Menopausal Hormone Therapy, Breast Cancer, and Mortality: The Same Story on a Different Day

by Clinical Consulting Team

Doreen Saltiel, MD, JD, FACC is board certified in Internal Medicine and an Advanced Fellow in Anti-Aging and Regenerative Medicine. Recently, she served as the Vice-President, Medical Affairs and Chief Medical Officer for Genova Diagnostics and is currently the Medical Director of Peak Health and Wellness in Asheville, NC. and a consultant for clinical materials at Precision Analytical Inc.

As I perused the cover of the July 28, 2020 issue of JAMA , I saw an article titled, “Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-Term Follow-up of the Women’s Health Initiative Randomized Clinical Trials ,” and knew this article was a must-read. Immediately, I noted the lead author, Dr. Chlebowski, was also the author of numerous other publications related to the Women’s Health Initiative study. 1

The first question I had was why do they continue to publish on drugs given to women who are not typical menopausal patients and have no relevance to clinical practice? Clinicians know that CEE and/or progestins carry unnecessary risks. In fact, traditional guidelines and position papers 13 ^, 14 ^, 15 recommend against CEE or progestins. It is fair to say transdermal estradiol (TD E2) combined with oral or vaginal micronized progesterone is the standard of care.

I also wondered if this article was going to be more of the same, and sadly, the answer was yes. It was the same story on a different day! First, and most importantly, the good: CEE-alone does NOT increase breast cancer. In postmenopausal women, CEE-alone decreases breast cancer incidence and breast cancer mortality after treatment for seven years with twenty years of cumulative follow-up. 1 ^, 2 ^, 3 This finding is consistent with Hodis and Sarrel’s 2018 Women’s Health Initiative reanalysis 2 and the FINNISH study which included both younger and older postmenopausal women. 3 In the latter study, TD E2 was safe when continued for longer than ten years.

Therefore, the questions regarding estradiol-based hormone therapy and breast cancer should be resolved as long as everyone understands that estradiol-based menopausal hormone therapy needs to be prescribed to the right patient, at the right time, using the most appropriate delivery system and dose. In addition, postmenopausal or VMP should also be prescribed, even in women with a uterus.

Unfortunately, the fears continue to perpetuate: combined hormone therapy, in this case CEE + MPA, increased breast cancer incidence, but not breast cancer mortality. 1 Progestins probably increase breast cancer when combined with estrogen, but the Women’s Health Initiative authors’ initial flawed data analysis leads to questions about the validity of these findings, especially in the group who used hormone therapy previously.

The bottom line is it may never be known whether CEE + MPA increases breast cancer, but it really does not matter. Physicians should not be prescribing CEE and/or MPA anyway. In addition, other studies have documented that combined therapy decreases breast cancer incidence and mortality. 3 Furthermore, expert societies recommend transdermal estradiol and oral micronized progesterone or vaginal micronized progesterone.

The Women’s Health Initiative set out to determine if the menopausal hormone therapy health advantages seen in younger postmenopausal women would translate into health advantages, i.e., cardiovascular disease, in older women further from menopause. The primary end-point was cardiovascular disease, not breast cancer, though breast cancer was the primary outcome monitored for harm. Both arms of the study, the CEE-alone (0.625mg/d) vs placebo, and the CEE (0.625mg/d) + MPA (2.5mg/d) vs placebo, were stopped early. The CEE + MPA study was discontinued in 2002 and the CEE-alone trial was discontinued in 2004. The initial study and follow-up studies found an increased breast cancer incidence in the MPA + CEE arm and a decreased breast cancer incidence and mortality in the CEE-alone arm. 1

This follow-up study documents similar results to other Women’s Health Initiative follow-ups; increased breast cancer incidence with CEE + MPA with no increased breast cancer mortality, and decreased breast cancer incidence and mortality with CEE-alone after 20 follow-up years. 1 ^, 16

Hodis and Sarrel’s 2018 review similarly documented a 45% decreased breast mortality in women treated with CEE-alone after 18 follow-up years. 2 FINNISH documented an up to 54% breast cancer mortality reduction in women using bioidentical estradiol. In FINNISH, the greatest mortality benefit was seen in women using estradiol alone (including transdermal estradiol). 3 So, the good continues to be good!

The discrepancy comes when evaluating the CEE + MPA data. The data is confusing, and some experts feel the original Women’s Health Initiative authors’ interpretation continued in this writing, was a misrepresentation. Especially since the use of statistical methods set forth for cardiovascular disease is the primary outcome measure and not breast cancer. 2

Hodis and Sarrel’s review was eye-opening but not surprising. One major takeaway was that the “so-called” breast cancer increase in the group of women with prior hormone use was not an increase at all. The divergent curves which occurred approximately at 2.5 years were not due to an increased breast cancer risk in the treatment arm, but due to the unusually low breast cancer incidence noted in that placebo arm. It is important to recognize that it typically takes more than ten years for breast cancer cells to become clinically evident, again questioning these results. 2 Regrettably, the Women’s Health Initiative authors keep relying on the same flawed data analysis. 1

The CEE + MPA results do not matter. CEE + MPA should not be part of a 2020 menopausal hormone therapy regimen. There are safer options. There are many FDA-approved bioidentical options (patches, gels, and even oral E2) as well as compounded products.

