Conclusions
Although DNA sequencing has high sensitivity and specificity, RNA sequencing of RET SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for NCOA4-RET fusions.
Purpose
Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced RET fusion-positive lung and thyroid cancer. RET fusion testing strategies with rapid and reliable
Results
A total of 171 of 41,869 patients with DNA NGS harbored RET structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic RET fusions. The most common RET fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were KIF5B (45%), CCDC6 (29.1%), and NCOA4 (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for NCOA4-RET (66.7%, 8/12). A total of 87.5% (7/8) of RET SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: KIF5B sensitivity was highest (100%, 31/31), followed by CCDC6 (88.9%, 16/18) and NCOA4 (50%, 6/12). Specificity of RET IHC was 82% (73/89). Conclusions: Although DNA sequencing has high sensitivity and specificity, RNA sequencing of RET SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for NCOA4-RET fusions.