Breast Cancer Risk and Menopausal Hormone Therapy - The Latest in the Ongoing Debate

Revisiting the Women's Health Initiative trial

The debate surrounding the risk of breast cancer and the use of menopausal hormone therapy (MHT) has been raging since 2002 when the combined estrogen (Conjugated Equine Estrogen (CEE))/progestin (Medroxyprogesterone Acetate (MPA)) arm of the Women’s Health Initiative (WHI) randomized controlled trial was terminated due to a statistically significant increase in the risk of breast cancer in the participants randomized to this arm of the study compared to the placebo group. This led to a media frenzy resulting in a sharp decline in prescriptions for MHT due to provider concerns over breast cancer risk as well as fear of the same in menopausal women experiencing symptoms.

Through the years, there has been rigorous follow-up study of these risks with increasing reassurance that the benefits of HT for treating menopausal symptoms in early menopause outweigh the risks of breast cancer, thromboembolism, and gallbladder disease. However, debate continues over the interpretation of the original WHI and subsequent follow-up studies with varying conclusions and perspectives.

The following article published in the April 2023 issue of Menopause presents the discordance between the results of the WHI randomized trials and other cohort studies describing the relationship between MHT and breast cancer. The authors also provide a rebuttal to many of the challenges to the original findings and interpretation of the WHI research.

Below is a summary of the article including highlights of the debate points presented. *Of note, the authors disclose that the entities that provide support for the WHI also partially supported their article. My personal opinion, commentary, and analysis follow the summary.

Definitions

Cohort study: Observational study of a group of individuals that share certain characteristics who have had a common “exposure” (in this case, MHT) and followed over a period of time.

Randomized controlled trial: A scientific study where participants are selected based on specific criteria/characteristics and then randomized and assigned to a “control” group (receives a “placebo” treatment) and an “experimental” group (receives the therapy of interest). These studies are designed to study cause-effect relationships between therapies and outcomes.

Progestogen: A term that refers to any natural progesterone or synthetic derivative of progesterone found in MHT formulations.

The Women’s Health Initiative randomized trials of menopausal hormone therapy and breast cancer: findings in context

Rowan T Chelbowski and Aaron K Aragaki. Menopause Vol 30 No 4 2023.

Goal of the study

Summarize the findings for the impact of MHT on breast cancer from cohort studies and the WHI randomized trials and address concerns raised regarding the WHI findings.

Study methods

The author’s referred to 2 analyses in their review of findings from cohort studies:

1. Collaborative Group on Hormonal Factors in Breast Cancer meta-analysis: 52,000 with and 108,000 women without breast cancer beginning in 1997 and updated in 2019.

2. Million Women Study: 1,084,110 post-menopausal women age 50-64, with 9,364 breast cancer cases beginning in 2003 and updated in 2019.

The Authors identified commentaries and editorials from the journals Menopause and Climacteric from 2002 to the present. A total of 30 commentaries challenged the conclusions of the WHI.

Highlights of the Discussion Points

The authors summarized the findings from the Collaborative Group and the Million Women Study and compared the findings to those of the WHI randomized trials.

• The Collaborative Group and Million Women Study report a statistically significant increase in breast cancer incidence in women taking combined estrogen/progestin MHT and MHT containing only estrogen.

• The WHI randomized trials reported a decrease in breast cancer incidence in the group taking MHT containing only estrogen.

• Findings from the WHI randomized trials and the findings from the Collaborative Group and Million Women study revealed an increased incidence of breast cancer in women taking MHT containing estrogen and a progestogen.

The authors address multiple challenges to the findings of the WHI randomized trials raised in the 30 editorials and commentaries they reviewed as part of their analysis. Below are excerpts addressing some of the more common arguments.

Challenge. The decrease in breast cancer incidence in the estrogen (CEE)-only group of the WHI randomized trial could be simply due to chance.

• Authors’ rebuttal: The lower breast cancer incidence seen with estrogen (CEE) alone was seen across all decades; 50s, 60s, and 70s in more than 10,000 randomized participants with the placebo and MHT groups having comparable baseline risk as defined by the Gail-5 year breast cancer risk tool. Given the robust size, the randomized structure of the study, and comparable baseline risk, these findings are unlikely due to chance.

Challenge: The increased incidence of breast cancer in the CEE + MPA group in women with prior hormone use was based on a lower breast cancer incidence among former hormone users in the placebo group rather than an increased incidence in the CEE + MPA group.

• Authors’ rebuttal: After long-term follow-up (20 years) there does not appear to be any significant difference in breast cancer incidence comparing prior hormone users to never-users taking estrogen/progestogen MHT.

Challenge: The WHI findings are not relevant for current practice because different types of progestogens may carry different risks for cancer outcomes.

• Authors’ Rebuttal: Micronized progesterone has been associated with lower breast cancer risk in some but not all observational studies. The Million Women study reported an “increased risk of breast cancer risk with estrogen plus progestin MHT use.” The study further states that “results varied little between different types of estrogen and progestogen”.

Challenge: Breast cancer risk with estrogen and progestin use is low.

• Rebuttal: The authors cite studies that reported a rapid and sustained reduction in age-adjusted breast cancer seen in the United States that followed the decrease in MHT use. A modeling study of this trend estimates that 126,000 fewer breast cancers occurred between 2002 and 2012 had the WHI trial results not been available. The authors cite another modeling study performed by Santen et al. that calculated attributable 5-year breast cancer incidence risk from the Collaborative Group findings in low, intermediate, and high-risk groups of women at 1.5%, 3.0%, and 6.0% baseline risk, respectively. Their findings report 12, 42, and 85 additional cases of breast cancer per 1000 women per year in the low, medium, and high-risk groups, respectively. “Against this background, individual women can decide whether such risks are “rare””.

