Breast Cancer Risk and Hormone Therapy - New Data Emerges
More pieces of a complicated puzzle
My Friends, This highly charged topic is by no means a closed book. This article published just days ago investigates an important question that any woman and her provider should consider in the decision to use HT. Enjoy the review! -Carla DiGirolamo, MD
Since the publication of the Women’s Health Initiative (WIH) study in 2002, patients and the medical community have exercised caution surrounding the use of hormone therapy (HT) for peri-menopausal and menopausal women due to concerns about breast cancer risk. When the results of the WIH went public, a media firestorm created a narrative that, frankly, petrified the general public and health care providers alike, casting a dark cloud over the use of HT for menopausal symptoms. As a result, women with life-altering symptoms have gone without treatment jeopardizing their quality of life and overall health and wellness.
After years of continued study and challenges to this damaging narrative by many in the medical community, most notably, Dr. Avrum Bluming in his provocative book Estrogen Matters, the field of menopausal medicine is re-setting the table on this important issue. The North American Menopause Society (NAMS) convened a task force to critically evaluate the collective body of evidence surrounding the risks and benefits of HT and issued a comprehensive position statement in 2017. Over time, the menopausal population and the medical community have gained a more informed perspective on the risks and benefits of HT, however, there is more work to be done.
One of the limitations of the WIH study was that only two hormonal formulations (conjugated equine estrogen with or without medroxyprogesterone acetate) were studied.
In the June 2022 issue of Obstetrics and Gynecology, researchers from McGill University investigated whether HT formulation impacts breast cancer risk.
Menopausal Hormone Therapy Formulation and Breast Cancer Risk
Haim A. Abenhaim, MD MPH, Samy Suissa, PhD, Laurent Azoulay, PhD, Andrea R Spence, PhD, Nicholas Czuzoj-Shulman, MMA, and Togas Tulandi MD MHCM
Obstetrics and Gynecology Vol 139, No. 6, June 2022
Type of study: Case-Control using data from the UK Clinical Practice Research Datalink.
Timeframe: Women were followed from the time they were registered in the database starting in 1995-ending in 2014.
Participants: 43,183 women who developed breast cancer after registration in the database were matched with 431,830 women without breast cancer in the database as the control group.
Exclusions: age 75 or greater or breast cancer diagnosis at the time of entry into the registry.
Covariates: Data on obesity, smoking status, alcohol use, medical history of endometrial cancer, hysterectomy, oophorectomy (removal of ovaries), Oral Contraceptive Pill (OCP) use, and family history of breast cancer were also collected and included in statistical analysis.
Main Outcome Measure: Risk of developing breast cancer in women using the following HT formulations: bioidentical estrogens, animal-derived estrogens, micronized (bioidentical) progesterone, and synthetic progestin compared to HT non-users.
The Case group (those that developed breast cancer) had a statistically higher incidence of obesity (BMI of 30 or >), those reporting smoking and alcohol use, history of endometrial cancer, use of OCPs, and family history of breast cancer.
HT use was associated with an increased risk of breast cancer, with an odds ratio of 1.12 after adjustment for the above covariates (obesity, smoking, etc). This translates into a 12% increased risk above the control group (no HT use). This is comparable to the magnitude of risk observed in the WHI report for the estrogen/progesterone arm of the study.
When the data were stratified by type of HT formulation and controlled for the above covariates:
Use of Estrogens alone (bioidentical or animal-derived) was not associated with an increased risk of developing breast cancer compared to HT non-users.
The use of synthetic progestins showed an increased risk of breast cancer whereas micronized progesterone (bioidentical progesterone) did not show an increased risk.
When the data analysis was restricted to women aged 50-60 years and controlled for the above covariates, the same statistically significant associations were observed.
Authors Discussion - Key Points
Previous studies including WHI suggest that the use of estrogens alone - regardless of formulation - did not confer a higher risk of breast cancer. However, the risk appears to be related more to progestin use.
Other studies support the notion that synthetic progestins have very different biological effects on breast tissue and may incur a greater breast cancer risk.
HT may be related to breast cancer in promoting the growth of occult (not yet detected) cancers vs de-novo (new-onset) cancers.
Administrative study of registry entries as compared to medical chart review.
Other relevant covariate data such as race, ethnicity, socioeconomic class, and education level were not available.
Rigorous statistical analysis and validity testing.
Reflected actual prescribing practices allowing for the analysis of different HT formulations and age-appropriate use.
In My Humble Opinion (IMHO)
This study reiterates the findings in prior studies - including the WHI - that the risk of developing breast cancer related to HT use is SMALL, but it is not zero. Just as there is an increased risk of developing deep venous blood clots (DVT) with HT use, HT can be used safely in women when their personal risks and benefits are assessed by a qualified provider. That being said, be wary of anyone who tries to tell you that HT is no different from supplements. HT is safe for most women - but it’s not like candy that can be taken indiscriminately as many suggest!
The second key takeaway is the distinction between the risks associated with bioidentical vs. synthetic progestins. There are a wide variety of HT formulations and routes of administration from which women and their providers can choose. My personal practice is to prescribe FDA-approved, bioidentical estradiol (17-beta estradiol) and micronized progesterone whenever possible. Before deciding on HT, work with your provider to learn exactly what types of estrogens and progestogens comprise their recommended therapy.
But what about the progesterone IUD? Mirena, Skyla, Kylena, and Liletta all secrete the synthetic progestin, Levonorgestrel. However, the exposure of the progestin is largely limited to the uterus, and rarely are these progestins detectable in the bloodstream. Although there has been very little, if any, study specifically looking at breast cancer risk as it relates to progesterone IUD use, I would speculate that the low to undetectable presence of the progestin in the circulation favors a much safer situation than the orally ingested synthetic progestins found in other types of HT. If you are in a country where oral micronized progesterone is not available in HT formulations, your safest bet may be a Mirena IUD combined with 17-beta estradiol skin patches or 17-beta estradiol oral pills.
But what about oral contraceptive pills (OCPs)? Most OCPs on the market contain synthetic progestins. They are also most commonly prescribed in pre/peri-menopausal women - a younger age group than the participants in the studies noted previously. It has been suggested that a possible mechanism by which HT increases the risk of breast cancer is through stimulating the growth of an existing, occult (undetected) cancer rather than causing a new cancer. Because younger women are at a significantly lower risk of breast cancer compared to postmenopausal women, breast cancer risk in those taking OCPs is less apparent. My personal practice is to insist that any woman age 40 and over have a negative mammogram prior to starting HT and yearly mammograms while taking HT.