Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies

Abstract

Substantial advances have been made in understanding critical molecular and cellular mechanisms driving tumor initiation, maintenance, and progression in non-small-cell lung cancer (NSCLC). Over the last decade, these findings have led to the discovery of a variety of novel drug targets and the development of new treatment strategies. Already, the standard of care for patients with advanced-stage NSCLC is shifting from selecting therapy empirically based on a patient's clinicopathologic features to using biomarker-driven treatment algorithms based on the molecular profile of a patient's tumor. This approach is currently best exemplified by treating patients with NSCLC with first-line tyrosine kinase inhibitors when their cancers harbor gain-of-function hotspot mutations in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. These genotype-based targeted therapies represent the first step toward personalizing NSCLC therapy. Recent technology advances in multiplex genotyping and high-throughput genomic profiling by next-generation sequencing technologies now offer the possibility of rapidly and comprehensively interrogating the cancer genome of individual patients from small tumor biopsies. This advance provides the basis for categorizing molecular-defined subsets of patients with NSCLC in whom a growing list of novel molecularly targeted therapeutics are clinically evaluable and additional novel drug targets can be discovered. Increasingly, practicing oncologists are facing the challenge of determining how to select, interpret, and apply these new genetic and genomic assays. This review summarizes the evolution, early success, current status, challenges, and opportunities for clinical application of genotyping and genomic tests in therapeutic decision making for NSCLC.

Fig 1.

Improved drug-biomarker development paradigms: marriage of drug-biomarker development. Data adapted.

Fig 2.

Advances in sequencing technologies and human genomics.

Fig 3.

Genotyping and genomic profiling in personalized medicine: a scientific revolution of cancer molecular diagnosis and treatment. CNV, copy number variation; FFPE, formalin-fixed paraffin-embedded; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry; RT-PCR, reverse transcriptase polymerase chain reaction; SNP, single nucleotide polymorphism.

Fig 4.

Evolution of non–small-cell lung cancer (NSCLC) subtyping from histologic to molecular based. Data adapted. EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; MAP2K1, mitogen-activated protein kinase kinase 1.