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A Comparison of Survival Outcomes and Side Effects of Toremifene Or Gu et al. BMC Cancer 2012, 12:161 http://www.biomedcentral.com/1471-2407/12/161 RESEARCH ARTICLE Open Access A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study Ran Gu1†, Weijuan Jia1†, Yunjie Zeng2†, Nanyan Rao1†, Yue Hu1, Shunrong Li1, Jiannan Wu1, Liang Jin1, Lijuan Chen3, Meijun Long1, Kai Chen1, Lili Chen1, Qiaozhen Xiao1, Mei Wu1, Erwei Song1* and Fengxi Su1* Abstract Background: In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen. Methods: Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups. Results: Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer. Conclusion: Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer. Keywords: Tamoxifen, Toremifene, Breast cancer, Adjuvant endocrine therapy, Premenopausal * Correspondence: [email protected]; [email protected] †Equal contributors 1Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510260, China Full list of author information is available at the end of the article © 2012 Gu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gu et al. BMC Cancer 2012, 12:161 Page 2 of 10 http://www.biomedcentral.com/1471-2407/12/161 Background [29]; however, those studies mostly focused on postme- The optimal adjuvant therapy for premenopausal women nopausal patients. For premenopausal women receiving with hormone-responsive breast cancer still remains un- tamoxifen, menopausal symptoms seemed to be a sig- clear despite the many clinical trials over the past 60 years nificant concern, although the side effects of tamoxifen that have attempted to address this issue. Historically, alone were milder, with the exception of vaginal dis- tamoxifen has been overlooked for the treatment of charge [30]. Thus, the gynecological side-effects of endo- breast cancer in premenopausal women, due to the false crine therapy differ according to menstrual status. This belief that it is ineffective in this patient group. Indeed, it may be related to the action of tamoxifen on the human was not until 1995 that the Early Breast Cancer Trialists' endometrium in postmenopausal women, where it has Collaborative Group review unequivocally rejected this simple estrogenic effects including hyperplasia, whereas misconception by demonstrating its efficacy in lowering in premenopausal women it is linked with endometrial the rate of recurrence and mortality in premenopausal cystic atrophy. Moreover, postmenopausal patients trea- women with HR-positive breast cancer [1]. In recent ted with tamoxifen may develop endometriosis, adeno- years, the impact of endocrine therapies – primarily con- myosis and leiomyomata. Tamoxifen also disrupts the sisting of tamoxifen and ovarian suppression strategies – menstrual cycle and increases the incidence of ovarian as an adjuvant treatment for premenopausal patients cysts in premenopausal breast cancer patients while in with early breast cancer is well established. Moreover, the postmenopausal patients it induces ovarian cystic expert panel of the 2009 St Gallen Conference accepted tumors and endometriomas [31,32]. In addition, tamoxi- tamoxifen (or tamoxifen plus ovarian suppression) as the fen causes a decrease in bone mineral density in preme- gold standard in endocrine therapy for this group [2]. nopausal women [33,34]. However, in postmenopausal Although there is mounting evidence to show that women, only a mild bone-sparing effect during breast tamoxifen has the potential to serve as adjuvant endo- cancer therapy has been reported, suggesting that in crine therapy for women of all ages with breast cancer, these women, anti-estrogens may act as estrogen ago- questions on the long-term safety of tamoxifen have nists in the bone [35,36]. Taken together, such findings been raised, due to the adverse event associated with this prompt the question: as an adjuvant endocrine therapy therapy, including the increased risk of secondary endo- for premenopausal breast cancer patients, is toremifene metrial cancers, the formation of pulmonary embolism, superior to tamoxifen? deep vein thrombosis and stroke [3-7]. More rarely, hep- The use of toremifene as an adjuvant endocrine ther- atotoxicity, ocular problems and an increased risk of apy for premenopausal patients with breast cancer is colorectal cancer have also been reported [8-16]. rarely reported. Although one can point to a study on Recently, several alternative hormonal adjuvant ther- 632 patients aged under 50 receiving toremifene as an apies for the treatment of breast cancer have become adjuvant therapy, this report was aimed at tamoxifen available. Of these, toremifene is a synthetic analogue of therapy in very young breast cancer patients, and it did tamoxifen and, like tamoxifen, acts on the estrogen re- not compare the different effects of toremifene and tam- ceptor. Although, the clinical efficacy of toremifene and oxifen, and did not evaluate the duration of treatment tamoxifen are comparable, both as palliative and post- [37]. In view of these limitations, the purpose of this menopausal adjuvant therapies [17-23], toremifene and study was to compare these SERMs in premenopausal tamoxifen are metabolized differently, due to a single estrogen or progesterone receptor positive women and side chain chloride ion, leading to a more favorable tox- planned to perform a safety analysis, using a retrospect- icity profile [24-27]. Data on secondary endometrial can- ive and cohort clinical study. cer showed that the incidence of this cancer was lower with toremifene than tamoxifen, prompting speculation Methods that toremifene may unmask existing endometrial Patients tumors rather than induce new events. Further, the risk Patients with early invasive breast cancer who were trea- of stroke, pulmonary embolism, and cataract may be ted between January 1998 and June 2009, were selected lower with toremifene than with tamoxifen. Other evi- by searching breast tumor registries at the Sun Yat-Sen dence suggests that the beneficial estrogen agonist Memorial Hospital. Premenopausal patients with endo- effects of toremifene, including changes in bone mineral crine responsive breast cancer who underwent standard density and lipid profiles, were equivalent to those of therapy and adjuvant TAM/TOR for 5 years were eli- tamoxifen [28]. gible for inclusion in our study. Their premenopausal A prospective study using MRI demonstrated that status was confirmed by measuring E2 and FSH levels uterine changes associated with adjuvant drugs for before surgery (in accordance with the menopausal cri- breast cancer occur exclusively in postmenopausal terion of the 2010 National Comprehensive Cancer Net- patients receiving selective estrogen receptor modulators work). Patients were excluded if they had breast Gu et al. BMC Cancer 2012, 12:161 Page 3 of 10 http://www.biomedcentral.com/1471-2407/12/161 sarcoma, carcinosarcoma, or concurrent contralateral shown that daily toremifene (60 mg) is as effective as primary breast cancer, had distant metastasis at diagno- daily tamoxifen (20 mg) in the treatment of postmeno- sis, or had not undergone surgery in combination with pausal hormone-dependent breast cancer, hence in our endocrine therapy. study, 20 mg of tamoxifen and 60 mg of toremifene were given daily, orally, for 5 years [39]. Besides those listed above, no
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