Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation

Menée sur des échantillons tumoraux prélevés sur 997 patients chinois atteints d'un cancer du poumon, cette étude évalue la présence concomitante de mutations du gène EGFR et de réarrangements ALK et analyse leurs effets sur la réponse au crizotinib et aux inhibiteurs de l'activité tyrosine kinase de l'EGFR

Résumé en anglais

Purpose: We investigated the incidence of concomitant EGFR mutations and 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 polymerase chain reaction sequencing and fluorescence in situ hybridization. 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) ALK-rearranged 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. Co-expression 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 co-exist 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.