Despite worries among some researchers, physicians and patients, menopausal hormone therapy for breast cancer survivors is not associated with breast cancer reoccurrence.

This is the conclusion from a study, funded by Breast Friends, a part of the Danish Cancer Society, and published in the Journal of the National Cancer Institute.[1]

Hot flashes and night sweats, known as vasomotor symptoms, and genitourinary symptoms, which may include vaginal dryness, dysuria, urinary tract infections, and dyspareunia as well as distressing and difficult to resolve sexual dysfunction frequently plague breast cancer survivor. [2]

These symptoms have been recognized as a result of declining estrogen levels and are highly prevalent side effect of adjuvant aromatase inhibitor (AI) therapy for breast cancer. In turn, these adverse events reduce the overall health related Quality of Life (hrQoL) and can lead patients to discontinue their therapy. [3][4]

These symptoms may be alleviated by vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT). However, the safety of systemic and vaginal estrogen use among breast cancer survivors, particularly those with estrogen receptor-positive disease, has been unclear.[3][4]

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Based on the occurrence of adverse symptoms, many doctors caution breast cancer survivors against using menopausal hormone therapy following the demonstration of an increased risk of breast cancer recurrence in two trials in the 1990s. Though subsequent studies have not shown increased recurrence, such studies had serious limitations, including small sample sizes and short follow-up periods.

Study design
Researchers investigated the association between hormonal treatment with the risk of breast cancer recurrence and mortality in a large cohort of Danish postmenopausal women treated for early-stage estrogen receptor-positive breast cancer.

The study included longitudinal data from a national cohort of postmenopausal women, diagnosed between 1997 and 2004 with early-stage breast cancer who received no treatment or five years of hormone therapy, as ascertained from Denmark’s national prescription registry.

Study results
Among 8,461 participating women who had not received vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT) before a breast cancer diagnosis, 1,957 and 133 used vaginal estrogen therapy or menopausal hormone therapy, respectively, after diagnosis. The median follow-up was 9.8 years for recurrence and 15.2 years for mortality.

The adjusted relative risk of recurrence was 1.08 (95% confidence interval [CI] = 0.89 to 1.32) for vaginal estrogen therapy (1.39 [95% CI = 1.04 to 1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62 to 1.78) for menopausal hormone therapy. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71 to 0.87) and 0.94 (95% CI = 0.70 to 1.26) for vaginal estrogen therapy and menopausal hormone therapy, respectively.

The study’s outcome demonstrated that in postmenopausal women treated for early-stage estrogen receptor–positive breast cancer, neither vaginal estrogen therapy nor menopausal hormone therapy was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving vaginal estrogen therapy with adjuvant aromatase inhibitors.

“This large cohort study helps to inform the nuanced discussions between clinicians and breast cancer survivors about the safety of vaginal estrogen therapy,” said Elizabeth Cathcart-Rake, MD, a breast cancer oncologist at the department of oncology, Mayo Clinic, Rochester, MD, USA, who wrote an editorial to accompany the article.

“These results suggest that breast cancer survivors on tamoxifen (Nolvadex*, AstraZeneca and Soltamox, DARA BioSciences) with severe genitourinary symptoms can take vaginal estrogen therapy without experiencing an increase in their risk for breast cancer recurrence. However, caution is still advised when considering vaginal estrogen for breast cancer survivors on aromatase inhibitors, or when considering menopausal hormonal therapy,” Cathcart-Rake added.

“But,” she added, “given that women in this study who were prescribed aromatase inhibitors were at a higher risk for breast cancer recurrence if they received vaginal estrogen therapy, oncologists should should pause before prescribing vaginal estrogen therapy to women on aromatase inhibitors.”[2]

Cathcart-Rake finally notes that vaginal dehydroepiandrosterone (DHEA) can be considered a hormonal option for treatment of genitourinary symptoms in patients taking aromatase inhibitors,” adding that “transferring highly symptomatic women from aromatase inhibitors to tamoxifen could be also be considered. “However, tamoxifen does not reduce the risk of breast cancer recurrence as substantially as aromatase inhibitors, while it does increase risk of thrombosis and uterine cancer in postmenopausal women,” she concluded.[2]

Note:* discontinued by AstraZeneca in June 2008 in lieu of generic forms of tamoxifen.

Highlights of prescribing information
Tamoxifen (Nolvadex®*, AstraZeneca and Soltamox®, DARA BioSciences) [Prescribing Information Nolvadex][Prescribing Information Soltamox]

[1] Cold S, Cold F, Jensen MB, Cronin-Fenton D, Christiansen P, Ejlertsen B. Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study. J Natl Cancer Inst. 2022 Jul 20:djac112. doi: 10.1093/jnci/djac112. Epub ahead of print. PMID: 35854422. [Article]
[2] Cathcart-Rake EJ, Ruddy KJ. Vaginal Estrogen Therapy for the Genitourinary Symptoms of Menopause: Caution or Reassurance? J Natl Cancer Inst. 2022 Jul 20:djac113. doi: 10.1093/jnci/djac113. Epub ahead of print. PMID: 35854417.
[3] Schover LR, Baum GP, Fuson LA, Brewster A, Melhem-Bertrandt A. Sexual problems during the first 2 years of adjuvant treatment with aromatase inhibitors. J Sex Med. 2014 Dec;11(12):3102-11. doi: 10.1111/jsm.12684. Epub 2014 Aug 21. PMID: 25141792; PMCID: PMC4370340.
[4] Frechette D, Paquet L, Verma S, Clemons M, Wheatley-Price P, Gertler SZ, Song X, Graham N, Dent S. The impact of endocrine therapy on sexual dysfunction in postmenopausal women with early stage breast cancer: encouraging results from a prospective study. Breast Cancer Res Treat. 2013 Aug;141(1):111-7. doi: 10.1007/s10549-013-2659-y. Epub 2013 Aug 14. PMID: 23942873.

Featured image: Patient and caregiver. Photo courtesy: © 2016 – 2022. Fotolia/Adobe. Used with permission.

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