Advancements in breast cancer screening and treatment have led to a growing number of female survivors, boasting a reported 5-year survival rate of up to 90%.¹ However, despite these improvements, over 70% of postmenopausal women who survive breast cancer and undergo systemic therapies often face genitourinary syndrome of menopause (GSM).¹ One of the most effective treatments for vulvovaginal atrophy, a common aspect of GSM, is vaginal estrogen therapy.² Surprisingly, our recent research revealed that very few eligible patients with GSM and a history of breast cancer are prescribed this therapy.³ This hesitancy among clinicians to use vaginal estrogen in high-risk breast cancer survivors is largely attributed to a lack of safety data, as highlighted in a recent expert consensus statement.⁴ To address this gap, we conducted a cohort analysis to investigate the association between vaginal estrogen therapy and recurrence rates in female survivors of breast cancer, utilizing the TriNetX Diamond research network.

The study included adult women diagnosed with GSM 3 months to 5 years after breast cancer diagnosis. The vaginal estrogen cohort received 3 or more vaginal estrogen prescriptions, with at least 1 within 1 year of GSM diagnosis, while the control cohort did not receive vaginal estrogen. A subanalysis looked at concurrent aromatase inhibitor (AI) use with vaginal estrogen. The primary outcome, analyzed after propensity matching, was breast cancer recurrence or secondary malignancy occurrence within 3 months to 5 years after starting vaginal estrogen therapy for GSM.

We identified 42,113 adult women with a diagnosis of GSM; among this group, 5.0% (2111) received vaginal estrogen. Risk of breast cancer recurrence was comparable between those who did and did not receive vaginal estrogen, with a recurrence rate of 17.6% in the vaginal estrogen group and 17.1% in the control group (risk ratio [RR] 1.03, 95% CI 0.91-1.18). No significant difference in all-cause mortality at 5 years was observed between those with or without vaginal estrogen prescriptions. However, vaginal estrogen prescriptions were associated with a decreased risk for all-cause mortality at 10 years compared to control (3.0% vs 4.3%, RR 0.70, 95% CI 0.51-0.96).

In our study population of those with GSM after breast cancer, 30% had available estrogen receptor (ER) status data: 10,584 had a history of ER-positive breast cancer, and 2036 had a history of ER-negative breast cancer. Among these patients, 3.9% of those with a history of ER-positive breast cancer and 5.0% of those with a history of ER-negative breast cancer were in the vaginal estrogen group. Interestingly, significantly fewer individuals with a history of ER-positive breast cancer (P = .02) received vaginal estrogen compared to those with a history of ER-negative breast cancer. Among those with ER-positive breast cancer, no significant difference was observed in risk of breast cancer recurrence between those with or without vaginal estrogen prescriptions (RR 0.94, 95% CI 0.77-1.15).

A secondary analysis compared women prescribed both vaginal estrogen and AIs (anastrozole, letrozole, or exemestane) to those prescribed only vaginal estrogen. Among the 2111 women prescribed vaginal estrogen, 91 were also prescribed AIs. The study revealed a significantly higher risk of breast cancer recurrence in women prescribed both vaginal estrogen and AIs compared to those prescribed vaginal estrogen alone, with recurrence rates of 77.8% versus 15.6% (RR 5, 95% CI 3.05-8.19). Furthermore, significant differences in recurrence-free survival were observed between the 2 groups (HR 9.98, 95% CI 5.50-17.73). Similarly, among the 410 women with a history of ER-positive breast cancer who were prescribed vaginal estrogen, 41 were also prescribed AIs. The study identified a significantly higher risk of breast cancer recurrence in women prescribed both vaginal estrogen and AIs compared to those prescribed vaginal estrogen alone, with recurrence rates of 76.32% versus 28.95% (RR 2.64, 95% CI 1.55-4.47). Significant differences in recurrence-free survival were also observed between the 2 groups (HR 4.82, 95% CI 2.36-9.84).

In summary, the utilization of vaginal estrogen therapy for GSM in breast cancer survivors remains low potentially due to concerns about cancer recurrence linked to the Food and Drug Administration’s black box warning when prescribing vaginal estrogen.^2,4-6 Additionally, the lack of current guidelines for the use of vaginal estrogen in patients with GSM may contribute to its underutilization.

Although evidence suggests that vaginal estrogen therapy does not significantly increase systemic estrogen levels, there is a paucity of studies examining the association between cancer recurrence risk and vaginal estrogen therapy, including a lack of data from randomized clinical trials. A large, nested, case-control study found no increased relative risk of breast cancer recurrence with the use of local estrogen during concurrent use or after treatment with AI.⁷ However, a Danish cohort study observed a significantly increased risk of breast cancer recurrence among those with concurrent AI and vaginal estrogen prescriptions.⁸ Clearly this complex interaction requires further investigation, considering factors such as breast cancer characteristics, dosage of vaginal estrogen and AIs, and the temporal relationship of breast cancer diagnosis to vaginal estrogen therapy initiation. Despite these concerns, vaginal estrogen therapy remains a valuable treatment option for GSM in breast cancer survivors. Its safety and efficacy should be further studied to provide more comprehensive guidelines for clinical practice, ensuring that patients receive appropriate and effective treatment for GSM while minimizing the risk of cancer recurrence.