High c‐Met expression in stage I–<scp>II</scp> pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis

Neuzillet, Cindy; Couvelard, Anne; Tijeras‐Raballand, Annemilaï; Mestier, Louis de; Gramont, Armand de; Bédossa, Pierre; Paradis, Valérie; Sauvanet, Alain; Bachet, Jean‐Baptiste; Ruszniewski, Philippe; Raymond, Éric; Hammel, Pascal; Cros, Jérôme

doi:10.1111/his.12691

Cited by 21 publications

(14 citation statements)

References 43 publications

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“…We divided all 70 PDAC patients into two survival groups (≤ or > median), using overall median survival (11.5 months, range 0.2 months ∼ 5 years) as a cut-off (Table 4). When markers between these two survival groups were compared, we found that tumors associated with poor survival had a strong trend towards having higher total c-MET level compared to those with better survival ( p = 0.05), resonating previous report showing c-MET to be frequently overexpressed and represents an independent poor prognostic factor in resected PDAC patients [18, 19]. Interestingly, patients with poor survival had significantly lower levels of p-SHC ( p = 0.002), p-PRAS40 (p = 0.002) and p-AKT ( p = 0.025).…”

Section: Resultssupporting

confidence: 86%

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A clinically feasible multiplex proteomic immunoassay as a novel functional diagnostic for pancreatic ductal adenocarcinoma

et al. 2017

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To date, targeted therapy for pancreatic ductal adenocarcinoma (PDAC) remains largely unsuccessful in the clinic. Current genomics-based technologies are unable to reflect the quantitative, dynamic signaling changes in the tumor, and require larger tumor samples that are difficult to obtain in PDAC patients. Therefore, a highly sensitive functional tool that can reliably and comprehensively inform intra-tumoral signaling events is direly needed to guide treatment decision. We tested the utility of a highly sensitive proteomics-based functional diagnostic platform, Collaborative Enzyme Enhanced Reactive-immunoassay (CEERTM), on fine-needle aspiration (FNA) samples obtained from 102 patients with radiographically-evident pancreatic tumors. Two FNA passes were collected from each patient, hybridized to customized chips coated with an array of capture antibodies, and detected using two enzyme-conjugated antibodies which emit quantifiable signals. We demonstrate that this technique is highly sensitive in detecting total and phosphorylated forms of multiple signaling molecules in FNA specimens, with reasonable correlation of marker intensities between two different FNA passes. Notably, signals of several markers were significantly higher in PDAC compared to non-cancerous samples. In PDAC samples, we found high total c-Met signal to be associated with poor survival, and confirmed this finding using an independent PDAC tissue microarray.

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Section: Resultssupporting

confidence: 86%

“…First, high level of c-MET immunohistochemical staining in resected PDAC tumors has already been reported by different groups to be a poor prognostic marker [18, 19]. Second, to further confirm this finding, we performed c-MET IHC staining on an independent PDAC tissue microarray built at our institution.…”

Section: Resultssupporting

confidence: 59%

A clinically feasible multiplex proteomic immunoassay as a novel functional diagnostic for pancreatic ductal adenocarcinoma

et al. 2017

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“…Immunohistochemical staining and evaluation of protein expression were performed on TMA as previously described. [9][10][11][12][13][14] DNA Panel Sequencing DNA was extracted from the same 279 samples that were also used for transcriptome microarrays. Sequencing libraries were prepared using Ion AmpliSeq Cancer HotSpot Panel, version 2 (Life Technologies) by following the manufacturer's recommendations.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features

et al. 2018

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We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.

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“…Several clinical studies have addressed these issues and reported MET aberrations as indicators of short survival and clinicopathological features of advanced disease in diverse types of cancer, such as gastric [52], colorectal [53], breast [54], hepatocellular [55], pancreatic [56], and lung cancer [57]. In addition, the predictive role of MET dysregulation has been explored in different settings, and some results indicate improved Figure 2.…”

Section: I-a-the Importance Of Hgf/met Aberrations As Clinical Biomarmentioning

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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High c‐Met expression in stage I–II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis

Abstract: Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.

Cited by 21 publications

References 43 publications

A clinically feasible multiplex proteomic immunoassay as a novel functional diagnostic for pancreatic ductal adenocarcinoma

A clinically feasible multiplex proteomic immunoassay as a novel functional diagnostic for pancreatic ductal adenocarcinoma

Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features

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

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