How Does Genetics Affect Outcomes in Nonsmokers With NSCLC?

Maurie Markman, MD


April 04, 2012

Distinct Clinical Features and Outcomes in Never-Smokers With Nonsmall Cell Lung Cancer Who Harbor EGFR or KRAS Mutations or ALK Rearrangements

Kim HR, Shim HS, Chung JH, et al
Cancer. 2012;118:729-739


Investigators at the Yonsei Cancer Center in Seoul sought to critically describe the incidence of and outcome associated with specific well-defined genetic abnormalities in nonsmoking individuals of East Asian ethnicity who developed nonsmall cell lung cancer (NSCLC). They analyzed 229 tumors for the presence of EGFR or KRAS mutations, or for the presence of a genetic rearrangement in ALK. Approximately 60% of patients had a mutation in EGFR (48%) or KRAS (3.5%) or an ALK rearrangement (8.3%); the remaining 40% of individuals were wild-type for all 3 genes.

A most striking finding in this study was the observation that the 3 genetic abnormalities were completely mutually exclusive, with no patient having more than 1 of these aberrations. The presence of the specific genetic abnormalities was strongly associated with time-to-disease progression following treatment with an EGFR tyrosine kinase inhibitor (TKI) such that the risk of progression was significantly lower for patients with EGFR mutations than for KRAS or ALK abnormalities -- both of which predicted for a shorter time to progression compared with the wild-type genotype.

Not surprisingly, overall survival followed the pattern observed for progression: survival was superior in the EGFR mutation-positive population (median 37.2 months) vs patients with ALK rearrangements (median 14.3 months) and KRAS mutations (median 15.6 months), and both of the latter cohorts fared worse compared with individuals without any documented mutation (median 33.3 months).

Finally, the objective response rate to treatment with an EGFR TKI was high in the group with an EGFR mutation (65%), but no objective responses were observed in individuals with KRAS mutations or ALK rearrangements. Patients without any of these mutations experienced a modest opportunity to achieve a response (10.3%).


This interesting series provides rather striking evidence for the importance of documenting the presence -- or absence -- of specific genetic abnormalities when considering treatment of NSCLC patients with an EGFR TKI. Two-thirds of patients with a documented EGFR mutation responded to treatment and experienced a quite reasonable median time-to-disease progression (12.8 months) and overall survival (37.2 months). Conversely, the presence of either an ALK rearrangement or KRAS mutation identified a population that was unresponsive to this therapeutic strategy and had a much worse outcome following such treatment, even compared with individuals who failed to demonstrate the presence of an EGFR mutation.

Collectively, these data provide strong support for molecular profiling of all patients with NSCLC considered for treatment with an EGFR TKI. Specifically, individual patient data related to the existence of a KRAS mutation or ALK rearrangement in a particular cancer are relevant in the decision to use this specific approach to disease management independent of the absence of a documented EGFR mutation.



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