Purpose: Selpercatinib and pralsetinib induce deep and durable responses in advanced RET fusion-positive lung and thyroid cancer patients. RET fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort. Experimental Design: Tumors underwent DNA-based next generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a RET structural variant of unknown significance (SVUS) were present. Canonical DNA-level RET fusions and RNA-confirmed RET fusions were considered true fusions. Break-apart fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) performance were assessed in subgroups. Results: 171 of 41,869 patients with DNA NGS harbored RET structural variants, including 139 canonical fusions and 32 SVUS. 12/32 (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% (4459/4479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for NCOA4-RET (66.7%, 8/12). 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: While 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.
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