Assessment of Resistance Mechanisms and Clinical Implications in Patients with KRAS Mutated-Metastatic Breast Cancer and Resistance to CDK4/6 Inhibitors

Simple Summary Palbociclib in combination with fulvestrant is used globally to treat metastatic breast cancer, but it was recognized that not all patients benefit from this combination of drugs. However, the predictive factors remain unknown. Here, we show KRAS ctDNA levels as predictive mechanisms of resistance to palbociclib and fulvestrant, and their association with the time to treatment discontinuation of the above treatment. These observations shed light on the potential clinical applications of ctDNA analysis in this setting of patients, in order to provide critical information about tumour dynamics, and to predict who will take advantage from CDK4/6 inhibitors. Despite therapeutic improvements, resistance to palbociclib is a growing clinical challenge which is poorly understood. This study was conducted in order to understand the molecular mechanisms of resistance to palbociclib, and to identify biomarkers to predict who will take advantage from cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). A total of about a thousand blood samples were collected from 106 patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer who received palbociclib in combination with fulvestrant as the first-line metastatic therapy enrolled in this study. The genotyping of their plasma cell-free DNA was studied, including serial plasma samples. Collectively, our findings identify the appearance of KRAS mutations leading to palbociclib resistance acquisition within 6 months, and provide critical information for the prediction of therapeutic responses in metastatic breast cancer. By monitoring KRAS status through liquid biopsy, we could predict who will take advantage from the combination of palbociclib and fulvestrant, offering highly-individualized treatment plans, thus ensuring the best patient quality of life.