What is the role of genetics in the pathogenesis of non-small cell lung cancer (NSCLC)?

Updated: Aug 21, 2019
  • Author: Maurie Markman, MD, MS; Chief Editor: Keith K Vaux, MD  more...
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Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in the progression to metastatic disease. Mutations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) are mutually exclusive in patients with NSCLC, and the presence of one mutation in lieu of another can influence response to targeted therapy. Therefore, testing for these mutations and tailoring therapy accordingly are widely accepted as standard practice. [1, 2, 3]

EGFR is expressed on the cell surface of a substantial percentage of NSCLCs. Initial studies with the EGFR tyrosine kinase inhibitors (TKIs) gefitnib (Iressa) and erlotinib (Tarceva) demonstrated biologic and clinical activity in only a relatively limited subset of lung cancers. [4] Further investigation demonstrated that the highest response rates to these TKIs were seen in patients with somatic mutations within the EGFR-TK domain, particularly exon 19 deletion, exon 21 L858R, and exon 18 G719X. [5] By contrast, the exon 20 T790M mutation is associated with acquired resistance to TKI therapy. [6]

In general, activating EGFR mutations are more commonly observed in patients with adenocarcinomas and no prior history of smoking, as well as in females and those of Asian descent. Based on the new adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society, [7] researchers identified EGFR mutations in 50.5% of surgically resected lung adenocarcinomas. Mutations were associated with the micropapillary predominant subtype and the presence of the lepidic pattern (formerly known as bronchioloalveolar carcinoma). [8] These data support estimates from clinical trial evidence that activating EGFR mutations are seen in approximately 50% of Asians and 10% of non-Asians.

Use of the EGFR-TKIs gefitinib, erlotinib, and afatinib is limited to patients with adenocarcinomas who have known activating EGFR mutations. As discussed below, activity of the EGFR monoclonal antibody cetuximab seems to be independent of EGFR mutation status. It is unclear how the presence of an acquired EGFR mutation such as T790M should influence therapeutic decisions. [1]

KRAS mutations are also predominantly found in adenocarcinomas and are seen in approximately 25% of cases. However, they are less common among those of Asian descent and are more common in smokers. [9] Most importantly, patients with KRAS mutations seem to have a poorer prognosis and seem to be resistant to EGFR-TKIs, although the extent to which this might influence treatment selection remains somewhat unclear. [9, 10]

Finally, fusion between echinoderm microtubule-associated proteinlike 4 (EML4) and ALK is seen in approximately 2-7% of patients with NSCLC adenocarcinomas. This and other ALK rearrangements are more common in nonsmokers or light smokers and in those with adenocarcinomas. Because EGFR and ALK mutations are mutually exclusive, patients with ALK rearrangements are not thought to benefit from EGFR-targeting TKIs. Instead, treatment with an ALK inhibitor (crizotinib [Xalkori], ceritinib [Zykadia], brigatinib [Alunbrig]) is indicated. [11, 12, 13]

ROS-1 gene alterations, thought to lead to abnormal cells, have been identified in various cancers, including NSCLC. ROS-1 gene alterations are present in approximately 1% of patients with NSCLC. [14]

To see complete information, please see the Medscape Reference article Non-Small Cell Lung Cancer.

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