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|Ref Type||Journal Article|
|Authors||Gibson WJ, Ruan DT, Paulson VA, Barletta JA, Hanna GJ, Kraft S, Calles A, Nehs MA, Moore FD, Taylor-Weiner A, Wala JA, Zack TI, Lee TC, Fennessy FM, Alexander EK, Thomas T, Janne PA, Garraway LA, Carter SL, Beroukhim R, Lorch JH, Van Allen EM|
|Title||Genomic Heterogeneity and Exceptional Response to Dual Pathway Inhibition in Anaplastic Thyroid Cancer.|
|Abstract Text||Purpose: Cancers may resist single-agent targeted therapies when the flux of cellular growth signals is shifted from one pathway to another. Blockade of multiple pathways may be necessary for effective inhibition of tumor growth. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR/PI3K or combined RAF/MEK inhibition but experienced a dramatic response when both drug regimens were combined.Experimental Design: Multi-region whole-exome sequencing of five diagnostic and four autopsy tumor biopsies was performed. Meta-analysis of DNA and RNA sequencing studies of ATC was performed.Results: Sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways, respectively. Meta-analysis demonstrated 10.3% cooccurrence of MAPK and PI3K pathway alterations in ATC. These tumors display a separate transcriptional profile from other ATCs, consistent with a novel subgroup of ATC.Conclusions: BRAF and PIK3CA mutations define a distinct subset of ATC. Blockade of the MAPK and PI3K pathways appears necessary for tumor response in this subset of ATC. This identification of synergistic activity between targeted agents may inform clinical trial design in ATC. Clin Cancer Res; 23(9); 2367-73. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF V600E PIK3CA H1047R||thyroid gland carcinoma||resistant||Everolimus||Case Reports/Case Series||Actionable||In a clinical case study, a patient with anaplastic thyroid carcinoma co-harboring BRAF V600E and PIK3CA H1047R demonstrated resistance to treatment with Afinitor (everolimus) (PMID: 27797976).||27797976|
|BRAF V600E PIK3CA H1047R||thyroid gland carcinoma||predicted - sensitive||Dabrafenib + Everolimus + Trametinib||Case Reports/Case Series||Actionable||In a clinical case study, a patient with anaplastic thyroid carcinoma co-harboring BRAF V600E and PIK3CA H1047R demonstrated tumor regression when treated with the triple combination, Tafinlar (dabrafenib), Mekinist (trametinib), and Afinitor (everolimus) (PMID: 27797976).||27797976|
|BRAF V600E PIK3CA H1047R||thyroid gland carcinoma||resistant||Dabrafenib + Trametinib||Case Reports/Case Series||Actionable||In a clinical case study, a patient with anaplastic thyroid carcinoma co-harboring BRAF V600E and PIK3CA H1047R demonstrated resistance to the combination therapy, Mekinist (trametinib) and Tafinlar (dabrafenib) (PMID: 27797976).||27797976|