Adjuvant endocrine therapy for breast cancer.
ABSTRACT Endocrine therapy is a critical part of adjuvant therapy in women with hormone receptor-positive breast cancer, and has been shown to reduce the risk of recurrence and death from breast cancer. For decades, 5 years of tamoxifen has been the standard treatment. For premenopausal women, it remains so, and we await the results of ongoing trials to define the role of ovarian suppression or ablation with endocrine therapy. If a woman becomes postmenopausal during treatment, consideration should be given to extended adjuvant therapy with an aromatase inhibitor (AI) for another 5 years. In postmenopausal women, trials have shown that AIs are more beneficial than tamoxifen in preventing disease recurrence.They have been compared as upfront treatment for 5 years, as sequential therapy after 2 to 3 years of tamoxifen, and as extended treatment for 5 years after 5 years of tamoxifen. Among the questions still being studied are the optimal duration of extended adjuvant therapy with AIs, how one AI performs compared to another, and whether there is a benefit to intermittent extended adjuvant treatment.
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ABSTRACT: Targeting the estrogen pathway has been proven effective in the treatment of estrogen receptor positive breast cancer. There are currently two common groups of anti-estrogenic compounds used in the clinic; Selective Estrogen Receptor Modulators (SERMs, e.g. tamoxifen) and Selective Estrogen Enzyme Modulators (SEEMs e.g. letrozole). Among various naturally occurring, biologically active compounds, resveratrol and melatonin have been suggested to act as aromatase inhibitors, which makes them potential candidates in hormonal treatment of breast cancer. Here we used a co-culture model in which we previously demonstrated that primary human breast adipose fibroblasts (BAFs) can convert testosterone to estradiol, which subsequently results in estrogen receptor-mediated breast cancer T47D cell proliferation. In the presence of testosterone in this model, we examined the effect of letrozole, resveratrol and melatonin on cell proliferation, estradiol (E2) production and gene expression of CYP19A1, pS2 and Ki-67. Both melatonin and resveratrol were found to be aromatase inhibitors in this co-culture system, albeit at different concentrations. Our co-culture model did not provide any indications that melatonin is also a selective estrogen receptor modulator. In the T47D-BAF co-culture, a melatonin concentration of 20 nM and resveratrol concentration of 20 μM have an aromatase inhibitory effect as potent as 20 nM letrozole, which is a clinically used anti-aromatase drug in breast cancer treatment. The SEEM mechanism of action of especially melatonin clearly offers potential advantages for breast cancer treatment.Toxicology in Vitro 06/2014; 28(7). DOI:10.1016/j.tiv.2014.05.015 · 3.21 Impact Factor
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ABSTRACT: Compliance and persistence are often underestimated in breast cancer (BC) treatment. The aim of our study was to analyze the persistence with tamoxifen (TAM) and aromatase inhibitors (AI) in postmenopausal women with hormone-receptor-positive BC and to identify determinants of non-persistence. We used data of the Disease Analyzer database (IMS HEALTH, Germany) including 2,067 general practices and 397 gynecological practices. Out of a dataset of 15 million patients, we identified BC patients with a first-time TAM or AI prescriptions from October 2001 to December 2010. For persistence analyses, 12,412 women on tamoxifen, 2,796 on anastrozole, 647 on exemestane, and 1,657 on letrozole met the inclusion/exclusion criteria. Within 3 years of follow-up, the discontinuation rates increased to 52.2 % for tamoxifen, 47 % for anastrozole, 55.1 % for exemestane, and 44.3 % for letrozole treated women. A minor proportion of patients switched to a different endocrine treatment; 33 % tamoxifen, 20 % anastrozole, 22.9 % exemestane, and 23 % letrozole. The multivariate hazard ratios of the cox regression models showed that patients younger than 50 were most likely to discontinue initial therapy when compared with the reference group of women over 70 (p < 0.001). In contrast, patients treated in gynecologist practice had significantly longer persistence than patients who obtained their prescriptions in general practitioner practice (p < 0.001). In addition, the presence of the co morbidities like diabetes (p < 0.001) or depression (p < 0.002) was also associated with decreased risk of treatment discontinuation. Persistence with all endocrine treatments in women with hormone-receptor-positive BC is low and needs to be significantly increased to improved outcome in clinical practice. Further research is required to understand this complex issue.Breast Cancer Research and Treatment 01/2013; DOI:10.1007/s10549-013-2417-1 · 4.20 Impact Factor
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ABSTRACT: The extragonadal synthesis of biological active steroid hormones from their inactive precursors in target tissues is named "intracrinology." Of particular importance for the progression of estrogen-dependent cancers is the formation of the biological most active estrogen, 17beta-estradiol (E2). In cancer cells, conversion of inactive steroid hormone precursors to E2 is accomplished from inactive, sulfated estrogens in the "sulfatase pathway" and from androgens in the "aromatase pathway." Here, we provide an overview about expression and function of enzymes of the "sulfatase pathway," particularly steroid sulfatase (STS) that activates estrogens and estrogen sulfotransferase (SULT1E1) that converts active estrone (E1) and other estrogens to their inactive sulfates. High expression of STS and low expression of SULT1E1 will increase levels of active estrogens in malignant tumor cells leading to the stimulation of cell proliferation and cancer progression. Therefore, blocking the "sulfatase pathway" by STS inhibitors may offer an attractive strategy to reduce levels of active estrogens. STS inhibitors either applied in combination with aromatase inhibitors or as novel, dual aromatase-steroid sulfatase inhibiting drugs are currently under investigation. Furthermore, STS inhibitors are also suitable as enzyme-based cancer imaging agents applied in the biomedical imaging technique positron emission tomography (PET) for cancer diagnosis.02/2013; 2013:957605. DOI:10.1155/2013/957605