New driver mutations in non-small-cell lung cancer

Summary

Treatment decisions for patients with lung cancer have historically been based on tumour histology. Some understanding of the molecular composition of tumours has led to the development of targeted agents, for which initial findings are promising. Clearer understanding of mutations in relevant genes and their effects on cancer cell proliferation and survival, is, therefore, of substantial interest. We review current knowledge about molecular subsets in non-small-cell lung cancer that have been identified as potentially having clinical relevance to targeted therapies. Since mutations in EGFR and KRAS have been extensively reviewed elsewhere, here, we discuss subsets defined by so-called driver mutations in ALK, HER2 (also known as ERBB2), BRAF, PIK3CA, AKT1, MAP2K1, and MET. The adoption of treatment tailored according to the genetic make-up of individual tumours would involve a paradigm shift, but might lead to substantial therapeutic improvements.

Introduction

Lung cancer is the most frequent cause of cancer-related death worldwide, accounting for more than 1 million deaths per year.¹ Despite therapeutic advances, the overall 5-year survival remains only 15%.² Novel treatment strategies are, therefore, needed.

Traditionally, decisions on lung cancer therapy have been based on histological considerations. Tumours are assigned to two histological types: small-cell lung cancers and non-small-cell lung cancers (NSCLC).³ NSCLC comprise three different subtypes: squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma. The last subtype currently accounts for more than 50% of all cases of lung cancer. Standard platinum-based doublet chemotherapeutic treatment of advanced NSCLC seems to have reached a plateau in terms of efficacy,² although the importance of specific histological features in the selection of therapy has been highlighted in a randomised trial that demonstrated better results for pemetrexed than for gemcitabine in patients with non-squamous NSCLC.⁴

One promising treatment strategy involves the further subdivision of NSCLC into clinically relevant molecular subsets, according to a classification schema based on specific so-called driver mutations (figure, table 1). These mutations occur in genes that encode signalling proteins crucial for cellular proliferation and survival. Mutant oncogenes drive tumour formation and also maintenance. Thus, cancers might rely on the expression of these single-mutant oncogenes for survival, even in the absence of tumour-suppressor genes. This concept is also called oncogene addiction.5, 6 This notion suggests that tumours harbouring complex genetic lesions have weaknesses that could be systematically identified and exploited with specific targeted agents.

Mutations in EGFR best illustrate the therapeutic relevance of molecular clusters. Clinical and biological data have been extensively reviewed elsewhere,⁷ but a feature of note is that EGFR mutations strongly predict the efficacy of inhibitors of epidermal growth factor receptors (EGFR), with response rates higher than 70% seen in multiple studies.⁸ Two prospective, randomised, phase 3 studies of patients with untreated metastatic NSCLC (Iressa Pan-Asia Study⁸ and WJTOG3405⁹) have found that first-line gefitinib leads to longer progression-free survival in patients with tumours positive for EGFR mutations than does platinum-based doublet chemotherapy.

Over the past decade, a wealth of data from genomic,¹⁰ expression,¹¹ mutational,¹² and proteomic profiling¹³ studies, as well as from various mouse lung tumour models,⁶ have led to the identification of additional molecular driver mutations in lung cancer. We review current knowledge about emerging clinically relevant driver mutations that define new molecular subsets of NSCLC.