Predictive Biomarkers of Response to Neoadjuvant Chemotherapy in Breast Cancer: Current and Future Perspectives for Precision Medicine

SIMPLE SUMMARY: Despite the increased use of neoadjuvant chemotherapy in the early setting of breast cancer, there is a clinical need for predictive markers of response in daily practice. In the era of precision medicine and personalized treatment, new predictive markers that enable the better selection of patients for specific therapies are required. In this review, we describe the current knowledge about the molecular biomarkers used for clinical decision making for patients with breast cancer. We also report how microenvironment-driven intratumoral heterogeneity may influence the validation of biomarkers useful for precision medicine. We provide an overview of promising biomarkers, including pathological markers, genetic signatures, radiological techniques and liquid biopsies, with a great potential to be implemented in routine clinical practice. Finally, we discuss the use of relevant pre-clinical models of breast cancer to integrate microenvironmental specificities in order to identify and validate reliable biomarkers of (non-)response to neoadjuvant chemotherapy. ABSTRACT: Pathological complete response (pCR) after neoadjuvant chemotherapy in patients with early breast cancer is correlated with better survival. Meanwhile, an expanding arsenal of post-neoadjuvant treatment strategies have proven beneficial in the absence of pCR, leading to an increased use of neoadjuvant systemic therapy in patients with early breast cancer and the search for predictive biomarkers of response. The better prediction of response to neoadjuvant chemotherapy could enable the escalation or de-escalation of neoadjuvant treatment strategies, with the ultimate goal of improving the clinical management of early breast cancer. Clinico-pathological prognostic factors are currently used to estimate the potential benefit of neoadjuvant systemic treatment but are not accurate enough to allow for personalized response prediction. Other factors have recently been proposed but are not yet implementable in daily clinical practice or remain of limited utility due to the intertumoral heterogeneity of breast cancer. In this review, we describe the current knowledge about predictive factors for response to neoadjuvant chemotherapy in breast cancer patients and highlight the future perspectives that could lead to the better prediction of response, focusing on the current biomarkers used for clinical decision making and the different gene signatures that have recently been proposed for patient stratification and the prediction of response to therapies. We also discuss the intratumoral phenotypic heterogeneity in breast cancers as well as the emerging techniques and relevant pre-clinical models that could integrate this biological factor currently limiting the reliable prediction of response to neoadjuvant systemic therapy.