Title | Oncogenic Mutations in PI3K/AKT/mTOR Pathway Effectors Associate with Worse Prognosis in BRAFV600E -Driven Papillary Thyroid Cancer Patients. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Pappa T, Ahmadi S, Marqusee E, Johnson HL, Nehs MA, Cho NL, Barletta JA, Lorch JH, Doherty GM, Lindeman NI, Alexander EK, Landa I |
Journal | Clin Cancer Res |
Volume | 27 |
Issue | 15 |
Pagination | 4256-4264 |
Date Published | 2021 Aug 01 |
ISSN | 1557-3265 |
Keywords | Adult, Female, Humans, Male, Middle Aged, Mutation, Phosphatidylinositol 3-Kinases, Prognosis, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Signal Transduction, Thyroid Cancer, Papillary, Thyroid Neoplasms, TOR Serine-Threonine Kinases |
Abstract | PURPOSE: The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600E -mutant 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 "BRAF+additional mutations" group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 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 = 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; P = 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. |
DOI | 10.1158/1078-0432.CCR-21-0874 |
Alternate Journal | Clin Cancer Res |
PubMed ID | 34088725 |
Related Faculty:
Neal Lindeman, M.D.