HER2 Amplification and Cetuximab Efficacy in Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF

Jeong, Jae Ho; Kim, Jihun; Hong, Yong Sang; Kim, Dalyong; Kim, Jeong Eun; Kim, Sun Young; Kim, Kyu-Pyo; Yoon, Young-Kwang; Kim, Deokhoon; Chun, Sung-Min; Park, Yangsoon; Jang, Se Jin; Kim, Tae Won

doi:10.1016/j.clcc.2017.01.005

Cited by 32 publications

(26 citation statements)

References 29 publications

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“…In a cetuximab clinical trial on patients with CRC, those with HER2 amplification had shorter progression free survival after treatment. The study suggests that HER2 may confer resistance to cetuximab treatment in patients with wildtype RAS and BRAF [50]. ERBB2 copy number amplification was also evident in CRC liquid biopsies in patient plasma.…”

Section: Discussionmentioning

confidence: 78%

Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients

Shaath

Toor

Nair

et al. 2019

Cancers

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Colorectal cancer (CRC) is among the leading causes of cancer-related deaths worldwide, underscoring a need for better understanding of the disease and development of novel diagnostic biomarkers and therapeutic interventions. Herein, we performed transcriptome analyses on peripheral blood mononuclear cells (PBMCs), CRC tumor tissue and adjacent normal tissue from 10 CRC patients and PBMCs from 15 healthy controls. Up regulated transcripts from CRC PBMCs were associated with functions related to immune cell trafficking and cellular movement, while downregulated transcripts were enriched in cellular processes related to cell death. Most affected signaling networks were those involved in tumor necrosis factor (TNF) and interleukin signaling. The expression of selected immune-related genes from the RNA-Seq data were further validated using qRT-PCR. Transcriptome analysis of CRC tumors and ingenuity pathway analysis revealed enrichment in several functional categories related to cellular movement, cell growth and proliferation, DNA replication, recombination and repair, while functional categories related to cell death were suppressed. Upstream regulator analysis revealed activation of ERBB2 and FOXM1 networks. Interestingly, there were 18 common upregulated and 36 common downregulated genes when comparing PBMCs and tumor tissue, suggesting transcriptomic changes in the tumor microenvironment could be reflected, in part, in the periphery with potential utilization as disease biomarkers.

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Section: Discussionmentioning

confidence: 78%

Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients

Shaath

Toor

Nair

et al. 2019

Cancers

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“…ERBB2 amplification has been reported to correlate with a lack of response to EGFR-directed therapy ( Martin et al 2013 ; Jeong et al 2017 ) and is a potential explanation for the patient's lack of response to cetuximab in Case 1. Several other molecular alterations have been associated with resistance to EGFR-directed therapy in CRC ( Bertotti et al 2015 ), although none were detected in Case 1.…”

Section: Discussionmentioning

confidence: 94%

Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases

Owen

Wong

Bonakdar

et al. 2018

Cold Spring Harb Mol Case Stud

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ERBB2 amplification has been identified in ∼5% of KRAS wild-type colorectal cancers (CRCs). A recent clinical trial showed response to HER2-directed therapy in a subset of ERBB2-amplified metastatic CRCs resistant to chemotherapy and EGFR-directed therapy. With the aim of better understanding mechanisms of resistance to HER2-directed and EGFR-directed therapies, we report the complete molecular characterization of two cases of ERBB2-amplified CRC. PCR-free whole-genome sequencing was used to identify mutations, copy-number alterations, structural variations, and losses of heterozygosity. ERBB2 copy number was also measured by fluorescence in situ hybridization. Single-stranded mRNA sequencing was used for gene expression profiling. Immunohistochemistry and protein mass spectrometry were used to quantify HER2 protein expression. The cases showed ERBB2 copy number of 86 and 92, respectively. Both cases were immunohistochemically positive for HER2 according to CRC-specific scoring criteria. Fluorescence in situ hybridization and protein mass spectrometry corroborated significantly elevated ERBB2 copy number and abundance of HER2 protein. Both cases were microsatellite stable and without mutation of RAS pathway genes. Additional findings included altered expression of PTEN, MET, and MUC1 and mutation of PIK3CA. The potential effects of the molecular alterations on sensitivity to EGFR and HER2-directed therapies were discussed. Identification of ERBB2 amplification in CRC is necessary to select patients who may respond to HER2-directed therapy. An improved understanding of the molecular characteristics of ERBB2-amplified CRCs and their potential mechanisms of resistance will be useful for future research into targeted therapies and may eventually inform therapeutic decision-making.

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“…It has been reported that HER2 positive was associated with favorable pathological features including lower T and N stage and better tumor differentiation in patients with esophageal adenocarcinoma [34]. Jeong J H et al [35] showed that HER2 amplification is predictive of shorter progression-free survival after cetuximab treatment in patients with metastatic colorectal cancer harboring wild-type RAS and BRAF gene. In fact, the international consensus has been reached that determination of HER2 amplification status is really important not only for treatment options but also for therapeutic efficacy evaluation of breast cancer [36][37][38][39].…”

Section: Discussionmentioning

confidence: 98%

Preliminary study on discriminating HER2 2+ amplification status of breast cancers based on texture features semi-automatically derived from pre-, post-contrast, and subtraction images of DCE-MRI

Song

Yin

2020

PLoS ONE

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Objective To investigate whether texture features extracted from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are associated with human epidermal growth factor receptor type 2 (HER2) 2+ status of breast cancer. Materials and methods 92 MRI cases including 52 HER2 2+ positive and 40 negative patients confirmed by fluorescence in situ hybridization were retrospectively selected. The lesion area was semi-automatically delineated, and a total of 488 texture features were respectively extracted from precontrast, postcontrast, and subtraction images. The Student's t-test or Mann-Whitney U test was performed to identify statistically significant features between different HER2 2+ amplification groups. Least absolute shrinkage and selection operator (LASSO) was used to search for the optimal feature subsets. Three machine learning classifiers, logistic regression analysis (LRA), quadratic discriminant analysis (QDA), and support vector machine (SVM), were used with a leave-one-out cross validation method to establish the classification models of HER2 2+ status. Classification performance was evaluated by receiver operating characteristic (ROC) analysis. Results Based on the texture analysis with SVM model, the areas under the ROC curve (AUCs) were 0.890 for subtraction images, 0.736 for postcontrast images, and 0.672 for precontrast images, respectively. For LRA model, the AUCs were 0.884, 0.733, and 0.623, respectively. For QDA model, the AUCs were 0.831, 0.726, and 0.568, respectively. LRA and the SVM

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HER2 Amplification and Cetuximab Efficacy in Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF

Cited by 32 publications

References 29 publications

Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients

Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients

Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases

Preliminary study on discriminating HER2 2+ amplification status of breast cancers based on texture features semi-automatically derived from pre-, post-contrast, and subtraction images of DCE-MRI

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