Abstract A053: Specific cancer cell and immune features mediate atezolizumab-regimen clinical benefit in anaplastic thyroid cancer (ATC) independent of BRAF or RAS oncogenic status
Anaplastic thyroid cancer (ATC) is a rare, highly aggressive malignancy, responsible for a disproportionate share of thyroid cancer–related mortality and with limited therapeutic options. We reported results from a phase II trial (NCT03181100) in which ATC pts received atezolizumab plus targeted therapy: BRAF V600E (vemurafenib + cobimetinib) or RAS/NF mutant (cobimetinib). mOS was longer in the BRAF V600E cohort (43 months, 95% CI 16-NE) than the RAS/NF mutant cohort (8.7 months, 95% CI 5.1-37.0), but outcomes overlapped; pts with BRAF V600E had OS as short as 81 days, while pts with RAS/NF mutations had OS up to 1702 days. We sought to identify pre-treatment molecular features associated with OS, independent of oncogene status. Clinical NGS was performed on all tumors; whole-exome and transcriptome sequencing were available for pretreatment samples (n=14,16). Germline/somatic mutations, copy number alterations, and structural variants were assessed. Differential gene expression (DGE), gene set enrichment, and predefined gene profiles were analyzed. Patients were stratified by OS (>2-year vs <2-year). Among <2-year OS pts (n=9), 6 were RAS-mutant and 3 BRAF V600E; among >2-year OS pts (n=7), 5 were BRAF V600E and 2 RAS-mutant. Three pts were still alive (3.4–4.3 yrs), 2 BRAF V600E and 1 RAS-mutant. No co-mutations were associated with OS. DGE (≥3-fold) between short (<2-year) and long (>2-year) OS pt tumors showed longer OS tumors to express epithelial/differentiation (e.g., PAX8) and immune activation programs, including antigen presentation (MHC-II) and inflammatory signaling, whereas shorter OS pt tumors were enriched for epithelial-to-mesenchymal transition, hypoxia and oncofetal markers, independent of mutation status. DGE of BRAF V600E-only tumors showed longer OS to be associated with immune and antigen presentation signatures with retained differentiation markers, whereas shorter OS corresponded with increased receptor tyrosine kinase signaling and extracellular matrix remodeling genes. DGE in RAS-mutant-only tumors showed shorter OS to be associated with increased proliferative, angiogenic, and mesenchymal/stromal gene profiles. Longer OS corresponded with higher epithelial/differentiation marker and metabolic/secretory programs. In addition, MAPK/ERK activity was associated with improved OS in BRAF V600E pts, but reduced OS in pts with RAS mutations, consistent with differences in targeted therapy. Survival in ATC is associated with baseline transcriptional programs rather than driver mutation status alone. Specific differentiation and immune activation features are associated with longer OS, whereas mesenchymal, hypoxic, and proliferative programs are associated with shorter OS. These associations differ by cohort, supporting integrated molecular stratification beyond oncogene status to inform prognosis and therapeutic strategies in ATC. Brian A. McKinley, Haifeng Zhu, Rare Tumor Initiative Team, Ramona Dadu, Jennifer R. Wang, Naifa L. Busaidy, Sabitha Prabhakaran, P Andrew. Futreal, Maria E. Cabanillas, Scott E. Woodman. Specific cancer cell and immune features mediate atezolizumab-regimen clinical benefit in anaplastic thyroid cancer (ATC) independent of BRAF or RAS oncogenic status [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A053.