out of context and will frighten women,” JoAnn E. Manson, MD, DrPH, FACE, FAHA, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, told Endocrine Today. “Menopausal hormone therapy has a complex balance of benefits and risks. It is important for clinicians to individualize decision-making and consider a woman’s severity of symptoms, underlying risk factor status and personal preferences, and not focus on only a single health outcome in isolation.”
Beral and colleagues analyzed individual participant data from 58 studies, among them 24 prospective cohort studies, conducted between January 1992 and January 2018 that assessed the type and timing of menopausal HT use (mean age at menopause, 50 years; mean age at HT initiation, 50 years). Current users were included up to 5 years (mean, 1.4 years) after last-reported menopausal HT use. Researchers used a nested, case-control design, comparing estrogen alone vs. never use and combination therapy vs. never use. Each women with a diagnosis of invasive breast cancer was matched with four controls by age, birth year and geographic location. Researchers used logistic regression analysis to estimate adjusted risk ratios for breast cancer, comparing menopausal HT users with never users.
Among women with complete information, mean menopausal HT duration was 10 years for current users and 7 years for past users. During prospective follow-up, 108,647 women developed breast cancer at a mean age of 65 years. Among these women, 55,575 (51%) had used menopausal HT.
Longer use, greater risk
Researchers found that every menopausal HT type, apart from vaginal estrogens, was associated with excess breast cancer risk, which increased steadily with duration of use and was greater for estrogen-progestogen than estrogen-only preparations. Among current users, excess risks were observed even during years 1 to 4, with an RR of 1.6 (95% CI, 1.52-1.69) for estrogen-progestogen preparations and 1.17 (95% CI, 1.1–1.26) for estrogen-only preparations. This risk doubled for current users during years 5 to 14, with RRs of 2.08 (95% CI, 2.02-2.15) for estrogen-progestogen preparations and 1.33 (95% CI, 1.28-1.37) for estrogen-only preparations.
The researchers noted that the estrogen-progestogen risks during years 5 to 14 were greater with daily vs. less frequent progestogen use, with RRs of 2.3 (95% CI, 2.21-2.4) vs. 1.93 (95% CI, 1.84-2.01; P < .0001 for heterogeneity).
For a given preparation, the RRs during years 5 to 14 of current use were greater for estrogen-receptor-positive tumors vs. estrogen-receptor-negative tumors. Risks for breast cancer were similar for women initiating menopausal HT at ages 40 to 44, 45 to 49, 50 to 54, and 55 to 59 years, but attenuated by starting after age 60 years or by adiposity.
“Although use of either type of [menopausal] HT for less than 1 year was associated with little subsequent risk, for women of average weight in developed countries, 5 years of use, starting at age 50 years, would cause an appreciable increase in the probability of developing breast cancer at ages 50-69 years,” the researchers wrote. “About half the excess would be during the first 5 years of current use of [menopausal] HT, and half would be during the next 15 years of past use.”
The researchers estimated that the absolute increase would be about 2 cases per 100 women (one in every 50 users) for estrogen plus daily progestogen, 1.4 per 10 women (one in 70 users) for estrogen plus intermittent progestogen and 0.5 per 100 women (one in 200 users) for estrogen-only HT.
Susan Davis, MBBS, FRACP, PhD, FAHMS, a professor in the School of Public Health and Preventive Medicine at Monash University, Australia and president of the International Menopause Society, said the study has “significant limitations” and needs to be thoughtfully appraised.
“It is also vital to consider this to be a unidimensional study,” Davis told Endocrine Today. “The only outcome was breast cancer risk. There was no consideration given to the established reduction in osteoporosis and fragility fracture with menopausal HT or reduced CVD risk with estrogen-only therapy, and alleviation of symptoms was not considered.”
In response to the study findings, the International Menopause Society (IMS) issued a statement noting that for observational studies in the meta-analysis, the use of menopausal HT, including dose and formulation, was a personal choice, as opposed to a randomized controlled trial.
“The authors have tried to minimize bias in their analyses, but it is important to recognize that observational studies include unquantifiable confounding effects, for which corrections cannot be made, and so as in all studies, there are limitations,” the IMS stated in a press release.
