ALK and MET genes in advanced lung adenocarcinomas: The Lung Cancer Mutation Consortium experience.

Abstract

7589 Background: The Lung Cancer Mutation Consortium (LCMC) consisting of 14 US Cancer Centers was established to evaluate a panel of molecular mutations in advanced lung adenocarcinoma. ALK gene fusions and MET gene amplification were assessed by FISH in CLIA certified laboratories. Methods: Molecular tests were performed in stage IIIB or IV lung adenocarcinoma. To date, FISH assays have been completed in 901 patients for ALK (ALK break-apart, Abbott Molecular) and in 654 patients for MET (in house/Abbott Molecular reagents). ALK+ specimens were defined by split 3’ALK/5’ALK signals (gap >2 signal diameters) or single 3’ALK signals in >15% of tumor cells. MET gene amplification (MET+) was defined by ratio mean MET/mean CEP7 ≥2. Results: The ALK+ patient subset (N=75, 8.3%) compared to the ALK- had significantly lower age at diagnosis (52 vs. 60, p<0.001) and less frequent heavy smoking history (61% never-smokers among ALK+ vs. 31% among ALK-, p<0.001; pack-year for current/former smokers 17 vs. 40, p=0.003). Liver metastases were significantly more frequent among ALK+ than ALK- (23% vs.10%, p=0.004); no difference was detected in bone, brain and adrenal gland metastases. MET+ (N=29, 4.4%) was significantly associated with female sex (72% female among MET+ vs. 39% among MET-, p<0.001) and marginally more frequent in patients with adrenal metastasis; no difference was detected for age at diagnosis and smoking history. Follow-up on 73 ALK+ patients indicated that 56% received crizotinib as targeted therapy. Response was unknown in 8% and unreportable in 22% patients enrolled in ongoing randomized trials. Among patients with evaluable response, complete response, partial response, stable disease, and progressive disease were found respectively in 3%, 66%, 28%, and 3%. Conclusions: The LCMC successfully tested ALK and MET FISH in a large number of lung adenocarcinomas. It was demonstrated that directing positive patients to specific interventions is feasible, and that grouping of testing and trials within consortia may maximise relevant trial accrual in rare molecular subtypes. Supported by NCI-GO award. Submitted on behalf of the LCMC.