Molecular Profiling and Real-world Outcomes of BRAF V600E–Mutated Papillary Thyroid Cancer

Abstract

Purpose: Radioactive iodine–refractory papillary thyroid cancers (PTC) containing BRAF V600E mutations can be treated with BRAF/MEK inhibitors (BRAF/MEKi), but their effectiveness compared with tyrosine kinase inhibitors (TKI) and immunotherapy (IO) remains unclear. Therefore, we compared real-world survival and molecular/transcriptional signatures in patients with BRAF V600E–mutated (BRAF-mut) and BRAF wild-type (WT) PTC. Experimental Design: Thyroid tumor samples underwent DNA/RNA next-generation sequencing and immunohistochemistry at Caris Life Sciences. Tumor microenvironment (TME) cell fractions were estimated by RNA deconvolution using quanTIseq. Insurance claims data were used to infer real-world overall survival (OS) and time on treatment. Results: A total of 1,348 patients with differentiated thyroid cancer were identified; 81.8% were classified as PTC, of which 68.4% harbored a BRAF V600E mutation. TERT promoter mutations were the most common mutation in PTC (72%) and were more prevalent in BRAF-mut versus BRAF-WT. Mutations in NRAS, HRAS, and KRAS, as well as RET, BRAF, and ETV6 gene fusions, were predominantly found in BRAF-WT PTC. BRAF-mut PTC were more often PD-L1+ (33% vs. 18%, P < 0.001) and had significantly higher IFNγ scores. OS was not significantly different between patients with BRAF-mut versus BRAF-WT PTC. Systemic treatment (BRAF/MEKi, TKI, or IO) was not associated with significant differences in OS in BRAF-mut PTC, although there was a trend for longer OS in those treated with TKI compared with BRAF/MEKi or IO. Conclusions: BRAF-mut PTC is associated with a proinflammatory TME milieu compared with BRAF-WT PTC. However, in this limited dataset, treatment choice was not associated with differences in OS in BRAF-mut PTC.