For many women going through premature or early menopause, there is relief to be found in HT, according to researchers. An Endocrine Society clinical practice guideline issued in 2015 advocates HT as an effective treatment for most women 60 years or younger or less than 10 years past the onset of menopause who experience bothersome hot flashes and other symptoms and do not have contraindications.
Many women, however, remain reluctant to use HT. The guideline, in part, was designed to address a decrease in the use of HT following the results of the 2002 WHI, which demonstrated that, in women aged 50 to 79 years (mean age, 63 years), estrogen plus progestin increased the risk for CV complications, deep vein thrombosis and breast cancer. The results led to widespread uncertainty among patients, and the use of estrogen and progestin and even estrogen alone has declined sharply since the WHI results were published.
The results have left some clinicians frustrated. Manson said that when it comes to menopausal HT, decision-making should be guided by the big picture.
“Many of these risks, on an absolute scale, are small,” Manson said in an interview. “Often, those risks are offset by reduction in symptoms, improved quality of life and benefits for other health outcomes, such as fractures. The net effects can be favorable for some women, particularly women in early menopause with moderate to severe vasomotor symptoms at low risk for breast cancer and cardiovascular disease.”
In a presentation at the 2017 North American Menopause Society annual meeting, Nanette Santoro, MD, professor and chair of reproductive endocrinology and infertility, department of obstetrics and gynecology at the University of Colorado Denver, said that menopausal HT is one of the best examples of precision medicine in clinical practice and remains the most effective first-line treatment for the common symptoms of menopause. The symptoms that can come with the menopause transition vary greatly among women and even by race, Santoro said, and the decisions of whether to initiate HT — and which formulation — are the embodiment of what precision medicine is all about.
The Lancet analysis, Santoro told Endocrine Today, reinforces the approximate breast cancer risks established by the WHI and indicates that most hormone preparations of estrogen plus progestin have the same effect on the breast.
“This is how I counsel my patients, because I do not want to minimize risks that are not truly known,” Santoro said. “[The study] also puts the lie to marketers of bioidentical hormones, who imply in their advertising that their particular preparations are more natural and therefore may avoid these risks. That is not true, and patients should not believe this.”
Santoro said the large cohort in the meta-analysis “helps to sharpen some of the blurry edges of knowledge in this area.”
Assess risks , benefits
In a commentary accompanying the study article, Joanne Kotsopoulos, PhD, a scientist at Women’s College Research Institute and associate professor at the Dalla Lana School of Public Health at the University of Toronto, noted that the main analysis was limited to prospective studies with detailed information on HT use and adjusted for potential confounders.
“The complexity of the study design makes it difficult to appraise the results, and most of us will take the results on face value,” Kotsopoulos wrote. “However, it is often difficult to avoid biases in prospective studies in which the period of exposure (HT use) overlaps with the period of risk (breast cancer incidence). Some women switch from being nonusers to users in the follow-up, and the duration of use is not a constant, but changes each year that hormones are used.”
According to Kotsopoulos, clinicians should take a “rational and comprehensive approach” to the management of menopausal symptoms, with careful consideration of the risks and benefits of initiating menopausal HT for each woman.
“This might be dependent on severity of the symptoms, contraindications for [menopausal] HT (ie, breast cancer, cardiovascular disease and stroke), and BMI, and could take into account patient preference,” Kotsopoulos wrote. “For likely candidates, [menopausal] HT (preferably estrogen alone) should be initiated around the time of natural menopause and ideally limited to 5 years of use.” – by Regina Schaffer
Beral V, et al. Lancet. 2019; doi:10.1016/s0140-6736(19)31709-x.
Santoro N. Hormone Therapy: No sweat for menopausal symptoms. Presented at: Annual Meeting of the North American Menopause Society; Oct. 11-14, 2017; Orlando, Fla.
Stuenkel CA, et al. J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2015-2236.
For more information:
Susan Davis, MBBS, FRACP, PhD, FAHMS, can be reached at firstname.lastname@example.org.
JoAnn E, Manson, MD, DrPH, FACE, FAHA, can be reached at email@example.com.
Nanette Santoro, MD, can be reached at firstname.lastname@example.org.
Disclosures: Beral, Davis, Manson and Kotsopoulos report no relevant financial disclosures. Santoro reports that she serves on a clinical advisory board for Astellas Pharma, Inc. and holds stock options for Menogenix, Inc.