Analytical Challenges in Development of Chemoresistance Predictors for Precision Oncology

Chemoresistance, i.e., tumor insensitivity to chemotherapy, shortens life expectancy of cancer patients. Despite the availability of new treatment options, initial systemic regimens for solid tumors are dominated by a set of standard chemotherapy drugs, and alternative therapies are used only when a patient has demonstrated chemoresistance clinically. Chemoresistance predictors use laboratory parameters measured on tissue samples to predict the patient's response to chemotherapy and help to avoid application of chemotherapy to chemoresistant patients. Despite thousands of publications on putative chemoresistance predictors, there are only about a dozen predictors that are sufficiently accurate for precision oncology. One of the major reasons for inaccuracy of predictors is inaccuracy of analytical methods utilized to measure their laboratory parameters: an inaccurate method leads to an inaccurate predictor. The goal of this study was to identify analytical challenges in chemoresistance-predictor development and suggest ways to overcome them. Here we describe principles of chemoresistance predictor development via correlating a clinical parameter, which manifests disease state, with a laboratory parameter. We further classify predictors based on the nature of laboratory parameters and analyze advantages and limitations of different predictors using the reliability of analytical methods utilized for measuring laboratory parameters as a criterion. Our eventual focus is on predictors with known mechanisms of reactions involved in drug resistance (drug extrusion, drug degradation, and DNA damage repair) and using rate constants of these reactions to establish accurate and robust laboratory parameters. Many aspects and conclusions of our analysis are applicable to all types of disease biomarkers built upon the correlation of clinical and laboratory parameters.