Chemotherapy and endocrine therapy used in the management of breast cancer (BC) are associated with the sudden onset of chemically induced menopause and its resultant genitourinary symptoms, which include vaginal itching, burning, painful sexual activity, and urinary incontinence. These symptoms adversely affect BC survivors’ quality of life and lead to nonadherence. Vaginal estrogen therapy can relieve many of these local symptoms, but there is concern about the risk of increased risk of BC when these products are employed.
To help address this concern, researchers conducted a large cohort study to determine whether the risk of BC-specific mortality was higher in females with BC who used vaginal estrogen therapy compared with females with BC who did not use hormone replacement therapy (HRT).
This study included data from two cohorts—one from Scotland using information from the Prescribing Information System and one from Wales using the SAIL Databank. This study included females aged 40 to 79 years with newly diagnosed BC (based on ICD-10 codes) from the cancer registries in Scotland from 2010 to 2017 and in Wales from 2000 to 2016. Patients diagnosed previously with cancer, except for nonmelanoma skin cancer, were excluded from the study.
In Wales, medication use was determined based on general practitioner prescribing patient records, whereas in Scotland, drug use was evaluated based on pharmacy dispensing records. As per the British National Formulary, HRT consisted of either vaginal estrogen therapy (i.e., estriol creams and estradiol tablets) and systemic HRT (i.e., estrogen- or tibolone-containing products).
Tamoxifen and aromatase inhibitor use was identified from prescribing or dispensing records. Data were gathered on cancer stage, grade, treatment, and hormone receptor status (last parameter was only analyzed in Scotland), prescribing or dispensing records, Charlson Comorbidity Index, anemia, surgical sterilization (i.e., hysterectomy or oophorectomy), smoking status, and BMI (the latter two parameters were evaluated in Wales only).
The primary outcome of this study was time to BC-specific mortality based on national mortality records censored June 2019 in Scotland and June 2020 in Wales.
The study population was comprised of 49,237 females with BC who were aged 40 to 79 years. Among this group, there were 5,795 BC-specific deaths (11.8%) with a median follow-up of 8 years in Wales and 5 years in Scotland. Following BC diagnosis, 5% (N = 2,551) of women used vaginal estrogen therapy and 1% (N = 556) used system HRT.
The investigators found that there was no evidence of higher BC-specific mortality in women who used vaginal estrogen therapy compared with those who did not use HRT. In fact, there was a 23% decrease in mortality among vaginal estrogen used in the pooled fully adjusted model (hazard ratio [HR] = .77; 95% CI, 0.63-0.94). In those who had five or more prescriptions for vaginal estrogen therapy, there was a 43% reduced risk of BC-specific mortality (HR = .57; 95% CI, 0.34-0.96, P = .03). There was no difference in BC-specific mortality between users of high-dose vaginal estrogen therapy (i.e., 25-mcg estradiol tablets) and lower doses of topical estradiol.
Data from the Scottish cohort only demonstrated no increased risk of BC-specific mortality among those with estrogen-receptor positive BC (HR fully adjusted = .88; 95% CI, 0.62-1.25).
A sensitivity analysis for the association between vaginal estrogen therapy use and no HRT following a BC diagnosis found no significant difference between “no tamoxifen or aromatase inhibitor” use and “aromatase inhibitor therapy with or without tamoxifen” but did show a reduced HR for tamoxifen only (HR fully adjusted = 0.41; 95% CI, 0.21-0.79) when stratifying only vaginal estrogen therapy users.
The authors of this study concluded that in the absence of trials of vaginal estrogen therapy in BC, the results of this trial provide some reassurance that patients with BC who received vaginal estrogen therapy were not at a markedly higher risk of BC-specific mortality. They suggested that vaginal estrogen therapy may be considered for relief of genitourinary menopausal symptoms in patients who have failed nonhormonal treatment options.
While this study has strengths such as a large sample size with up to 20 years of follow-up and objective data on medication prescribing and dispensing of all HRT products, it does have limitations. Among these limitations are that the researchers did not study BC recurrence, there was no assessment of medication adherence, there was a lack of follow-up of later BC-specific mortality, they had incomplete estrogen receptor tumor status data, and there was possible selection bias since women who received therapy for genitourinary symptoms of menopause may have had lower estradiol levels (which were not measured) and/or better medication adherence resulting in lower BC-specific mortality.
While this study does not offer a definitive answer about the potential risk associated with the vaginal estrogen therapy in women with a history of BC, pharmacists should be aware of these findings as patients may have questions about this study’s results.
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