A framework to predict the applicability of Oncotype DX, MammaPrint, and E2F4 gene signatures for improving breast cancer prognostic prediction.

To improve cancer precision medicine, prognostic and predictive biomarkers are critically needed to aid physicians in deciding treatment strategies in a personalized fashion. Due to the heterogeneous nature of cancer, most biomarkers are expected to be valid only in a subset of patients. Furthermore, there is no current approach to determine the applicability of biomarkers. In this study, we propose a framework to improve the clinical application of biomarkers. As part of this framework, we develop a clinical outcome prediction model (CPM) and a predictability prediction model (PPM) for each biomarker and use these models to calculate a prognostic score (P-score) and a confidence score (C-score) for each patient. Each biomarker's P-score indicates its association with patient clinical outcomes, while each C-score reflects the biomarker applicability of the biomarker's CPM to a patient and therefore the confidence of the clinical prediction. We assessed the effectiveness of this framework by applying it to three biomarkers, Oncotype DX, MammaPrint, and an E2F4 signature, which have been used for predicting patient response, pathologic complete response versus residual disease to neoadjuvant chemotherapy (a classification problem), and recurrence-free survival (a Cox regression problem) in breast cancer, respectively. In both applications, our analyses indicated patients with higher C scores were more likely to be correctly predicted by the biomarkers, indicating the effectiveness of our framework. This framework provides a useful approach to develop and apply biomarkers in the context of cancer precision medicine.