Although aromatase inhibitors are effective in reducing estrogen levels and the risk of cancer recurrence in women diagnosed with hormone receptor–positive breast cancer, they can also cause myriad side effects, including genitourinary problems associated with menopause such as vaginal dryness, itchiness, burning, overactive bladder, and urinary incontinence. And while these symptoms may be alleviated by the use of vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT), there are concerns the therapies could increase the risks of breast cancer recurrence and death following treatment.

A large Danish observational cohort study evaluating the association between the use of VET and MHT and the risk of breast cancer recurrence and mortality in postmenopausal women treated for early-stage estrogen receptor (ER)-positive breast cancer has concluded that neither VET nor MHT is linked with an increased risk of recurrence or mortality. However, a subgroup analysis did find an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors. The study by Cold et al was published in the Journal of the National Cancer Institute.

Study Methodology

The study cohort included 8,461 postmenopausal Danish women aged 35 to 95 years who were diagnosed with invasive early-stage ER-positive breast cancer between 1997 and 2004 who were registered in the Danish Breast Cancer Group clinical database. The women had not received chemotherapy. In accordance with national treatment guidelines during the study period, all women were allocated to receive either 5 years of tamoxifen or an aromatase inhibitor, or both treatments in sequence.

The researchers determined prescription data on hormone therapy, VET, or MHT from Denmark’s national prescription registry.

Results

Among the 8,461 women who had not received VET or MHT before their breast cancer diagnosis, 1,957 and 133 used VET and MHT, respectively, after their diagnosis. 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] = 0.89–1.32) for VET (1.39 [95% CI = 1.04–1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62–1.78) for MHT. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71–0.87) and 0.94 (95% CI = 0.70–1.26) for VET and MHT, respectively.

“In postmenopausal women treated for early-stage ER-positive breast cancer, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors,” concluded the study authors.

Accompanying Editorial

Elizabeth Jane Cathcart-Rake, MD

“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 Jane Cathcart-Rake, MD, a physician at the Mayo Clinic in Rochester, Minnesota, who coauthored an accompanying editorial also published in the Journal of the National Cancer Institute. “These results suggest that breast cancer survivors on tamoxifen with severe genitourinary symptoms can take VET 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.”

Søren Cold, MD, PhD, of Odense University Hospital in Denmark, is the corresponding author of this study.

Disclosure: Funding for this study was provided by Breast Friends, a part of the Danish Cancer Society. For full disclosures of the study authors, visit academic.oup.com/jnci.