RARE EGFR MUTATIONS

Certain rare epidermal growth factor receptor (EGFR) mutations are associated with tobacco smoking, worse prognosis, and poor response to EGFR tyrosine kinase inhibitor therapy, compared with more common, classic EGFR mutations. However, as not all rare mutations are the same, testing and therapy may need to be evaluated for each individual mutation. These findings were reported in a new study by Lohinai et al in the Journal of Thoracic Oncology.

Alterations within EGFR are the most frequently therapeutically targeted genomic alterations in non–small cell lung cancer (NSCLC). Deletions within exon 19 or a point mutation in exon 21 are the common mutations predictive of response to EGFR tyrosine kinase inhibitor therapy and the ones most often—and sometimes exclusively—tested for. However, less common EGFR mutations exist and some—for example, G719x and L861Q—appear sensitive to tyrosine kinase inhibitor therapy.

Study Details

In the current study, researchers in Austria and Hungary examined the EGFR mutation status of 814 Hungarian patients with pathologically confirmed adenocarcinoma and compared the epidemiology and clinical consequence of rare vs classic EGFR mutations. Clinical and pathologic data were available for 645 of those examined, and disease outcome data were available for 419.

The researchers’ results showed that 5% of patients had classic (exon 19 or 21) mutations, 6% had rare mutations, and 3% had synonymous (nonprotein-altering) mutations. Of note, 10% of patients with rare mutations carried alterations known to be sensitive to EGFR tyrosine kinase inhibitors. As expected, the classic mutations were associated with never-smokers (P < .0001). However, rare mutations were associated with tobacco smokers (P = .0062). Classic EGFR mutations, but not rare ones, were independent predictors of increased overall survival (hazard ratio = 0.45, 95% confidence interval = 0.25–0.82, P = .009).

The response rate to tyrosine kinase inhibitor therapy was significantly higher (71% vs 37%; P = .039) in classic vs rare mutations. Patients with classic or sensitizing rare (G719x and L861Q) EGFRmutations had significantly longer progression-free survival when compared to the remaining rare mutation cases (12 vs 6.2 months; P = .048).

Balazs Dome, MD, PhD, and Balazs Hegedus, PhD, cosenior authors of the study, stated, “Our study clearly demonstrates that rare and classic EGFR mutations show distinct epidemiologic features and have different impacts on disease outcome and [tyrosine kinase inhibitor] therapy response. Based on our findings, we conclude that the determination of the sensitizing status of each particular rare EGFRmutation has clinical relevance and important implications for [tyrosine kinase inhibitor] therapy. All in all, the molecular screening methods should extend beyond the identification of classic EGFRmutations to prevent the exclusion of patients who may benefit from anti-EGFR therapy.”