Correlations between the percentage of tumor cells showing an anaplastic lymphoma kinase (ALK) gene rearrangement, ALK signal copy number, and response to crizotinib therapy in ALK fluorescence in situ hybridization-positive nonsmall cell lung cancer

BACKGROUND: Fluorescence in situ hybridization (FISH), using break-apart red (3') and green (5') ALK (anaplastic lymphoma kinase) probes, consistently shows rearrangements in <100% of tumor cells in ALK-positive (ALK+) nonsmall cell lung cancer (NSCLC). Increased copy numbers of fused and rearranged signals also occur. Here, correlations are explored between the percentage of ALK+ cells and signal copy number and their association with response to ALK inhibition. METHODS: Ninety ALK+ NSCLC cases were evaluated. The percentage of positive cells, pattern of positivity (split, single red, or both), and copy number of fused, isolated red and green signals were recorded. Thirty patients had received crizotinib. RESULTS: Increased isolated red signal copy number (contributing to both single red and split patterns of positivity) correlated with a higher percentage of ALK+ cells (r = 0.743, P < .0001). Mean fused copy number was negatively associated with isolated red signal copy number (r = -0.409, P < .0001). Neither percentage of positive cells (r = 0.192, P = .3), nor copy number of isolated red signal (r = 0.274, P = .195) correlated with maximal tumor shrinkage with crizotinib. CONCLUSIONS: The strong association between increased copy number of key ALK signals and percentage of positive cells suggests that the <100% rate of cellular positivity in ALK+ tumors is due to technical factors, not biological factors. In ALK+ tumors, neither the percentage of positive cells nor signal copy number appear to be informative variables for predicting benefit from ALK inhibition. The inverse relationship between fused and isolated red copy number suggests ALK+ may be a distinct near-diploid subtype of NSCLC that develops before significant chromosomal aneusomy occurs. Cancer 2012. (c) 2012 American Cancer Society.