Hormone Therapy Risk in Postmenopausal ER+ Breast Cancer


Hormone therapy did not increase mortality in postmenopausal women treated for early-stage estrogen receptor-positive breast cancer, but, according to longitudinal data from Denmark, vaginal estrogen therapy was associated with a risk of recurrence among women treated with aromatase inhibitors.

Genitourinary syndrome of menopause (GSM), including vaginal dryness, burning, and urinary incontinence, is common in women treated for breast cancer. Adjuvant endocrine therapy, especially aromatase inhibitors, may exacerbate these symptoms. Both topical and systemic estrogen therapy are recommended to relieve symptoms of GSM in healthy women, but concerns have been raised about their use in women with breast cancer. Previous studies looking into this suggested possible risks of breast cancer recurrence, but these studies had several limitations, including small samples and short follow-up, especially for vaginal estrogen therapy.

In a new study in a Danish cohort of 8461 postmenopausal women who were diagnosed with invasive estrogen receptor-positive early-stage non-metastatic breast cancer between 1997 and 2004, neither systemic menopausal hormone therapy (MHT) nor topical vaginal estrogen therapy (VET) was not used. were associated with an overall increased risk of breast cancer recurrence or mortality. However, in the subgroup treated with an aromatase inhibitor—with or without tamoxifen—there was a statistically significantly increased risk of breast cancer recurrence, but not mortality.


The results were published in the Journal of the National Cancer Institute.

“These data are reassuring for the majority of women who have not received adjuvant therapy or tamoxifen. But for those who use adjuvant aromatase inhibitors, there may be little risk,” said study lead author Soren Cold, MD, senior oncologist in the Department of Oncology. at Odense University Hospital (Denmark), Odense, said in an interview.

What’s more, Cold noted, while this study did not find an increased risk of relapse with MHT in women taking aromatase inhibitors, other studies did. One in particular was stopped due to damage. The reason for this difference is probably that the previous sample was small – only 133 women.


“Our research is mainly focused on the use of vaginal estrogen. We have had so few patients using systemic menopausal hormone therapy that these data mean little… Risk with systemic therapy has been established. have been carefully studied before,” he said.

Breast Cancer Recurrence Increased with VET and Aromatase Inhibitors

The study cohort consisted of 9,710 women undergoing total resection for estrogen-positive breast cancer, all of whom were allocated 5 years of adjuvant endocrine therapy or no adjuvant therapy, as recommended. Overall, 3112 patients received no adjuvant endocrine therapy, 2007 received tamoxifen only, 403 an aromatase inhibitor, and 2939 a combination of tamoxifen and an aromatase inhibitor.


After excluding 1249 people who received VET or MHT prior to breast cancer diagnosis, 6391 were not prescribed estrogen hormone treatment, 1957 were prescribed VET, and 133 were prescribed MHT with or without VET.

During approximately 9.8 years of follow-up, 1333 women (16%) had a recurrence of breast cancer. Of these, 111 received no PIA, 16 MHT and 1206 received neither. Compared with those who did not receive hormonal treatment, the adjusted risk of relapse was the same for OET users (hazard ratio 1.08; 95% confidence interval 0.89-1.32).

However, there was an increased risk of recurrence associated with initiation of VET during treatment with an aromatase inhibitor (RR, 1.39; 95% CI, 1.04–1.85). For women treated with MHT, the adjusted relative risk of relapse with aromatase inhibitors was not significant (RR 1.05; 95% CI 0.62–1.78).


Overall, compared with women who never used hormonal therapy, the absolute 10-year risk of breast cancer recurrence was 19.2% for women who never used OET or MHT, 15.4% for OOT users, and 17.1 % for MHT users.

No difference in mortality was found

Of the 8461 women who participated in the study, 40% (3370) died within approximately 15.2 years of follow-up. Of these, 497 received VET, 47 MHT and 2826 neither. Compared to those who never took estrogen therapy, the adjusted HR for overall survival in OET users was 0.78 (95% CI, 0.71–0.87). An analysis stratified by adjuvant endocrine therapy showed no increase in OET users with aromatase inhibitors (aHR, 0.94, 95% CI, 0.70-1.26). The same was found for women who were prescribed MHT compared with women who never took it (aHR, 0.94; 95% CI, 0.70–1.26).

In women who never used OEL or MHT, the absolute 10-year overall survival was 73.8% compared with 79.5% and 80.5% among women who used OOR or MHT, respectively.


Asked for comment, Nanette Santoro, MD, E. Stewart Taylor Professor and Chair of the Department of Obstetrics and Gynecology at the University of Colorado Denver, Aurora, said in an interview: “It is important to address this issue. We cannot answer the question that vaginal estradiol may not be as safe as we hope for women with breast cancer using an aromatase inhibitor.”

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However, she also noted that “the overall increase in risk is small; the risk of mortality has not increased. Women should consider that this option may involve some risk when deciding whether to take it. Sex life satisfaction is also important for many women! This is indeed a compassionate use to improve the quality of life, so there is always this unknown element of risk in the discussion. This unknown risk must be balanced by the benefits that estrogen provides.”

And Santoro also noted that the use of prescription data imposes limitations. “He cannot tell us what was going on in the minds of the patient and the doctor who prescribed the medicine. There may be differences in the doctor’s opinion about the patient’s risk of relapse that influenced the decision to write a prescription…Women using AI [aromatase inhibitors] often get pretty severe symptoms of vaginal dryness and may need more estrogen to feel comfortable during intercourse, but we really can’t tell from what this article says.”

Indeed, Kholod said: “We acknowledge that this is not a randomized trial, but we have done our best to [confounding] factors including age, tumor size, nodule status, histology, and comorbidities.”

He suggested that a potential therapeutic approach to reduce the risk of relapse could be to switch women on VET to tamoxifen after 2-3 years of aromatase inhibitors.

This work was supported by Breast Friends, which is part of the Danish Cancer Society. Cold has received support from Breast Friends for the current study. Some other co-authors disclose information about pharmaceutical companies. Santoro is a member of the scientific advisory boards of Astellas, Menogenix, Que Oncology and Amazon Ember, and a consultant for Ansh Labs.

This article originally appeared on, part of the Medscape professional network.


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