Tumours with defective DNA repair by the homologous recombination repair (HRR) pathway are exquisitely sensitive to DNA damaging agents and to novel agents that block parallel pathways, including PARP inhibitors (PARPi). PARPi have been approved for the treatment of metastatic ovarian cancer (OvC) or breast cancer (BC). Currently used selection biomarkers to enrich the population of patients (pt) most likely to respond, namely the platinum-sensitive or BRCA1/2-mutated pts, have limited predictive capacity. There is a need for more specific biomarkers to guide personalized treatment. Genomic scar signatures have been proposed as a putative biomarker associated with DNA repair deficiency. A major limitation of these assays is the lack of specificity in HRR-altered tumours once they have restored the HRR function as mechanism of drug resistance. Instead, RAD51 foci formation is a functional and dynamic biomarker of HRR that correlates with PARPi response. We will review the current knowledge on PARPi sensitivity and resistance in breast cancer, response biomarkers and the potential of therapeutic combinations.
I will talk about the uses of cycline inhibitors in South America. I will make a fast review of cylines inhibitors contribution in advanced breast cancer, the discussions opened during last 2020 in the adjuvant setting, and then the participation studies with the drugs and their availability in the real world.
Preclinical data indicates that antiprogestins inhibit cell proliferation of luminal breast
carcinomas expressing higher levels of progesterone receptor isoform A (PRA) than those of
isoform B (PRB). MIPRA (NCT02651844) is an open-label, one-arm, prospective interventional
study designed to test the effect of mifepristone (MFP; 200 mg, PO, QD, 14 days) in 20 breast
cancer patients selected by their high PRA/PRB isoform ratio. The primary endpoint was to
compare the Ki67 levels of the core needle biopsies and the post-therapy surgical
specimens. Wilcoxon rank test was used to compare paired samples. A 49.62% decrease in the
median was registered in all surgical specimens compared to baseline (p=0.0003). Using the prespecified response parameter (30% reduction), we identified 14/20 (70%) responders. The
degree of inhibition was similar to that reported for tamoxifen in luminal breast cancer patients
in short-term treatment studies. RNA-seq analysis was performed in samples from 8 patients (4
responders and 4 non-responders) pre- and post-treatment. Interestingly, in responsive
patients, MFP regulated genes related to the immune system and downregulated genes
involved in cell-cycle and proliferative pathways. Our results show that MFP treatment may be
effective in patients with a high PRA/PRB ratio. Ongoing analysis will determine changes in other
markers that may help to further define MFP-responsive patients.
USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer
The development of metastasis in patients suffering from cancer represents a significant reduction in their survival. Tumor cell migration and invasion are required for metastasis formation. In order to investigate the role of the Ubiquitin-Proteasome System (UPS) in the regulation of these processes, we performed a genetic screen using an shRNA library against UPS genes and Boyden chambers to analyze the migrating potential of breast cancer (BC) cells infected with this library. After the selection process, we characterized the non-migrating population and obtained a list of 30 candidate positive regulator genes. We focused on a specific DUB, USP19 and demonstrated that its silencing reduces the migratory/invasive potential of different BC cell lines. Since silenced cells proliferation was impaired using in vitro 3D setups, we furthered our investigation with in vivo studies. Mice inoculated with USP19 silenced cells presented Kaplan Meier curves for tumor free survival with a clear separation from the control group, as well as a delay in the onset of tumor formation. In addition, we observed a significant reduction in the generation of metastatic foci. Overexpression experiments in poorly migrating BC cells further validated our findings. Finally, we performed a retrospective clinical study which demonstrated that USP19 protein expression is a prognostic predictor of distant relapse free survival in BC patients. Altogether, USP19 might represent a novel therapeutic target.
