Effects of Liarozole Fumarate (R85246) in Combination with Tamoxifen on N-methyl-N-nitrosourea (MNU)-induced Mammary Carcinoma and Uterus in the Rat Model

Background: Liarozole fumarate (liarozole – R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA). Our objective was to determine the effects of liarozole alone or in combination with tamoxifen on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in ovariectomized immature rats. Methods: (1) Tumor burden experiments: Animals bearing one or more tumors greater than 10 mm in diameter were treated for 56 consecutive days with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 100 μg/kg by subcutaneous injection, or a combination of liarozole and tamoxifen. At the end of the treatment period, total cumulative tumor volume as well as retinoic acid levels were measured. (2) Uterotrophic assay and proliferation experiments: 21-day-old ovariectomized (OVX) Sprague-Dawley rats were treated with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 1 mg/kg by subcutaneous injection, and combination of both for 4 consecutive days. At the end of the treatment period, uterine weight, epithelial lining cell height and indices of proliferation cell nuclear antigen (PCNA) were measured. Results: The tumor burden experiments in rats bearing estrogen receptor (ER) positive mammary tumours showed that liarozole has a marked anti-tumour effect. In combination with tamoxifen, liarozole had neither an additive nor an antagonistic effect. However, liarozole markedly reduced the uterotrophic effects induced by tamoxifen. Conclusion: Liarozole's antitumor effects on ER positive mammary tumors and its protective effect on the uterus merit further studies to confirm its clinical value in combination with tamoxifen in ER positive postmenopausal breast cancer. Liarozole and other retinomimetics might also be suitable chemoprevention drugs in combination with tamoxifen because of their favorable toxicity profile

Competing Risks in Low-Risk Breast Cancer

In recent years a growing amount of data on prognostic features of breast cancer has allowed for identification of tumors with a very low risk of recurrence. Markers used to predict the risk of distant spread include classic clinicopathologic features as well as newer tumor gene signatures, which have been validated and are being used in cohorts of patients with breast cancer patients who have low-risk disease. However, the definition of “low-risk” breast cancer requires consideration of patient-related factors such as comorbidities and age in addition to tumor characteristics, as high competing risks for mortality might be more important than cancer recurrence from a patient's point of view. In addition, identification of low-risk breast cancer cohorts is only valuable if treatment decisions are based on this information. Therefore, the magnitude of any treatment benefit in low-risk disease needs to be quantified in a comprehensible way. However, treatment benefit in low-risk situations is hard to quantify, may vary over time, and needs to be compared to individual risks for side effects. Decision models considering tumor and patient characteristics as well as predictive markers for treatment efficacy and toxicity will be needed. Tools such as Adjuvant! Online ultimately need to include information from gene signatures in order to reliably recommend specific treatment options for patients with breast cancer patients who have low-risk disease.</jats:p