Filippo Montemurro, M.D.
Biomarkers of resitance to endocrine therapy in hormone-receptor positive breast cancer
The efficacy of endocrine therapy, which represents a pivotal treatment for those 70% of women whose breast cancers express hormone-receptors, is limited by primary and acquired resistance mechanisms. Therefore, newer biomarkers that can predict endocrine-responsiveness are eagerly awaited. Our group has recently found that a microRNA (a short sequence of non-coding RNA acting as a post-transcriptional regulator of gene expression) may be implicated in the acquisition of an endocrine-sensitive phenotype in hormone-receptor positive breast cancer cells. Goal: 1) to provide clinical evidence that miR-100 levels predict response to endocrine therapy; 2) to study the prognostic value of miR-100 in patients undergoing surgery for early, hormone-receptor positive breast cancer by comparing levels between patients relapsing and non relapsing within 5 years from diagnosis 3) to identify potential druggable targets for combined treatments in this patient population by studying genes that are regulated by miR-100 and that may be relevant to its role in sustaining and endocrine-sensitive phenotype.
We observed that ectopic expression if miR-100 in breast cancer stem cells derived from hormone-receptor and HER2 negative tumors (basal like) induced loss of stemness features. Furthermore, miR-100 expression induced hormone-receptor expression and sensitivity to endocrine therapy. Finally, low levels of tumor miR-100 were found to predict worse prognosis in four small, independent clinical series of hormone-receptor positive early breast cancer patients (Petrelli A et al. Oncotarget 2015). A phase II pre-surgical study is ongoing and has enrolled 90 of the 180 planned patients. In this study, pre and post-treatment tumor samples will be studied and levels of miR-100 will be correlated with proliferative response. Furthermore, primary tumors from a historical series of 184 patients have been tested for miR-100. Levels of miR-100 will be correlated with prognosis. Extensive gene expression analyses will be carried out to establish signatures of highly endocrine responsive turmors.