PMID- 24022839 OWN - NLM STAT- MEDLINE DCOM- 20140702 LR - 20211021 IS - 1097-0142 (Electronic) IS - 0008-543X (Print) IS - 0008-543X (Linking) VI - 119 IP - 22 DP - 2013 Nov 15 TI - Native and rearranged ALK copy number and rearranged cell count in non-small cell lung cancer: implications for ALK inhibitor therapy. PG - 3968-75 LID - 10.1002/cncr.28311 [doi] AB - BACKGROUND: Patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) respond to ALK inhibitors. Clinically, the presence of >/=15% cells with rearrangements identified on break-apart fluorescence in situ hybridization (FISH) classifies tumors as positive. Increases in native and rearranged ALK copy number also occur. METHODS: In total, 1426 NSCLC clinical specimens (174 ALK-positive specimens and 1252 ALK-negative specimens) and 24 ALK-negative NSCLC cell lines were investigated. ALK copy number and genomic status were assessed by FISH. RESULTS: Clinical specimens with 0% to 9%, 10% to 15%, 16% to 30%, 31% to 50%, and >50% ALK-positive cells were identified in 79.3%, 8.5%, 1.4%, 2.7%, and 8.1%, respectively. An increased native ALK copy number (>/=3 copies per cell in >/=40% of cells) was detected in 19% of ALK-positive tumors and in 62% of ALK-negative tumors. In ALK-negative tumors, abundant, focal amplification of native ALK was rare (0.8%). Other atypical patterns occurred in approximately 6% of tumors. The mean native ALK copy number ranged from 2.1 to 6.9 copies in cell lines and was not correlated with crizotinib sensitivity (50% inhibitory concentration, 0.34-2.8 muM; r = 0.279; P = .1764). Neither native or rearranged ALK copy number nor the percentage of positive cells correlated with extra-central nervous system progression-free survival in ALK-positive patients who were receiving crizotinib. CONCLUSIONS: Overall, 8.5% of tumors fell below the established positivity threshold by