The good news is the CEE-alone results documenting decreased breast cancer incidence and mortality can be extrapolated to estradiol (E2), especially transdermal estradiol. The latter is safer than any oral preparation (including oral E2). The data is clear: in younger women closer to menopause and in older women (average age 63.3 years old) further from menopause, estradiol decreases breast cancer incidence and breast cancer mortality, 1 ^, 2 ^, 3 whereas current treatments for breast cancer prevention (i.e., tamoxifen, raloxifene, and aromatase inhibitors) have not been shown to decrease mortality. In fact, in one tamoxifen trial, though breast cancer incidence decreased, there were six more breast cancer deaths in the tamoxifen group. 1

I am not recommending initiating estradiol for breast cancer prevention or recommending prescribing estradiol in every woman regardless of risk. I am certainly not recommending estradiol be prescribed alone, without oral or vaginal micronized progesterone. I am reassuring practitioners that ultralow-dose and low-dose transdermal estradiol patches, gels, and creams, along with either OMP or VMP are safe for patients considered for estradiol-based menopausal hormone therapy, or who are already using estradiol-based menopausal hormone therapy as long as risk stratification and surveillance are ongoing.

Remember, TD E2 decreases cardiovascular disease, 4 ^, 5 improves vasomotor symptoms, 6 ^, 7 ^, 8 and prevents osteoporosis. 9 What about when adding progesterone? Oral micronized progesterone (OMP) does not increase breast cancer. 10 ^, 11 Vaginal micronized progesterone (VMP) has not been studied directly regarding breast cancer. However, there is indirect data that VMP 45mg (the dose and delivery prescribed during the ELITE trial) does not increase breast cancer. 12

The four concerns raised by the Women’s Health Initiative publications (venous thromboembolic disease, myocardial infarction, stroke, and breast cancer) are minimized or negated by using TD E2 and OMP or VMP. Therefore, there is no role for any synthetic estrogen or progestin.

In conclusion, it is important to ask why the Women’s Health Initiative authors continue to publish follow-up analysis on obsolete drugs in women who are not the typical menopausal patient? Are the Women’s Health Initiative authors trying to scare physicians from treating these women? More importantly, why are respectable journals accepting these papers?!

Precision Analytical has written several evidence-based opinion papers on best practices, lab testing, and dosing for transdermal estradiol and oral progesterone to dive deeper into breast cancer as well as the other menopausal hormone therapy -related benefits and risks.

References

[1] Chlebowski RT, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA . 2020; 324(4): 369-380.

[2] Hodis HN, Sarrel PM. Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials? Climacteric . 2018; 21(6): 521-528.

[3] Mikkola TS, et al. Reduced risk of breast cancer mortality in women using postmenopausal hormone therapy: a Finnish nationwide comparative study. Menopause . 2016; 23(11): 1199-1203.

[4] Mikkola TS, et al. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause . 2015; 22(9): 976-983.

[5] Mikkola TS, et al. New evidence for cardiac benefits of postmenopausal hormone therapy. Climacteric . 2017; 20(1): 5-10.

[6] Cobin RH, Goodman NF. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on Menopause – 2017 Update. Endocr Pract . 2017; 23(7): 869-881.

[7] Pinkerton JAV, et al. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause . 2017; 24(7): 728-753.

[8] Corbelli J, et al. Low-dose transdermal estradiol for vasomotor symptoms: a systematic review. Menopause . 2015; 22(1): 114-121.

[9] Levin VA, et al. Estrogen therapy for osteoporosis in the modern era. Osteoporos Int . 2018; 29(5):1049-1055.

[10] de Lignières B, et al. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric . 2002; 5(4): 332-340.

[11] Espie M, et al. Breast cancer incidence and hormone replacement therapy: Results from the MISSION study, prospective phase. Gynecol Endocrinol . 2007; 23(7): 391-397.

[12] Hodis HN, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med . 2016; 374(13): 1221-1231.

[13] Pinkerton JAV, et al. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause . 2017; 24(7): 728-753.

[14] Cobin RH, Goodman NF. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on Menopause – 2017 Update. Endocr Pract . 2017; 23(7): 869-881.

[15] Stuenkel CA, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab . 2015; 100(11): 3975-4011.

[16] Manson J, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality. The Women’s Health Initiative Randomized Trials. JAMA . 2017; 318(10): 927-938.