Double mutations do not significantly decrease overall survival (OS), but do alter progression-free survival (PFS) under first line treatment for patients with non-small cell lung cancer (NSCLC) who have mutations to epidermal growth factor receptor (EGFR), according to results presented at the International Association for the Study of Lung Cancer (IASLC) 17th Annual World Conference on Lung Cancer in Austria.1

NSCLC carcinogenesis can be driven by “oncogenic addiction,” in which the tumor cells exhibit an apparent dependence on a single oncogenic pathway or protein for sustained proliferation. These molecular alterations can be targeted by specific inhibitors. While it is generally accepted that the molecular alterations are mutually exclusive, new evidence suggests that concomitant molecular alteration can occur in lung cancer.

Study authors used the French Cooperative Thoracic Intergroup’s (IFCT) Biomarker France database, which collected molecular profiles of tumors from 17,664 patients with NSCLC. They calculated the prevalence of multiple alterations and of each association, and established their impact on OS and response to targeted or conventional treatments (PFS and objective response rate [ORR]). They compared these results with the population of patients harboring single mutations and full wild-type.

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One hundred and sixty-two (0.9%) patients had double genetic alterations and 3 had triple alterations. Multiple mutations preferentially involved KRAS (67.3%), PI3K (53.3%) and EGFR (42.4%). OS was not significantly different between single and multiple alterations whatever the type of mutations.

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Patients with EGFR/KRAS and EGFR/PI3K mutated tumors had worse PFS after biomarker analysis than patients with EGFR single mutation (7.1 and 7.1 months vs 14.9 months, respectively). Concomitant mutations in patients with ALK rearrangement had little impact on OS (17.7 months vs 20.3 months) or PFS (10.3 months vs 12.1 months).

The authors claimed that given their findings that nearly 1% of patients with NSCLC had multiple genomic alterations, the common belief that mutations are mutually exclusive “should be reconsidered.”


  1. Guibert N, Barlesi F, Descourt R, et al. Characteristics and outcomes of patients with lung cancer harboring multiple molecular alterations (biomarker IFCT study). Paper presented at: International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer; December 2016; Vienna, Austria.