Reference Detail

Ref Type

Journal Article

PMID

(27797976)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	9	2017 May 01	2367-2373	Clin Cancer Res

URL

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.

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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	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
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