<i>BRAF</i> -V600E papillary thyroid cancer: Updated analysis of real-world patient data.

Abstract

6099 Background: Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, usually characterized by a good prognosis after surgery with or without radioactive iodine therapy (RAI). However, ~5-15% of patients become RAI refractory, and some require systemic therapy, often with multi tyrosine kinase inhibitors (mTKIs). BRAF -V600E, the most common mutation in PTC (~60% of patients), is associated with poor outcomes. The effectiveness of mTKIs compared to BRAF-targeted therapy (BRAF/MEKi) and immunotherapy (IO) remains unclear in the BRAF -V600E mutant ( BRAF -m) population. Therefore, we conducted an updated analysis comparing real-world (rw) survival and molecular/transcriptional signatures in patients with BRAF -m and BRAF -wildtype (WT) PTC. Methods: Differentiated thyroid cancer (DTC) tumor samples underwent DNA/RNA next-gen sequencing at Caris Life Sciences. Tumor microenvironment (TME) cell fractions were estimated by RNA deconvolution using QuanTIseq. A transcriptional IFNγ signature score associated with response to IO was calculated. PD-L1 + (SP142) was defined as ≥2 + in stain intensity and ≥5% of tumor cells stained. Insurance claims data was used to infer rw overall survival (rwOS) from the time of initial diagnosis to death/last contact, and time on treatment (TOT) was assessed from the first to last date of treatment, with hazard ratios (HR) and p-values calculated using the Cox proportional hazards model and log-rank test, respectively. Results: A total of 1,348 patients with DTC were identified, of which 82% (n=1,102) were PTC and 18% (n=246) were follicular thyroid cancer (FTC). The majority (95%) of PTC patients were naïve to mTKIs or BRAF/MEKi. BRAF -V600E mutations were present in 68% (n=754) PTC patients and only 0.8% (n=2) FTC patients. TERT promoter mutations were the most common mutation overall in PTC (72%), more prevalent in BRAF -m vs BRAF -WT PTC (79% vs 54%, p&lt;0.001). Mutations in NRAS , HRAS and KRAS were largely exclusive to BRAF -WT PTC (22%, 9% and 6% vs 0.1%, 0% and 0% in BRAF -m PTC, p&lt;0.001), as were RET , BRAF , and ETV6 gene fusions (24%, 5% and 5% vs 0%, 0.4% and 0% in BRAF -m PTC, p&lt;0.01). BRAF -m PTC were more often PD-L1 + (33% vs 18%, p&lt;0.001), consistent with higher IFNγ scores. This was accompanied by higher Treg and M1 macrophage TME fractions, and lower M2 macrophage, T cell (CD4 + and CD8 + ), NK cell, monocyte and myeloid dendritic TME fractions compared to BRAF -WT PTC (p&lt;0.05). There was no difference in rwOS between BRAF -m and BRAF -WT PTC (HR=0.845, 95% CI 0.654-1.092, p=0.197), nor per treatment received in BRAF -m PTC (BRAF/MEKi vs mTKIs, BRAF/MEKi vs IO, IO vs mTKIs). Similarly, TOT for BRAF/MEKi, mTKIs and IO were similar between BRAF -m and BRAF -WT PTC. Conclusions: BRAF -m PTC is associated with a more pro-inflammatory TME milieu compared to BRAF -WT PTC. However, in this limited data set, treatment choice was not associated with differences in overall survival in BRAF -m PTC.