Predictors of chemotherapy efficacy in non-small-cell lung cancer: A challenging landscape

Background: Conventional cytotoxic chemotherapy (CCC) is the backbone of non-small-cell lung cancer (NSCLC) treatment since decades and still represents a key element of the therapeutic armamentarium. Contrary to molecularly targeted therapies and immune therapies, for which predictive biomarkers of activity have been actively looked for and developed in parallel to the drug development process ('companion biomarkers'), no patient selection biomarker is currently available for CCC, precluding customizing treatment. Materials and methods: We reviewed preclinical and clinical studies that assessed potential predictive biomarkers of CCC used in NSCLC (platinum, antimetabolites, topoisomerase inhibitors, and spindle poisons). Biomarker evaluation method, analytical validity, and robustness are described and challenged for each biomarker. Results: The best-validated predictive biomarkers for efficacy are currently ERCC1, RRM1, and TS for platinum agents, gemcitabine and pemetrexed, respectively. Other potential biomarkers include hENT1 for gemcitabine, class III β-tubulin for spindle poisons, TOP2A expression and CEP17 duplication (mostly studied for predicting anthracyclines efficacy) whose applicability concerning etoposide would deserve further evaluation. However, none of these biomarkers has till now been validated prospectively in an appropriately designed and powered randomised trial, and none of them is currently ready for implementation in routine clinical practice. Conclusion: The search for predictive biomarkers to CCC has been proven challenging. If a plethora of biomarkers have been evaluated either in the preclinical or in the clinical setting, none of them is ready for clinical implementation yet. Considering that most mechanisms of resistance or sensitivity to CCC are multifactorial, a combinatorial approach might be relevant and further efforts are required.