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Native and rearranged ALK copy number and rearranged cell count in non–small cell lung cancer
Author(s) -
Camidge D. Ross,
Skokan Margaret,
Kiatsimkul Porntip,
Helfrich Barbara,
Lu Xian,
Barón Anna E.,
Schulte Nathan,
Maxson DeLee,
Aisner Dara L.,
Franklin Wilbur A.,
Doebele Robert C.,
VarellaGarcia Marileila
Publication year - 2013
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.28311
Subject(s) - crizotinib , anaplastic lymphoma kinase , fluorescence in situ hybridization , alk inhibitor , lung cancer , cancer research , medicine , pathology , copy number variation , microbiology and biotechnology , biology , genetics , gene , chromosome , genome , malignant pleural effusion
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 μM; 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 ≤5%. Further investigation of ALK by other diagnostic techniques in such cases may be warranted. Native ALK copy number increases alone were not associated with sensitivity to ALK inhibition in vitro. However, rare, complex patterns of increased native ALK in patients should be studied further; because, otherwise, atypical rearrangements contained within these may be missed. Cancer 2013 ;119:3968–3975. © 2013 American Cancer Society .