Real-World Genomic Characteristics and Prognostic Association in Advanced Papillary Thyroid Carcinoma.

Abstract

Most thyroid cancers are initiated by alterations activating the mitogen-activated protein kinase (MAPK) pathway and progress via additional genomic events. Because papillary thyroid carcinoma (PTC) generally has a favorable prognosis and rarely advances, knowledge about later-acquired genomic alterations and their impact on prognosis is limited. This study is a real-world database study using a nationwide database that contains clinical data and comprehensive genomic profiling (CGP) test results. We investigated gene alterations and their impact on prognosis in advanced PTC. The study included 322 patients with advanced papillary carcinoma who underwent CGP tests for drug selection between June 2019 and April 2024. Metastases were present in 96% of cases, and 70% received systemic therapy. The most common genomic abnormalities were mutations in the <i>TERT</i> promoter and <i>BRAF</i>. <i>BRAF</i> alterations were mutually exclusive with <i>RBM10</i> and other MAPK pathway genes such as <i>RET, NRAS,</i> and <i>NTRK1</i>, but co-occurred with <i>TERT</i> and <i>AKT1</i>. The MAPK pathway had the highest frequency of alterations (96%), followed by the phosphoinositide 3-kinase (PI3K; 23%), cell cycle (13%), and p53 (11%) pathways. Survival analysis showed that alterations in <i>PTEN</i> and <i>CDKN2A</i> were independent poor prognostic factors. Patients harboring alterations in the PI3K or cell cycle pathway showed significantly shorter overall survival. Our study clarified the frequency, co-occurrence, and exclusivity of gene alterations in advanced PTC. Alterations in the PI3K or cell cycle pathways are linked to poor prognosis, and therapies targeting these pathways may warrant further investigation.