Lung Cancers with Concomitant EGFR Mutations and ALK Rearrangements: Diverse Responses to EGFR-TKI and Crizotinib in Relation to Diverse Receptors Phosphorylation

Abstract

Purpose: We investigated the incidence of concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements in Chinese patients with non-small cell lung cancer (NSCLC), and assessed responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib in such tumors.Experimental Design: We screened 977 consecutive patients with NSCLC for the presence of concomitant EGFR mutations and ALK rearrangements by rapid amplification of cDNA ends-coupled PCR sequencing and FISH. Immunohistochemistry (IHC) and Western blotting were used to correlate the activation of EGFR, ALK, and downstream proteins with responses to EGFR-TKIs and crizotinib.Results: The overall frequency of concomitant EGFR mutations and ALK rearrangements was 1.3% (13/ 977). EGFR/ALK co-alterations were found in 3.9% (13/336) EGFR-mutant and 18.6% (13/70) ALKrearranged patients. Ten tumors were treated with first-line EGFR-TKIs, with a response rate of 80% (8/10). Two tumors with high phospho-ALK levels and low phospho-EGFR levels achieved stable and progressive disease, respectively. Median progression-free survival was 11.2 months. Coexpression of mutant EGFR and ALK fusion proteins in the same tumor cell populations was detected by IHC. Two cases with high phospho-ALK levels treated with crizotinib achieved partial responses; two cases with low phospho-ALK levels had progressive or stable disease.Conclusion: ALK rearrangements and EGFR mutations could coexist in a small subgroup of NSCLC. Advanced pulmonary adenocarcinomas with such co-alterations could have diverse responses to EGFR-TKIs and crizotinib. Relative phospho-ALK and phospho-EGFR levels could predict the efficacy of EGFR-TKI and crizotinib. Clin Cancer Res; 20(5); 1383-92. Ó2014 AACR.

Systemic treatment in EGFR-ALK NSCLC patients: second line therapy and beyond

“…. Tumors harboring co-altered EGFR and ALK could have diverse responses to first-line EGFR-TKIs, which were associated with phospho-EGFR levels 57 . Phospho-ALK levels correlated with efficacy of subsequent crizotinib treatment.…”

“…Phospho-ALK levels correlated with efficacy of subsequent crizotinib treatment. In clinical practice, we should pay attention to the specific biological behavior and corresponding management of NSCLC with dual altered EGFR and ALK genes 57 .…”

A Case Report of a Metastatic Adenocarcinoma of Lung with Dual Positivity for EGFR Mutation and ALK Fusion

“…ALK rearrangements and EGFR mutations have been largely reported to be mutually exclusive [1] and as mutual causes of resistance to EGFR tyrosine kinase inhibitors (TKIs) and ALK TKI [4,5]. There is a possibility that similar to the prevalence of EGFR mutations, the coexistence of ALK rearrangement may be higher in East-Asian lung adenocarcinoma patients as compared to the Caucasians [6][7][8]. Recently, rare case reports have emerged noting the coexistence of EGFR mutation in EML4-ALK fusion positive patients [1,[7][8][9][10][11][12].…”

“…There is a possibility that similar to the prevalence of EGFR mutations, the coexistence of ALK rearrangement may be higher in East-Asian lung adenocarcinoma patients as compared to the Caucasians [6][7][8]. Recently, rare case reports have emerged noting the coexistence of EGFR mutation in EML4-ALK fusion positive patients [1,[7][8][9][10][11][12]. However, the frequency of such co-alterations is yet to be fully described [9][10][11].…”

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

“…ALK and ROS1 fusionpositive tumors seem to have a significantly shorter diseasefree survival after adjusting for confounding factors (30); however, this does not necessarily translate into a short overall survival, since some patients present a favorable natural history of disease and may be candidate to several lines of therapy. ALK rearrangements in NSCLC initially appeared to be mutually exclusive with activation occurring in other oncogenic drivers (31); however, recent studies revealed concomitant EGFR or KRAS mutations and ALK rearrangements (32)(33)(34).…”