Authors’ Conclusions

• The WHI randomized trials evaluating MHT provide reliable evidence regarding CEE alone and CEE + MPA influence on breast cancer incidence and breast cancer mortality.

• The North American Menopause Society (NAMS) 2022 position statement supports the distinction in breast cancer risk in women taking HT containing only estrogen as compared to combined estrogen / progestogen MHT.

• “For younger women with prior hysterectomy, besides the reduction in breast cancer incidence, and breast cancer mortality, it can be reassuring that in the WHI trial, there was a nominal decrease in all-cause mortality.” The authors further state that the same reduction in all-cause mortality was not seen in the combined CEE + MPA group of the WHI trial.

In My Humble Opinion….

The premise for this article is certainly warranted given the impact that the interpretation of the initial findings of the WHI trial had on the practice of menopausal medicine for the decades that followed and that continue today.

What stood out to me the most about this article was the Authors’ rebuttal to the challenge that breast cancer risk with estrogen and progestogen use is low. The Authors cite modeling studies that put forth numbers of excess breast cancer cases in estrogen/progestogen users literally orders of magnitude greater than what was reported in the WHI, which is the very study they are trying to defend. The WHI reported 8-10 additional cases per 10,000 women in the CEE + MPA users relative to the control group. The modeling studies cited by the authors suggest between 12-85 additional breast cancer cases per 1000 women using combined MHT, which is more than 10-fold higher than the risk suggested by the WHI findings.

It’s critically important to note that modeling studies are not randomized controlled trials and do not carry the same validity. Modeling studies are not studies of actual individuals but rather mathematical and statistical models based on findings from other studies and should be considered only at face value. These studies provide support more for the Authors’ sentiment about the level of risk associated with combined MHT rather than supporting the actual data in the WHI trial. However, in fairness, the observed reduction in breast cancer cases seen following the decrease in the MHT prescribing patterns should not be ignored.

Another point that is important to speak to is the Authors' statement that the WHI data did not see a decrease in all-cause mortality in women using CEE + MPA. Although this may be true of the study they cite, this contradicts the statement in the NAMS 2022 Position Statement on Hormone Therapy which states that in women < age 60 and <10 years from menopause taking combined estrogen/progestogen HT for appropriate indications, a reduction in all-cause mortality has, in fact, been observed for both combined estrogen/progestogen HT and HT containing only estrogen.

Where does this leave us?

In my opinion, the recommendations outlined in the NAMS 2022 Position statement as well as the combined statement from the British Menopause Society and the Royal College represent the most objective, evidence-based analysis of the safety and efficacy of MHT based on decades of study that was built upon the foundation of several well-done studies including the WHI randomized trials as well as the cohort studies of the Collaborative Group and the Million Women Study. Some of the points in the NAMS 2022 position statement that have stood the test of time are as follows:

• Benefits outweigh the risks of estrogen/progestogen MHT in healthy women <10 years since menopause onset, <60 years old taking MHT for appropriate indications. A decrease in all-cause mortality has been observed in these women taking combined estrogen/progestogen as well as estrogen-only MHT.

• Data does not support the general use of MHT for the sole purpose of disease prevention as risks often outweigh potential benefits.

• Choosing MHT requires an individualized, risk/benefit analysis for each woman’s specific situation. There should be no arbitrary limits on the duration of MHT use.

How this affects my personal practice

For every woman I see for menopausal care, the approach is highly individualized taking into account risks, benefits, and her personal goals for care. The foundation of my care begins with fitness, nutrition, appropriate supplementation, and lifestyle factors with the use of pharmacology when indicated.

Truth be told, in my opinion, I do not think the breast cancer risk is as low as the initial WHI suggests. I also take the thromboembolism (blood clot) risk very seriously, as this risk underlies cardiac events, stroke and dementia. But regardless of what the actual “numerical” risks are in the published literature, what is most important and has stood the test of time is that the benefits outweigh the risks in younger menopausal women and I have no hesitation in prescribing HT for these women with no set limits on duration.

For other women where it may not be so straightforward, the risk/benefit equation carries the day, taking into account her symptoms, the effectiveness of HT in resolving those symptoms, risks for fracture, and other components of her medical history.

My first line is bioidentical FDA-approved estrogen and progesterone and generally prefer the transdermal (skin patch) route for estrogen. For all women, I strongly recommend a mammogram prior to the start of HT and annually while taking HT.

They way forward

This debate is far from over, and with time, new questions will emerge. I applaud the task forces created by NAMS who have done an excellent job of objectively assessing the original literature and the follow-up studies that are the basis for their recommendations. The trends in the NAMS Position Statements over more than a decade have demonstrated increased reassurance of the safety of MHT in younger women, older women at low risk, and even women with genetic predispositions for heritable breast cancer without a personal history of cancer. So with every new article that emerges, the approach is the same. Give it credence, but always put it in the context of the “bigger picture”.

References

Ravdin PM et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007;356:1670-1674.

Hersh AL et al. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004;291:47-53.

Roth JA et al. Economic return from the Women’s Health Initiative estrogen plus progestin clinical trial: a modeling study. Ann Intern Med 2014;160:594-602.

Reference Santen RJ et al. Underlying breast cancer risk and menopausal hormone therapy. J Cln Endocrinol Metab 2020 (105) 105.