Chemotherapy-induced menopause, natural menopause, and the antiestrogenic effects of aromatase inhibitors (AIs) can contribute to the development of genitourinary symptoms GS—which include vaginal dryness, itchiness, burning, overactive bladder, and urinary incontinence—can adversely impact a woman’s quality of life. Estrogen therapy is very effective in managing GS, but questions remain regarding its safety in women diagnosed with early BC.

Numerous studies have examined the effects of estrogen-based therapy for GS in BC patients. Generally, vaginal estrogen therapy (VET) has been found to be relatively safe in BC survivors, but concern has been expressed about the increased risk of BC recurrence with the use of menopausal hormone therapy (MHT).

A large, observational, Danish population–based cohort study was conducted to determine the association of the use of VET and MHT with the risk of BC recurrence and mortality in postmenopausal women treated for early-stage estrogen-receptor positive (ER+) BC.

The Danish health system provides tax-funded healthcare and has national databases linking patient data. Patients were included in this study if they were postmenopausal women aged 35 to 95 years who were diagnosed with invasive early stage nonmetastatic ER+ BC between 1997 to 2004 and who did not receive chemotherapy. All women received guideline-directed adjuvant ET (i.e., either 5 years of tamoxifen, an AI, or both in sequence; the latter was used in women with tumors >2 cm, node+ disease, or malignancy grade 2-3) or no ET.

Women were followed from the date of primary BC surgery until either a first event, which was defined as recurrence of BC, diagnosis of a secondary malignancy, or death, or up to a maximum of 10 years. Adherence was defined as continuation of ET for at least 4.5 years in the absence of a BC event.

Women were categorized as VET or MHT users (if they had redeemed two or more prescriptions for the hormonal product after the diagnosis of BC) or as never-users; users of both VET and MHT were considered MHT users. Women were excluded from the analysis if they had used either VET or MHT prior to being diagnosed with BC. VET products included Estring, Ovestin, and Vagifem, whereas MHT products included Aerodiol, Climara, Divigel, Elleste, Ercostrol, Estraderm, Estrofem, Estrogel, Evorel, Femseven, Oestring, Ovestin, Premarin, Progynon, Sandrena, Synapasa, Vivelle, and oestradiol.

A total of 9,710 postmenopausal women underwent surgery for incident invasive ER+ BC between January 1997 to December 2004 and were allocated to one of the three ET options. Of these women 1,249 (13%) had been prescribed either VET or MHT prior to a BC diagnosis and were excluded leaving 8,461 women (median age 61 years) in the analysis. Additionally, 3,112 women (36.8%) did not receive ET, 2,007 (23.7%) received tamoxifen, 403 (4.8%) received AIs, and 2,939 (34.7%) received a sequence of tamoxifen and an AI.

Over three-quarters (75.3%, n = 6,371) of the 8,461 study participants had not received estrogenic therapy for GS, whereas 1.6% (133) had received MHT and 23.1% (1957) had received VET. Nonusers of estrogenic therapy were older (36% aged 65 years and older compared with 22% for MHT and 32% for VET), had larger tumors (36% had tumors >2 cm vs. 28% for MHT, and 27% for VET), and more often had lymph node metastasis (44% had one or more positive lymph nodes vs. 35% for MHT and 39% for VET).

Among those who had not receive any estrogenic therapy for GS, 35% had also not received ET, 26% had received tamoxifen, 5% had received AIs, and 34% had received sequential tamoxifen and AI therapy. Among those who received MHT, 47% had not received ET, 25% had received tamoxifen, 6% had received AIs, and 22% had received sequential ET. Among the VET users, 40% had not received ET, 18% had received tamoxifen, 5% had received AIs, and 37% had received tamoxifen/AI therapy.

During the 9.8-year follow-up period, 1,333 (16%) women had had a BC recurrence. The risk of recurrence was increased (39-fold greater) only in women who received VET and were on AI therapy (hazard ratio = 1.39; 95% CI, 1.04-1.85), but this did not affect overall survival in this group. The 10-year cumulative incidence of recurrence was 19.2% in those who had never received either VET or MHT, 15.4% in VET users, and 17.1% in MHT users. Absolute 10-year overall survival was 73.8% for never-users of estrogenic GS products, 79.5% for VET users, and 80.5% for those receiving MHT.

While this study provides pharmacists with reassurance about the safety of the use of estrogenic products for GS in women with early BC, caution is advised for the use of VET in women on adjuvant AI therapy.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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