Hormone Replacement Therapy Does Not Increase Breast Cancer Recurrence, Mortality in Survivors

Undergoing hormone replacement therapy for menopausal symptoms does not increase the risk of breast cancer recurrence in women treated for breast cancer, according to a new study of more than 8000 women.

An analysis of longitudinal data from a national cohort of postmenopausal women diagnosed with early-stage invasive estrogen receptor (ER)–positive nonmetastatic breast cancer who received no treatment or 5 years of adjuvant endocrine therapy, results of the analysis suggests there was no statistically significant increase in the risk of recurrence or mortality for those who received either vaginal estrogen therapy or menopausal hormone therapy.

“In postmenopausal women treated for early-stage ER-positive breast cancer, use of vaginal estrogen therapy or menopausal hormone therapy was not associated with increased risk of recurrence or mortality. In patients treated with vaginal estrogen therapy and adjuvant aromatase inhibitors, we observed an increased risk of recurrence but not mortality. This association was not observed among women who received tamoxifen or in those who did not receive adjuvant endocrine therapy,” wrote investigators.

Despite more recent trials alleging no increased risk of recurrence with use, a pair of trials in the 1990s cast doubt over the safety of menopausal hormone therapy in women with history of breast cancer. Citing limitations within study demonstrating no increased risk of recurrence, a team representing Odense University Hospital, the Danish Breast Cancer Group (DBCG) at Copenhagen University Hospital, and Aarhus University Hospital conducted the current study to assess risk of recurrence of breast cancer and mortality following treatment with vaginal estrogen therapy or menopausal hormone therapy in postmenopausal women.

To do so, investigators designed their study as an analysis of longitudinal data from the DBCG clinical database, the Danish National Prescription Database, the Danish National Patient Registry, and the Danish Civil Registration System. With patients of interest defined as postmenopausal women aged 35-95 years, diagnosed with invasive early-stage nonmetastatic, ER-positive breast cancer from 1997-2004 registered in the DBCG clinical database, and who did not receive chemotherapy. From the databases, investigators identified 8461 women with a median follow-up of 9.8 years for recurrence and 15.2 years for mortality for inclusion in their analyses. Of these, 1957 used vaginal estrogen therapy and 133 used menopausal hormone therapy.

For the purpose of analysis, each woman included in the study was categorized as vaginal estrogen therapy, menopausal hormone therapy, or never-user according to hormone therapy prescription data obtained from the Danish National Prescription Database. Investigators noted women who received both vaginal estrogen therapy and menopausal hormone therapy were categorized as menopausal hormone therapy users and menopausal hormone therapy were categorized as menopausal hormone therapy alone or menopausal hormone therapy and vaginal estrogen therapy.

The primary outcome of interest for investigators analyses were mortality and risk of recurrence associated with use of vaginal estrogen therapy and menopausal hormone therapy vs nonuse using multivariable models adjusted for age at surgery, tumor size, nodal status, histological type and grade, ER, progesterone receptor, lymphovascular invasion, locoregional therapy, CCI, and, as time-dependent variables, use of tamoxifen, use of adjuvant aromatase inhibitors, and noncompliance for endocrine therapy.

Upon analysis, results indicated the adjusted relative risk of recurrence was 1.08 (95% CI, 0.89-1.32) for vaginal estrogen therapy, 1.39 (95% CI, 1.04-1.85) for a subgroup receiving vaginal estrogen therapy and adjuvant aromatase inhibitors, and 1.05 (95% CI, 0.62-1.78) for menopausal hormone therapy. Assessments of mortality risk yielded adjusted hazard ratios of e 0.78 (95% CI, 0.71-0.87) and 0.94 (95% CI, 0.70-1.26) for vaginal estrogen therapy and menopausal hormone therapy, respectively.

In an accompanying editorial, Elizabeth Cathcart-Rake, MD, and Kathryn Ruddy, MD, MPH, both of the Mayo Clinic, suggest the results of the current study provide reassurance of the safety of menopausal hormone therapy in this patient population, but warn against overinterpretation of results and underline the importance of patient monitoring.

“This large cohort study helps to inform the nuanced discussions between clinicians and breast cancer survivors about the safety of vaginal estrogen therapy,” wrote the pair. “These results suggest that breast cancer survivors on tamoxifen 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.”

This study, “Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study,” was published in the Journal of the National Cancer Institute.