Oncogenic Mutations in PI3K/AKT/mTOR Pathway Effectors Associate with Worse Prognosis in <i>BRAF^V600E</i> -Driven Papillary Thyroid Cancer Patients.

Abstract

The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among <i>BRAF^V600E</i> -mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes. We reviewed clinicopathologic data of 225 patients with <i>BRAF^V600E</i> -mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from <i>BRAF^V600E</i> ) and compared their clinical features and outcomes with those without additional oncogenic alterations. Additional oncogenic alterations were identified in 16% of tumors. Patients in the "<i>BRAF</i>+additional mutations" group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; <i>P</i> = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; <i>P</i> = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; <i>P</i> < 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the <i>BRAF</i>-only group; <i>P</i> = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5-1,246.5; <i>P</i> = 0.0043). Identification of additional PIK3/AKT/mTOR alterations in patients with <i>BRAF^V600E</i> -mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.