For women diagnosed with breast cancer (BC), endocrine options for treatment depend on menopausal status. In premenopausal women, choice of adjuvant endocrine therapy is often based on the patient’s risk of recurrence and involves the use of ovarian suppression plus endocrine therapy. Selective estrogen receptor modulators (SERMs) are the mainstay of adjuvant BC therapy in this population. SERMS used the management or risk reduction of BC include tamoxifen, toremifene, and raloxifene.
Adverse effects associated with tamoxifen therapy may contribute to the 42% discontinuation rate within the first 2 years of treatment. It is known that tamoxifen can cause hot flashes in over 40% of women. Ovarian cysts occur in about 20% of patients and can be as high as 30% to 50% in premenopausal women. Tamoxifen also increases the risk of endometrial hyperplasia or uterine cancer, causes fatty liver, and induces adverse lipid changes. Toremifene has similar efficacy to tamoxifen and offers the advantage of better efficacy in BC patients with CYP2D6*10T/T genotype as it does not require activation. It is associated with less vaginal bleeding, headaches and thromboembolic events. However, there are little comparative safety data about the use of these two SERMs in premenopausal women.
The purpose of this prospective, single-center, randomized, controlled, open-label trial was to compare the safety of toremifene relative to tamoxifen in premenopausal BC survivors. Following surgery, chemotherapy, and radiotherapy, women were randomized to either toremifene 60 mg/day or tamoxifen 20 mg/day; there was no placebo group. Patients were followed quarterly during the first year.
Premenopausal women were eligible for inclusion into the study if they had histologically confirmed hormone-receptor positive BC, had undergone BC surgery, had completed chemotherapy and/or radiation therapy, had a leukocyte count of >3.0 X 109/L, platelet count >75 x 109/L, liver function tests that were <2.5 times the upper limit of normal, normal serum creatinine, and an ECOG performance score of 0 to 2. Additionally, there was a fairly extensive list of exclusion criteria.
The primary endpoint was the 1-year development of ovarian cysts, and the secondary endpoints were the 1-year incidence of endometrial thickening, changes in female hormones (i.e., estradiol [E2], follicle stimulating hormone [FSH] and luteinizing hormone [LH]), the incidence of fatty liver, changes in the modified Kupperman score, and quality of life (assessed by the European Organization for Research and Treatment of Cancer [EORTC]). The Kupperman score rates 11 menopausal symptoms: hot flushes, paresthesia, insomnia, nervousness, melancholia, vertigo, weakness, arthralgia or myalgia, headache, palpitations, and formication on a severity scale of 0 to 3. The modified Kupperman score also includes two urogenital symptoms: urinary infection and sexual complaints.
Among the 92 women enrolled in this study, which took place between December 2014 and June 2017, 47 women received toremifene and 45 women received tamoxifen. The median ages of the toremifene and tamoxifen groups were 45 and 44 years, respectively. Almost 80% of women had invasive ductal carcinoma at the time of diagnosis, with a similar percentage having Stage I or II BC. A review of hormone receptor status found that 93.5% of tumors were 50% estrogen-receptor positive, three-quarters were >20% progesterone-receptor positive, and 6.5% of patients were HER-2 positive. About one-third of patients had received chemotherapy, and almost one-half underwent radiation therapy.
The investigators found that the 1-year incidence of ovarian cysts was 42.6% in the toremifene group compared with 51.1% in the tamoxifen group; this difference was not statistically significant. These cysts were at least 2.0 cm in diameter. Endometrial thickening occurred in 87.2% of toremifene patients and 80% of those receiving tamoxifen, with a mean thickness of 12.00 mm in the toremifene group and 11.80 mm in the tamoxifen group; these differences were also not statistically significant.
Mean E2 values were significantly higher in the toremifene group compared with tamoxifen, whereas FSH and LH did not significantly increase in either group. Fatty liver was observed in about one-third (31.9%) of toremifene users but in only about one-quarter (26.7%) of tamoxifen patients; however, this difference did not reach statistical significance. There were also no differences in modified Kupperman scores or in quality of life between the toremifene and tamoxifen groups, although there was a trend towards more appetite loss in the toremifene group.
The investigators concluded that adverse effects of toremifene and tamoxifen on the female genital system (as determined by the modified Kupperman scores) and on quality of life were similar between the two SERMs in premenopausal women. This comparative information on the safety profiles of toremifene and tamoxifen is helpful when pharmacists need to counsel premenopausal women on the use of these medications or when pharmacists assist in medication therapy selection.
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