MET amplification in metastatic colorectal cancer: an acquired response to EGFR inhibition, not a <i>de novo</i> phenomenon

Raghav, Kanwal; Morris, Van K.; Tang, Chad; Morelli, P.; Amin, Hesham M.; Chen, Ken; Manyam, Ganiraju C.; Broom, Bradley M.; Overman, Michael J.; Shaw, Kenna; Meric‐Bernstam, Funda; Maru, Dipen M.; Menter, David G.; Ellis, Lee M.; Eng, Cathy; Hong, David S.; Kopetz, Scott

doi:10.18632/oncotarget.10559

Cited by 60 publications

(49 citation statements)

References 19 publications

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“…Subsequent to completion of our study, the cfDNA test has become comprehensive (i.e. inclusive of all four major types of alterations), which will likely become important as new genomic targets such as RSPO3 and other fusions, or ERBB2 (HER2) and MET gene copy number amplifications, may become potential targets on the near horizon [ 5 , 40 , 41 ]. Findings from sequencing of cfDNA can inform the provider of matched biomarker-based clinical trials while also improving the perceived quality of care.…”

Section: Discussionmentioning

confidence: 99%

Clinical utility of circulating cell-free DNA in advanced colorectal cancer

et al. 2017

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BackgroundCirculating cell-free DNA (cfDNA) isolated from the plasma of cancer patients (pts) has been shown to reflect the genomic mutation profile of the tumor. However, physician and patient assessment of clinical utility of these assays in patients with metastatic colorectal cancer (mCRC) has not been previously described.MethodsPatients were prospectively consented to a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]), with collection of blood for cfDNA extraction and sequencing of a 54-gene panel in a CLIA-certified lab. Formalin-fixed, paraffin-embedded (FFPE) tissue from prior resections or biopsies underwent 50-gene sequencing. Results from both assays were returned to the treating physicians for patient care and clinical trial selection. Follow-up surveys of treating physicians and chart reviews assessed clinical utility.Results128 mCRC pts were enrolled between 6/2014 and 1/2015. Results were returned in median of 13 and 26 days for cfDNA and FFPE sequencing, respectively. With cfDNA sequencing, 78% (100/128) of samples had a detectable somatic genomic alteration. 50% of cfDNA cases had potentially actionable alterations, and 60% of these could be genomically matched to at least one clinical trial in our institution. 50% (15/30) of these pts enrolled onto an identified matched trial. Physicians reported that the cfDNA testing improved the quality of care they could provide in 73% of the cases, and that 89% of pts reported greater satisfaction with the efforts to personalize experimental therapeutic agents.ConclusionscfDNA sequencing can provide timely information on potentially actionable mutations and amplifications, thereby facilitating clinical trial enrollment and improving the perceived quality of care.

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Section: Discussionmentioning

confidence: 99%

Clinical utility of circulating cell-free DNA in advanced colorectal cancer

et al. 2017

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“…In addition to the above-mentioned use of MET dysregulation for biomarker discovery in tumor tissue, recently a promising noninvasive method based on the detection of circulating tumor DNA (ctDNA) in blood samples has also been suggested as a cancer biomarker [237][238][239][240][241][242][243]. One study comparing the MET amplification rate in different tissue-based and blood-based analysis methods showed that the frequency of MET amplification using ctDNA in metastatic colorectal cancer patients after exposure to anti-EGFR antibody therapy was significantly increased compared with antibodynaïve patients (p < .001) [237]. Similarly, a case report of a treatment refractory patient with metastatic colorectal cancer showed that MET amplification was detected in ctDNA using next-generation sequencing, but not in tissue biopsy samples.…”

Section: Vi-b-circulating Tumor Dnamentioning

confidence: 99%

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Moosavi

Giovannetti

Saso³

et al. 2019

Critical Reviews in Clinical Laboratory Sciences

129

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Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.

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“…Cotreatment with MET inhibitors and cetuximab caused robust and longlasting tumor shrinkage in patient-derived xenograft models of MET-amplified mCRC. In a study investigating the frequency of MET amplification in a large cohort of patients with mCRC, MET amplifications were detected in 1.7% (10/590) of tumor tissue biopsies tested by both fluorescence in situ hybridization and sequencing in the pretreatment cohort [68]. In contrast, an NGS panel detected MET amplification in the ctDNAs of 22.6% (12/53) of patients who had been treated with anti-EGFR therapy and showed disease progression, which was not detected in patients with pre-cetuximab treatment.…”

Section: Met Amplificationmentioning

confidence: 99%

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Nakamura

Yoshino

2018

The Oncologist

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Multiple genomic changes caused by clonal evolution induced by therapeutic pressure and corresponding intratumoral heterogeneity have posed great challenges for personalized therapy against metastatic colorectal cancer (mCRC) in the past decade. Liquid biopsy has emerged as an excellent molecular diagnostic tool for assessing predominant spatial and temporal intratumoral heterogeneity with minimal invasiveness.Previous studies have revealed that genomic alterations in ,, , and, as well as other cancer-related genes associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy, can be analyzed with high diagnostic accuracy by circulating tumor DNA (ctDNA) analysis. Furthermore, by longitudinally monitoring ctDNAs during anti-EGFR therapy, the emergence of genomic alterations can be detected as acquired resistance mechanisms in specific genes, mainly those associated with the mitogen-activated protein kinase signaling pathway. Analysis of ctDNA can also identify predictive biomarkers to immune checkpoint inhibitors, such as mutations in mismatch repair genes, microsatellite instability-high phenotype, and tumor mutation burden. Some prospective clinical trials evaluating targeted agents for genomic alterations in ctDNA or exploring resistance biomarkers by monitoring of ctDNA are ongoing.To determine the value of ctDNA analysis for decision-making by more accurate molecular marker-based selection of patients and identification of resistance mechanisms to targeted therapies or sensitive biomarkers for immune checkpoint inhibitors, clinical trials must be refined to evaluate the efficacy of study treatment in patients with targetable genomic alterations confirmed by ctDNA analysis, and resistance biomarkers should be explored by monitoring ctDNA in large-scale clinical trials. In the near future, ctDNA analysis will play an important role in precision medicine for mCRC. IMPLICATIONS FOR PRACTICE: Treatment strategies for metastatic colorectal cancer (mCRC) are determined according to the molecular profile, which is confirmed by analyzing tumor tissue. Analysis of circulating tumor DNA (ctDNA) may overcome the limitations of tissue-based analysis by capturing spatial and temporal intratumoral heterogeneity of mCRC. Clinical trials must be refined to test the value of ctDNA analysis in patient selection and identification of biomarkers. This review describes ctDNA analysis, which will have an important role in precision medicine for mCRC.

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MET amplification in metastatic colorectal cancer: an acquired response to EGFR inhibition, not a de novo phenomenon

Cited by 60 publications

References 19 publications

Clinical utility of circulating cell-free DNA in advanced colorectal cancer

Clinical utility of circulating cell-free DNA in advanced colorectal cancer

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

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