Among breast cancer survivors with GSM, vaginal estrogen was not associated with increased breast cancer recurrence, breast cancer-specific mortality, or overall mortality.

Background

Genitourinary syndrome of menopause (GSM) is common among breast cancer survivors and impairs quality of life. Although low-dose vaginal estrogen effectively treats GSM, clinicians often avoid prescribing it in this population due to safety concerns, including FDA labeling that lists prior breast cancer as a contraindication. This systematic review and meta-analysis evaluated whether vaginal estrogen use is associated with breast cancer recurrence or mortality in survivors.

Patients

• Breast cancer survivors with GSM using or not using vaginal estrogen.
• Eight observational studies included; countries: USA, UK (including Scotland/Wales), Sweden, Denmark, Australia.
• Sample sizes:
  • Recurrence analysis: 24,060 patients (4,494 users; 19,566 nonusers).
  • Breast cancer-specific mortality: 61,695 patients (3,579 users; 58,116 nonusers).
  • Overall mortality: 59,724 patients (4,684 users; 55,040 nonusers).

Intervention

Low-dose vaginal estrogen therapy for GSM (creams, tablets/inserts, and rings); exposure duration varied across studies.

Control

No vaginal estrogen use (usual care or nonhormonal therapies).

Outcome

• Primary: Breast cancer recurrence (local, contralateral, or distant).
• Secondary: Breast cancer-specific mortality and overall mortality.

Study Design

• Systematic review and meta-analysis of observational studies (cohort/case-control).
• Databases searched from inception to April 6, 2024; secondary search September 26, 2024 (Google Scholar, PubMed/MEDLINE, EMBASE, CINAHL, NCBI, ScienceDirect).
• Random-effects model (DerSimonian–Laird) using pooled, unadjusted odds ratios (OR) with 95% CI; 95% prediction intervals and fragility indices calculated; heterogeneity assessed (I²).
• PROSPERO registration: CRD42023479950.

Level of Evidence

Oxford CEBM Level 2a (systematic review of cohort studies).

Follow up period

• Reported mean follow-up where available ranged from approximately 4.2 to 9.8 years (eg, 4.2 years; 5.0–5.5 years; 9.8 years); several studies did not report follow-up duration.
• Exposure duration to vaginal estrogen varied (some reports ≥1 year; others unspecified).

Results

Primary outcome: Breast cancer recurrence

• Events: 11.6% (520/4,494) with vaginal estrogen vs 15.8% (3,086/19,566) without.
• Effect: OR 0.48 (95% CI 0.23–0.98).
• Absolute risk reduction (ARR): 4.2%; NNT ≈ 24 to prevent one recurrence.
• Heterogeneity: I² 95.8%; 95% prediction interval 0.05–4.96; fragility index 1.

Secondary outcomes

• Breast cancer-specific mortality
  • Events: 8.0% (285/3,579) with vaginal estrogen vs 11.8% (6,885/58,116) without.
  • Effect: OR 0.60 (95% CI 0.18–1.95).
  • ARR: 3.8%; NNT ≈ 26 to prevent one breast cancer death.
  • Heterogeneity: I² 98.1%; 95% prediction interval 0.01–34.69; reverse fragility index 69.
• Overall mortality
  • Events: 17.2% (806/4,684) with vaginal estrogen vs 23.4% (12,869/55,040) without.
  • Effect: OR 0.46 (95% CI 0.42–0.49).
  • ARR: 6.2%; NNT ≈ 16 to prevent one death from any cause.
  • Heterogeneity: I² 0%; 95% prediction interval 0.40–0.51; fragility index 16.

Limitations

• All included studies were observational; no randomized trials identified.
• Evidence of substantial heterogeneity for recurrence and cancer-specific mortality; pooled ORs were unadjusted.
• Potential selection/healthy-user bias (vaginal estrogen users may have had more favorable baseline prognostic factors).
• Variability and incomplete reporting of estrogen formulations, dosing, exposure duration, and follow-up.
• Concomitant endocrine therapy (e.g., aromatase inhibitors) varied; some individual studies reported divergent subgroup signals.
• Publication bias not assessed (fewer than 10 studies per outcome); fragility index for recurrence indicates limited robustness.

Funding

No specific study funding reported. The Department of Obstetrics and Gynecology at the University of Florida College of Medicine–Jacksonville receives research support from Mylan for an unrelated clinical trial. One author (A.M.K.) reports consulting for Mylan; others report no conflicts of interest.

Citation

Beste ME, Kaunitz AM, McKinney JA, Sanchez-Ramos L. Vaginal estrogen use in breast cancer survivors: a systematic review and meta-analysis of recurrence and mortality risks. American Journal of Obstetrics & Gynecology. 2025 Mar; doi:10.1016/j.ajog.2024.10.054.