COMMENTARY

Targeted Therapies on the Horizon for Squamous Lung Cancers

Maurie Markman, MD

Disclosures

November 20, 2012

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Cancer Genome Atlas Research Network; Hammerman PS, Hayes DN, Wilkerson MD, et al
Nature. 2012;489:519-525

Summary

In an effort to develop a firmer understanding of the genomic landscape that characterizes the development and progression of squamous cell lung cancer, investigators conducted a detailed qualitative and quantitative assessment of 178 such tumors, assessing both the types of abnormalities observed and the total number and percentage of cases with particular findings. As anticipated, the large majority of these cancers came from individuals with a history of tobacco exposure (96%). The histologic diagnosis of the tumor type was confirmed by a panel of expert lung pathologists.

The analysis revealed that individual squamous cell lung cancers demonstrate a rather large number of mutations in their exons (mean, 360 per tumor) and copy number of various genetic segments (mean, 323 per tumor), as well as a substantial number of genetic rearrangements (mean, 165 per tumor). However, despite the complexity observed, the investigators found recurrent mutations in 11 specific genes, suggesting that these abnormalities may serve as valid targets and possible "driver mutations" for clinical interventions. Particularly noteworthy were abnormalities of genes known to be involved in squamous cell differentiation (44% of samples) and in the response to oxidative stress. Abnormalities that had previously been shown to be relevant targets in adenocarcinoma (eg, activating mutations in EGFR) were very rare (< 1%).

Overall, 96% of tumors were demonstrated to have a defect that, based on evidence from others settings, could possibly be "druggable," or capable of being affected by a systemically delivered antineoplastic agent.

Viewpoint

Rather spectacular advances in our understanding of unique molecular profiles in subgroups of patients with adenocarcinoma of the lung have led to management strategies targeted to these findings (eg, activating mutations of EGFR and ALK rearrangement). In fact, evidence supports obtaining such information in designing optimal initial treatment of advanced/metastatic adenocarcinoma of the lung.[1]

These specific mutations, however, are rarely, if ever, observed in squamous cell lung cancer, as confirmed in the current report. Furthermore, prior to the current report, there was very little evidence to even suggest that the development of molecularly targeted approaches was a viable therapeutic strategy in this tumor type. This landmark paper provides the first solid evidence that potentially "druggable" targets are observed in the large majority of squamous cell lung tumors and several relatively frequent groups of molecular abnormalities are seen in this setting. Future research in this arena will need to focus on targeting these mutations with existing antineoplastic agents, or on developing new classes of drugs that can interfere with potential "driver" mutations in these cancers.

Abstract

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