Abstract 1532P
Background
Actionability of a growing subset of gene fusions and RE is well established, with several alterations linked to approved targeted therapies. While there are FDA-approved assays for DNA-based detection of key recurring actionable RE (ALK, ROS1, RET, etc.), sarcomas can be enriched for rare RE not comprehensively covered on DNA panels.
Methods
We performed DNA and RNA-based CGP (FoundationOne®Heme) for 9,969 sarcoma tissue samples and analyzed detection of RE including gene fusions. Only samples passing DNA/RNA quality metrics, genes baited on DNA/RNA, and RE with anticipated diagnostic or therapeutic significance were included.
Results
1,360 RE were detected across 1,351 tumor samples: 898 (66%) with a RE in the same gene in DNA/RNA, 3,640 (27%) RNA only (most commonly fusions with atypical breakpoints) and 98 (7%) DNA only (most commonly non-fusion RE). The most common disease subtypes were Ewing sarcoma (25%), soft tissue sarcoma not otherwise specified (STS NOS) (14%), solitary fibrous tumor (11%), leiomyosarcoma (5%) and others (50%). The most common RE were in EWSR1 (51%), STAT6 (17%), ALK (8%), BCOR (4%) and NTRK1 (4%). In ALK cases (n=103; 38% leiomyosarcoma, 30% inflammatory myofibroblastic tumor, 9% STS NOS) 52% had the same RE in DNA/RNA (54/54 fusions), 31% RNA only (31/32 fusions, 28/31 with breakpoints outside of the baited region of DNA), 10% DNA only (4 5’ deletions, 5 fusions). In 6% of ALK cases an atypical DNA event (3 complex RE, 2 intron 19 RE without a partner, 1 internal duplication) was further resolved as a fusion in RNA. In NTRK1 cases (n=51; 43% STS NOS, 12% liposarcoma), 41% had the same RE in DNA/RNA, 27% DNA only (50% non-fusion RE), 25% RNA only (13/13 with breakpoints outside of the baited region of DNA), and 6% with a non-fusion RE on DNA and an RNA fusion.
Conclusions
FoundationOne®Heme was designed to include rare fusions not well captured with DNA-based approaches. As expected, in most cases REs were detected in both DNA/RNA, and RNA baiting increased the sensitivity for atypical fusions with noncanonical breakpoints. In a subset of ALK and NTRK1 cases with DNA non-fusion RE, RNA either further resolved the event as an actionable fusion or no RNA event was observed to support the actionability of the DNA finding.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Foundation Medicine.
Funding
Foundation Medicine.
Disclosure
K. Ganjoo: Financial Interests, Personal, Advisory Board: Foundation Medicine. R. Madison: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. M. Rosenzweig: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. G. Oxnard: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. J. Venstrom: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. A. Ward: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. A.B. Schrock: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche.