MON-785 Immunogenomic Analysis Of Advanced Thyroid Cancer Reveals A Distinct Immune Devoid Profile In RAS Mutant Tumors

Abstract T. Pappa: None. H. Patankar: None. A.N. Bikas: None. K. Sehgal: None. A.S. Alqahtani: None. J. Park: None. B. Reardon: None. S. Rodig: None. K. Pfaff: None. S. Jones: None. N. Besson: None. R. Haddad: None. E. Van Allen: None. E.K. Alexander: None. Background: Thyroid cancer (TC) is the most common endocrine malignancy, and in the last decade our understanding of its genomic landscape has significantly advanced. Yet, information about the immune microenvironment of TC and its association with prognosis is limited. This is important particularly in advanced disease, where systemic therapies, including immunotherapy, may be of benefit. Hypothesis: Given the interaction between tumor compartment and its microenvironment, we hypothesized that oncogenic drivers of thyroid cancer may be associated with distinct immune microenvironmental states.Methods: We assessed patients with TC, who received care at Brigham and Women’s Hospital and Dana-Farber Cancer Institute (DFCI), and in whom the DFCI OncoPanel (panel sequencing of 447 cancer genes) and ImmunoProfile (CD8, FOXP3, PD1, PDL1 staining) assays were performed on their tumor sample. We performed an immune-genomic correlation seeking to understand the link between oncogenic drivers of TC and immune biomarker expression. Chi-square test and one-way ANOVA were used for statistical analyses between categorical variables.Results: We studied 21 patients with both OncoPanel and ImmunoProfile annotations available. Mean age was 59.7 years, 52% were females. The cohort consisted of 7 patients with papillary TC, 1 follicular TC, 2 oncocytic TC, 8 anaplastic TC, 1 medullary TC and 1 NUT carcinoma. The prevalence of BRAFV600E mutation was 42.8% and of RAS (N/K/H) 23.8%. Four of 21 tumors had a TERT promoter mutation, 8 a variant in PI3K/AKT/mTOR pathway and 2 a variant within the SWI/SNF complex. Patients with RAS mutant tumors were more likely to have low CD8 expression (p=0.007), FOXP3 (p=0.009), PD1 (p=0.007) and PDL1 eIC (area of PDL1+inflammatory cells) (0.007). There was no significant association between immune activity and patient’s sex, BRAFV600 mutational status or TERT promoter mutation. In a larger cohort of 60 patients including non-thyroid solid tumors and available genomic and ImmunoProfile data, we similarly observed that RAS mutant tumors were more likely to have low CD8, FOXP3 and PD1 expression (p <0.05 for all markers), suggesting that the RAS-related immune pattern possibly extends beyond thyroid cancer. Conclusions: To our knowledge this is the first study illustrating that RAS mutant thyroid tumors have a distinct immune devoid profile. This might guide interpretation of our recent clinical trial (NCT03246958) findings that NRAS mutation was associated with worse outcomes after immunotherapy with ipilimumab/nivolumab (1). Validation of this immunogenomic relationship in larger thyroid cohorts will inform the role of the immune microenvironment in molecular subtypes of thyroid cancer. 1.Genomic correlates of response to dual immune checkpoint inhibition in advanced thyroid carcinoma. World Congress on Thyroid Cancer Academy 6/17/2023 London UK; 388169:139. Monday, June 3, 2024