Identification of a novel class of early exon ALK rearrangements across two pan-tumor sequencing databases

Abstract
Purpose – The vast majority of reported ALK rearrangements occur at exons 17-20. ALK-rearrangements occurring earlier in the ALK gene (eALK) are poorly characterized and rarely reported, potentially because most clinically available biomarker testing is optimized for detecting common ALK rearrangement regions.

Methods – Two databases, the Tempus deidentified database and Cedars-Sinai database, were retrospectively queried to characterize eALK rearrangements, as defined by rearrangements involving ALK exons 1-16. Select specimens harboring eALK rearrangements were evaluated using available FDA-approved methods (immunohistochemistry [IHC] and fluorescent in-situ hybridization [FISH]); clinical management and outcomes were evaluated for these cases.

Results – 39 eALK rearrangements were detected in the Tempus database and 3 were identified in the Cedars-Sinai database. Across these 42 rearrangements, there were 35 unique partner genes; rearrangements were identified in all early exons except exons 8, 10, 13 and 15, with exons 2 and 4 being most common. Prostatic, breast, leiomyosarcoma, and ovarian serous carcinoma were the most common tumor types, which may reflect database bias. In three cases, IHC and FISH were unreliable at detection (0/ 3 IHC positive, 1/3 FISH atypical positive). Limited clinical information shows partial response to ALK targeted therapies.

Conclusions – Novel eALK rearrangements are a distinct subclass of ALK rearrangements and were not reliably detected through FDA-approved testing modalities. Limited clinical data suggests these cancers could still respond to ALK targeted therapy.