Oncogenic mutations in PI3K/AKT/mTOR pathway effectors associate with worse prognosis in BRAFV600E-driven papillary thyroid cancer patients

Theodora Pappa, Sara Ahmadi, Ellen Marqusee, Hannah L. Johnson, Matthew A. Nehs, Nancy L. Cho, Justine A. Barletta, Jochen H. Lorch, Gerard M. Doherty, Neal I. Lindeman, Erik K. Alexander*, Iñigo Landa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Purpose: The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600Emutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes. Experimental Design: We reviewed clinicopathologic data of 225 patients with BRAFV600E-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 BRAFV600E) and compared their clinical features and outcomes with those without additional oncogenic alterations. Results: Additional oncogenic alterations were identified in 16% of tumors. Patients in the “BRAFþadditional mutations” group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P ¼ 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P ¼ 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P < 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 BRAF-only group; P ¼ 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 ¼ 47.9; 95% confidence interval, 3.5–1,246.5; P ¼ 0.0043). Conclusions: Identification of additional PIK3/AKT/mTOR alterations in patients with BRAFV600E-mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.

Original languageEnglish (US)
Pages (from-to)4256-4264
Number of pages9
JournalClinical Cancer Research
Issue number15
StatePublished - Aug 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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