Predictors of Chemotherapy Efficacy in Non-Small-Cell Lung Cancer

A Challenging Landscape

K. A. Olaussen; S. Postel-Vinay

Disclosures

Ann Oncol. 2016;27(11):2004-2016. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Innovation and research in the field of conventional cytotoxic chemotherapy (CCC) have markedly slowed down since the advent of targeted anticancer therapy and immune checkpoint inhibitors. Although these therapies have significantly improved the outcome of some selected patients with non-small-cell lung cancer (NSCLC), ~60% of tumours do not present targetable driver mutations, and only 15%–25% of NSCLC patients derive benefit from immunotherapy.[1–3] CCC, which benefits clinically to a majority of patients, particularly in the adjuvant setting,[4] and costs 10 to 1000 times less than targeted or immune therapies, still has a full role to play and remains the cornerstone of the treatment of hundreds of thousands lung cancer patients worldwide. Despite all recent therapeutic advances, NSCLC remains the leading cause of cancer death, and improvements are urgently needed.[5] Several factors explain this high mortality rate, including late patient diagnosis, preventing local curative approaches (surgery, radiotherapy). Inner biological aggressiveness, tumour heterogeneity, primary and acquired resistance mechanisms concur to restrict the potential of systemic treatments. Also, contrary to targeted therapies, CCC is unfortunately still used in a historical 'one-size fits all' approach, which is clearly suboptimal. Although several predictive biomarkers for CCC efficacy have been explored, none of them has gone through clinical implementation for routine daily practice, and predictive biomarkers or molecular tools designed to customise CCC to the patient's tumour molecular profile are crucially lacking. Such biomarkers would not only help identifying chemosensitive patients and selecting appropriate drug combinations upfront, but it would also avoid useless toxicities, decrease overall costs, and eventually improve patient outcome. Noteworthy, the remarkable failure rate in the development of biomarkers predicting CCC efficacy reflects how challenging this task is.

Here, we present molecular mechanisms involved in either sensitivity or resistance to CCC, and review the main biomarkers studied in the field of NSCLC. Their analytic validity, scientific robustness and potential for clinical implementation will also be discussed.

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