Prospective Comprehensive Genomic Profiling of Advanced Gastric Carcinoma Cases Reveals Frequent Clinically Relevant Genomic Alterations and New Routes for Targeted Therapies

Ali, Siraj M.; Sanford, Eric M.; Klempner, Samuel J.; Rubinson, Douglas A.; Wang, Kai; Palma, Norma Alonzo; Chmielecki, Juliann; Yelensky, Roman; Palmer, Gary A.; Morosini, Deborah; Lipson, Doron; Catenacci, Daniel V.T.; Braiteh, Fadi; Erlich, Rachel; Stephens, Philip J.; Ross, Jeffrey S.; Ou, Sai‐Hong Ignatius; Miller, Vincent A.

doi:10.1634/theoncologist.2014-0378

Cited by 65 publications

(54 citation statements)

References 53 publications

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“…We did not observe a significant association between HER2 status and MET amplification in our study, which is consistent with other studies (40). Of note, among the 44 patients with samples evaluable for both HER2 status and MET amplification, all four MET-amplified samples were HER2 negative.…”

Section: Discussionsupporting

confidence: 92%

Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer

Peng

Gao

et al. 2015

Molecular Cancer Therapeutics

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MET and its sole ligand, hepatocyte growth factor (HGF), are promising targets in gastric and gastroesophageal junction cancer. We evaluated whether MET protein expression or MET gene amplification is prognostic for overall survival (OS) in Chinese patients with advanced gastric or gastroesophageal junction cancer. Archival formalin-fixed, paraffin-embedded tumor samples from patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancer enrolled in clinical trials at Peking University Cancer Hospital from 2008 to 2010 were assessed for MET and phospho-MET (p-MET) expression by immunohistochemistry and MET amplification by FISH. MET-positive expression was defined as membrane protein staining in !25% of tumor cells. MET amplification was defined as MET:centromere 7 ratio >2.0. We tested the association of MET status with clinical characteristics and OS, and also evaluated the association between expression and amplification. One hundred sixty-eight patients were eligible. Of the evaluable samples, 53 of 137 (39%) were MET positive, eight of 134 (6%) were p-MET positive, and eight of 113 (7%) were MET amplified. Neither MET expression nor MET amplification were associated with clinical characteristics, except Lauren classification (P ¼ 0.04); MET amplification was associated with diffuse type. No significant OS difference was observed between MET-positive and MET-negative populations, regardless of first-line chemotherapy received. In 95 evaluable patients, MET expression was significantly associated with MET amplification (P < 0.001); all MET-amplified tumor samples showed some MET expression. In 96 evaluable patients, p-MET positivity was significantly associated with MET amplification (P < 0.001). Further evaluation in larger and independent sample sets is warranted to confirm our findings.

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Section: Discussionsupporting

confidence: 92%

Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer

Peng

Gao

et al. 2015

Molecular Cancer Therapeutics

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“…Previously, receptor tyrosine kinase genomic alterations were detected in 20.6% of cases, affecting ERBB2, FGFR2, and MET, suggesting potential benefit from targeted therapy including MET-amplified gastric tumors and ERBB2 base substitutions [32]. Temporary but durable response to anti-MET agents have already been described [33].…”

Section: Discussionmentioning

confidence: 99%

Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients

et al. 2016

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IntroductionMultiple gene expression based prognostic biomarkers have been repeatedly identified in gastric carcinoma. However, without confirmation in an independent validation study, their clinical utility is limited. Our goal was to establish a robust database enabling the swift validation of previous and future gastric cancer survival biomarker candidates.ResultsThe entire database incorporates 1,065 gastric carcinoma samples, gene expression data. Out of 29 established markers, higher expression of BECN1 (HR = 0.68, p = 1.5E-05), CASP3 (HR = 0.5, p = 6E-14), COX2 (HR = 0.72, p = 0.0013), CTGF (HR = 0.72, p = 0.00051), CTNNB1 (HR = 0.47, p = 4.3E-15), MET (HR = 0.63, p = 1.3E-05), and SIRT1 (HR = 0.64, p = 2.2E-07) correlated to longer OS. Higher expression of BIRC5 (HR = 1.45, p = 1E-04), CNTN1 (HR = 1.44, p = 3.5E- 05), EGFR (HR = 1.86, p = 8.5E-11), ERCC1 (HR = 1.36, p = 0.0012), HER2 (HR = 1.41, p = 0.00011), MMP2 (HR = 1.78, p = 2.6E-09), PFKB4 (HR = 1.56, p = 3.2E-07), SPHK1 (HR = 1.61, p = 3.1E-06), SP1 (HR = 1.45, p = 1.6E-05), TIMP1 (HR = 1.92, p = 2.2E- 10) and VEGF (HR = 1.53, p = 5.7E-06) were predictive for poor OS.MATERIALS AND METHODSWe integrated samples of three major cancer research centers (Berlin, Bethesda and Melbourne datasets) and publicly available datasets with available follow-up data to form a single integrated database. Subsequently, we performed a literature search for prognostic markers in gastric carcinomas (PubMed, 2012–2015) and re-validated their findings predicting first progression (FP) and overall survival (OS) using uni- and multivariate Cox proportional hazards regression analysis.ConclusionsThe major advantage of our analysis is that we evaluated all genes in the same set of patients thereby making direct comparison of the markers feasible. The best performing genes include BIRC5, CASP3, CTNNB1, TIMP-1, MMP-2, SIRT, and VEGF.

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“…On average, 2–4 oncogenic driver gene mutations are present in various tumors [52, 53]. It is not clear yet whether the extent of driver gene mutations correlates with overall mutational burden (including passenger mutations) and how this impacts on checkpoint molecule expression on T-cells.…”

Section: Predicting Response To Checkpoint Blockadementioning

confidence: 99%

Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

et al. 2017

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In favor of their outgrowth, cancer cells must resist immune surveillance and edit the immune response. Cancer immunoediting is characterized by fundamental changes in the cellular composition and the inflammatory cytokine profiles in the microenvironment of the primary tumor and metastatic niches, with an ever increasing complexity of interactions between tumor cells and the immune system. Recent data suggest that genetic instability and immunoediting are not necessarily disparate processes. Increasing mutational load may be associated with multiple neoepitopes expressed by the tumor cells and thus increased chances for the immune system to recognize and combat these cells. At the same time the immune system is more and more suppressed and exhausted by this process. Consequently, immune checkpoint modulation may have the potential to be most successful in genetically highly altered and usually extremely unfavorable types of cancer. Moreover, the fact that epitopes recognized by the immune system are preferentially encoded by passenger gene mutations opens windows of synergy in targeting cancer-specific signaling pathways by small molecules simultaneously with antibodies modifying T-cell activation or exhaustion.This review covers some aspects of the current understanding of the immunological basis necessary to understand the rapidly developing therapeutic endeavours in cancer treatment, the clinical achievements made, and raises some burning questions for translational research in this field.

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Prospective Comprehensive Genomic Profiling of Advanced Gastric Carcinoma Cases Reveals Frequent Clinically Relevant Genomic Alterations and New Routes for Targeted Therapies

Cited by 65 publications

References 53 publications

Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer

Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer

Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients

Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

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