PTCH1 and CTNNB1 emerge as pivotal predictors of resistance to neoadjuvant chemotherapy in ER+/HER2- breast cancer

Background: Endeavors in molecular characterization of breast cancer paved the way to endocrine therapies in ER+/HER2- breast cancer, increasing response rates. Despite that, taxane-based neoadjuvant chemotherapy is still a cornerstone for breast-conserving surgery and complete tumor resection in locally advanced cancers with high recurrence risk. Nonetheless, chemoresistance risk is high. Therefore, predicting unresponsiveness to chemotherapy is a significant task to prevent futile toxicities in patients. Despite several multi-gene assays being used for this purpose, their development as prognostic assays limits predictive strength, leading to discordant results. Moreover, high costs impediment their use in developing countries. For global health equity, robust predictors that can be cost-effectively incorporated into routine clinical management are essential. Methods: To identify robust predictors in ER+/HER2- breast cancer, we performed comprehensive profiling and gene set enrichment analysis in 5 GEO datasets. To validate the potential predictors we performed ROC analysis, KM-survival analysis and Cox Proportional Hazards Regression in two validation cohorts. To compare predictive power of potential predictors with the genes in the benchmark signatures we performed gene correlation and signature analysis in TCGA dataset. Results: Gene expression and gene set enrichment analysis revealed 63 upregulated genes and the enrichment of CTNNB1-related oncogenic signatures in non-responsive patients. We validated the upregulation and predictive strength of 18 genes, all exhibiting higher predictive powers for residual disease and higher specificities for ER+/HER2- breast cancers compared to one of the benchmark multi-gene assays. Cox Proportional Hazards Regression in three different treatment arms (neoadjuvant chemotherapy, endocrine therapy, and no systemic treatment) put forth PTCH1 and CTNNB1 as key predictors, with hazard ratios over 1.5, and 1.6 respectively in the univariate and multivariate models. Conclusions: Our results strongly suggest that PTCH1 and CTNNB1 can be used as robust and cost-effective predictors in developing countries to guide decisions on chemotherapy in ER+/HER2- breast cancer patients with a high risk of recurrence. The dual function of PTCH1 as a multidrug efflux pump and a hedgehog receptor, and the active involvement of CTNNB1 in breast cancer strongly indicate that PTCH1 and CTNNB1 can be potential drug targets to overcome chemoresistance in ER+/HER2- breast cancer patients.