The current criteria used to match lung cancers with the drug crizotinib may miss some patients who could benefit from the drug. Findings from a new study suggest that doctors should look closer at borderline or atypical anaplastic lymphoma kinase (ALK)-negative cases, and it may widen the population of lung cancer patients who are offered treatment with crizotinib or other ALK-inhibitor drugs.
ALK is a gene that is turned off in most adult tissues in the body, but it can be re-activated to cause cancer when it is fused with another nearby gene. The most widely-used tests for ALK-positive lung cancer use fluorescence in situ hybridization to test for the fusion of the ALK gene with another gene that turns ALK back on, allowing ALK to drive some lung cancers. When a cancer is ALK-positive, it can be very effectively treated with crizotinib, a targeted anti-ALK drug.
“The test is fairly definitive—either a cell is ALK positive or not using the criteria we initially implemented. However, what is less certain is the exact percentage of ALK-positive cells required to label an entire tumor as ALK-positive. Is there an exact threshold of ALK-positive cells that will make a patient respond to crizotinib or other ALK inhibitors?” said Leila Garcia, PhD, of the University of Colorado Cancer Center in Denver.
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“Since the beginning we have looked at the cells in a tumor, and if 15% or more of these cells show the changes classically associated with an ALK rearrangement, we classify that tumor as ALK-positive and offer treatment with crizotinib,” said Ross Camidge, MD, PhD, also of CU Cancer Center. Previous studies indicated that this cutoff point placed tumors in a clear gap between those that were obviously ALK-positive and those that were obviously ALK-negative, making it an attractive threshold.
“But what this study shows is that when you look not at tens, but hundreds of cases, tumors clearly exist that come right up to the 15% cutoff point,” Camidge said. This new study was published in Cancer (2013; doi:10.1002/cncr.28311).
Another possible gray area is when a gene rearrangement occurs but is very complex—like shuffling cards rather than just cutting the deck. In this situation, the typical separated dot pattern indicative of ALK rearrangement may not be present, but instead doublets or triplets of single or unseparated dots may exist. This atypical cellular footprint can tell an expert that, while officially ALK-negative, the cancer has made some changes in the region of the ALK gene that could still make the cancer sensitive to ALK-inhibitor drugs.
“We believe these data suggest that such borderline and atypical negative cases deserve a closer look, perhaps with new kinds of diagnostic tests,” said Camidge. The study found that 8.5% of non-small cell lung cancers were “borderline” negative, and 1% to 2% had atypical patterns and may need their ALK status re-evaluated.
