Reference Detail

Ref Type

Journal Article

PMID

(30463996)

Authors

Sanchez-Vega F, Hechtman JF, Castel P, Ku GY, Tuvy Y, Won H, Fong CJ, Bouvier N, Nanjangud GJ, Soong J, Vakiani E, Schattner M, Kelsen DP, Lefkowitz RA, Brown K, Lacouture ME, Capanu M, Mattar M, Qeriqi B, Cecchi F, Tian Y, Hembrough T, Nagy RJ, Lanman RB, Larson SM, Pandit-Taskar N, Schöder H, Iacobuzio-Donahue CA, Ilson DH, Weber WA, Berger MF, de Stanchina E, Taylor BS, Lewis JS, Solit DB, Carrasquillo JA, Scaltriti M, Schultz N, Janjigian YY

Title

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	9	2	2019 02	199-209	Cancer Discov

URL

Abstract Text

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer. SIGNIFICANCE: Analysis of patients with ERBB2-amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR/ERBB2 coamplification and MET amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones.See related commentary by Klempner and Catenacci, p. 166.This article is highlighted in the In This Issue feature, p. 151.

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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