Identification of Somatic Genomic Alterations in Circulating Tumors Cells: Another Step Forward in Non–Small-Cell Lung Cancer?

Abstract

The last decade has witnessed substantial progress in defining the molecular determinants of non–small-cell lung cancer (NSCLC) and demonstrating how these can be exploited in the clinic. In 2004, the identification of somatic mutations in the epidermal growth factor receptor (EGFR) gene provided the first insight into a clinically relevant NSCLC driver oncogene. EGFR mutations in NSCLC are transforming, enhance the activity of the kinase domain of EGFR, and increase the affinity for EGFR tyrosine kinase inhibitors (TKIs). In EGFR-mutated NSCLCs (ie, tumors with classic EGFR exon 19 deletions or the L858R mutation, which are found in approximately 15% of all NSCLCs), clinical and radiographic responses are achieved in most patients with the use of two commercially available reversible EGFR TKIs: gefitinib and erlotinib. These EGFR TKIs improve outcomes when compared with cytotoxic chemotherapies, and the evidence-based use of these drugs, as recommended by the American Society of Clinical Oncology and other practice and regulatory agencies, is now restricted to EGFR-mutated NSCLCs in the first-line treatment of advanced tumors. The significant palliative benefits that are offered by matching a tumor driver mutation with an appropriate inhibitor paved the way for the genomic characterization of NSCLCs and the development of novel TKIs that can target these changes. The deciphering of NSCLCs using next-generation sequencing (through whole-genome, exome, and transcriptome techniques) has identified numerous driver oncogenic events (ie, activating mutations or rearrangements) involving targetable kinases, including ROS1, ERBB2, BRAF, and RET, among others. The separation of NSCLCs into distinct, actionable subtypes is mostly clear in lung adenocarcinomas of never-smokers (Figure 1), in which almost all tumors have a mutually exclusive driver oncogene for which TKIs are either clinically available or in earlyto late-stage development. Amid the exciting series of discoveries that have occurred during the last decade, one of the most remarkable has been the story of how anaplastic lymphoma kinase (ALK) gene alterations became a biomarker and therapeutic target in NSCLC. ALK is a transmembrane tyrosine kinase that had been previously implicated in the pathogenesis of anaplastic large cell lymphoma and neuroblastoma. In 2007, a Japanese group from Jichi Medical University identified novel fusion oncogenes involving the kinase domain of ALK in patients with NSCLC. ALK rearrangements, either inversions or translocations, characterize the genomic changes observed in NSCLC. The most frequent event is an inversion in the short arm of chromosome 2 that results in the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) with ALK, leading to the production of an EML4-ALK fusion tyrosine kinase. Several EML4-ALK variants have now been described, with EML4-ALK E13;A20 and E20;A20 being the most common. Few other tumor types harbor these EML4-ALK rearrangements, and it remains unclear why NSCLCs can acquire these somatic changes. Interestingly, some clinical and pathologic features are associated with an increased incidence of tumors containing ALK rearrangements. These include never or light smoking history ( 15 pack-years), young age, and adenocarcinoma histology with signet rings. The reported prevalence of ALK rearrangements in NSCLC is approximately 5%; however, in neversmokers or light smokers with lung adenocarcinoma, the prevalence may be as high as 20%. Therefore, as many as 10,000 new cases of ALK-rearranged NSCLC are expected in the United States this year. Other/unknown