Changes in molecular profile following platinum chemotherapy in NSCLC.

Abstract

10518 Background: Platinum-based combination is the standard 1st-line chemotherapy for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKI) have shown striking treatment efficacy in in patients with specific molecular profiles. This study investigated whether the genomic profiles of NSCLC differ before and after platinum-based chemotherapy, a still pending question. Patients and Methods: Specimens from 50 stage IIIAN2, IIIB and IV NSCLC patients with diagnostic (therapy-naïve) and post-chemotherapy (paclitaxel, docetaxel or gemcitabine+cisplatin)/chemo-radiotherapy were screened by fluorescence in situ hybridization (FISH) for ALK fusions and copy number gain (CNG) of EGFR and MET . Complete results were obtained in pre- and post-treatment specimens for 45 patients. A positive marker was defined as follows: EGFR CNG: ≥4 copies in ≥ 40% cells; MET CNG: mean ≥5 copies/cell; ALK: rearrangement in >15% of the cells. Results: In diagnostic specimens, incidence of EGFR CNG (55%) was substantially higher than MET CNG (14%) or ALK+ (10%). All MET+ were also EGFR+ and all ALK+ were negative for EGFR and MET CNG. There was a significant association between EGFR CNG and female gender (p=0.001); no association was found between these biomarkers and age, smoking status, histology and stage. For ALK, there was no difference between diagnostic and post-treatment profiles in terms of presence or number of cells carrying the rearrangement (p=0.87). For EGFR and MET, no significant differences in mean copy number were detected (p=0.26 and p=0.87, respectively). However, 8 patients (18%) were classified in discordant EGFR copy number categories, 5 (10%) of which were likely due to real biological differences since similar discordance was also detected for MET. Conclusions: Platinum chemotherapy does not seem to impact occurrence of ALK gene fusions in NSCLC. Conversely, a relevant change in the copy number profile of EGFR and MET was detected in at least 10% of NSCLC, when diagnostic and resection specimens were compared. These results demonstrate variability of chemotherapy impact in molecular pathways and support that molecular testing be performed in specimens collected just prior to selecting patients for targeted therapy.