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Identifying ALK rearrangements that are not detected by FISH with targeted next-generation sequencing of lung carcinoma.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Genomic rearrangements of ALK are the defining feature of a subset of lung non-small cell carcinomas (NSCLC), and predict response to ALK-targeted therapies. We reviewed our experience with ALK rearranged lung carcinomas (LC) as detected by a clinical next generation sequencing (NGS)-based assay. Methods: Genomic profiling of 1,070 lung carcinomas was performed on >50 ng of DNA extracted from formalin fixed, paraffin embedded specimens, from either primary tumors or metastatic sites. Libraries constructed from such DNA were subjected to hybrid capture of all exons of 236 cancer related genes and 47 introns of 19 genes frequently rearranged in cancer, and followed by clinical NGS with high uniform coverage to a median exon coverage depth exceeding 700x. Data regarding prior diagnostic studies for genomic alterations and response to targeted therapies was provided by treating physicians. Results: Of 1.070 total lung carcinomas profiled, 47 harbored ALK rearrangements (4.4%); including lung adenocarcinomas (n=39/724), NSCLC (n=4/146), adenosquamous carcinomas (n=2/12), and mucoepidermoid and large cell neuroendocrine carcinomas (n=1/3 and n=1/23). The median age of the patients was 52 years, with an equal sex ratio, and 38 patients had Stage IV disease. Of the 28 ALK rearranged specimens also tested by ALK FISH, 9 (32%) were negative, and 19 were positive. Of the 47 ALK rearranged cases, all fusions had a breakpoint in intron 19 of ALK. Six cases harbored non-EML4 5’ partners. Of the 41 EML4-ALK fusions, there were 17 cases with a breakpoint in intron 13 of EML4 (variant1), 2 cases in intron 18, 2 cases in intron 2(v5), 4 cases in intron 20 (v2), and 16 cases in intron 6 (v3). Twenty-two patients were treated with crizotinib and had response data available; 19 responded by investigator assessment. Of the 9 cases negative by FISH, 5 patients responded to crizotinib, 2 patients did not, and the response data for the remaining 2 patients is unavailable. Conclusions: Targeted NGS may be more sensitive for the detection of ALK rearrangements than FISH. In light of the responsiveness of ALK NGS+/FISH- tumors to crizotinib, the use of FISH as the gold standard for ALK detection in LC warrants prospective study.
Abstracts by Siraj M. Ali:
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