Prognostic Value of Angiopoietin-2 for Death Risk Stratification in Patients with Metastatic Colorectal Carcinoma

Jary, Marine; Vernerey, Déwi; Lecomte, Thierry; Dobi, Erion; Ghiringhelli, François; Monnien, Franck; Godet, Yann; Kim, Stéfano; Bouché, Olivier; Fratté, S.; Gonçalvès, Anthony; Léger, Julie; Queiroz, Lise; Adotévi, Olivier; Bonnetain, Franck; Borg, Christophe

doi:10.1158/1055-9965.epi-14-1059

Cited by 13 publications

(10 citation statements)

References 45 publications

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“…Moreover, exploratory biomarker analysis revealed no patient subgroups that would be likely to benefit from the dual Ang‐2–VEGF inhibition. To this point and consistent with recent findings from other trials exploring the angiopoietin‐Tie2 signaling pathway in mCRC, soluble Ang‐2 levels at baseline were prognostic in both arms but not predictive for treatment response to vanucizumab . Likewise, other prognostic factors, including RAS and BRAF mutation status and tumor sidedness, were largely balanced between arms and did not result in significantly different PFS outcomes across treatment arms.…”

Section: Discussionsupporting

confidence: 86%

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

et al. 2019

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Background Bevacizumab, a VEGF‐A inhibitor, in combination with chemotherapy, has proven to increase progression‐free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin‐2 (Ang‐2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF‐A and Ang‐2, suggesting that the dual VEGF‐A and Ang‐2 blocker vanucizumab (RO5520985 or RG‐7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX‐6 (folinic acid (leucovorin), fluorouracil (5‐FU) and oxaliplatin) versus bevacizumab/mFOLFOX‐6 for first‐line mCRC. Patients and Methods All patients received mFOLFOX‐6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator‐assessed PFS. Results One hundred eighty‐nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64–1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang‐2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm. Conclusion Vanucizumab/mFOLFOX‐6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX‐6. Our results suggest that Ang‐2 is not a relevant therapeutic target in first‐line mCRC. Implications for Practice This randomized phase II study demonstrates that additional angiopoietin‐2 (Ang‐2) inhibition does not result in superior benefit over anti–VEGF‐A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang‐2 is not a relevant therapeutic target in the clinical setting of treatment‐naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF‐A and Ang‐2 inhibitor vanucizumab was discontinued.

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Section: Discussionsupporting

confidence: 86%

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

et al. 2019

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“…Ang‐2 was previously described to be associated with mCRC patients'OS . While CD138 expression is related to cancer invasion and extracellular matrix regulation, Ang‐2 is a biomarker of neoangiogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…We have recently shown that angiopoietin-2 (Ang-2), which is involved in angiogenesis, is an interesting prognostic parameter for OS in mCRC patients. 9 We next sought to investigate the prognostic value of syndecan-1 (SDC-1, also named CD138), a type-1 transmembrane heparan sulfate proteoglycans (HSPGs), involved in angiogenesis, but also in cancer invasion. [10][11][12] CD138 has been described to have an important role in the colorectal adenoma-adenocarcinoma sequence and in the epithelial-mesenchymal transition (EMT), using immunohistochemical (IHC) staining.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of baseline seric Syndecan‐1 in initially unresectable metastatic colorectal cancer patients: a simple biological score

Jary

Lecomte

Bouché

et al. 2016

Intl Journal of Cancer

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In first-line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan-1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS). mCRC patients with unresectable disease at diagnosis were treated with bevacizumab-based chemotherapy in two independent prospective clinical trials (development set: n = 126, validation set: n = 51, study NCT00489697 and study NCT00544011, respectively). Serums were collected at baseline for CD138 measurement. OS determinants were assessed and, based on the final multivariate model, a prognostic score was proposed. Two independent OS prognostic factors were identified: Lactate Dehydrogenase (LDH) high level (p = 0.0066) and log-CD138 high level (p = 0.0190). The determination of CD138 binary information (cutoff: 75 ng/mL) allowed the assessment of a biological prognostic score with CD138 and LDH values, identifying three risk groups for death (median OS= 38.9, 30.1 and 19.8 months for the low, intermediate and high risk groups, respectively; p < 0.0001). This score had a good discrimination ability (C-index = 0.63). These results were externally confirmed in the validation set. Our study provides robust evidence in favor of the additional baseline soluble CD138 prognostic value for OS, in mCRC patients. A simple biological scoring system is proposed including LDH and CD138 binary status values.

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“…In addition, ANGPT2 is often highly upregulated in the tumor vascular system compared to its low content in normal tissues 23 . Elevated circulating ANGPT2 is closely associated with malignant invasion and worse prognosis in various cancers 24 , 25 . Besides, Jo MJ et al 26 suggested that preoperative serum ANGPT2 levels correlated to lymph node metastasis in early GC patients.…”

Section: Discussionmentioning

confidence: 99%

LINC00184 involved in the regulatory network of ANGPT2 via ceRNA mediated miR-145 inhibition in gastric cancer

et al. 2021

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Background: Disrupted gene levels are intimately correlated with the occurrence and prognosis of gastric cancer (GC). As genes do not function in isolation, we set out to investigate the possible relationship among mRNA and non-coding RNAs (ncRNAs). Materials and methods: RNA sequencing from 406 cases of GC was acquired through the TCGA database. R packages were utilized to assess differential RNA expression. The competing endogenous RNA (ceRNA) network was predicted using miRcode, miRDB, mirTarBase, Target Scan and constructed by Cytoscape 3.6.1. GO enrichment analysis, KEGG pathway analysis, GSEA, and WGCNA were applied for pathway analysis. The expression of select candidate molecules was confirmed using western blot and RT-PCR in GC cells and tissues. CCK-8, EdU staining, and Transwell assays were conducted to assess the influence of candidate molecules on proliferation and invasion. The gain and loss-of-function were achieved by co-culture with sh-lncRNA, mimics and sh-mRNA. Luciferase reporters were created using the psiCHECK2 vector, and the relative luciferase activity was calculated. Results: Using data from TCGA, we determined differentially expressed RNAs and created a ceRNA regulatory network. Interestingly, we identified a regulatory complex surrounding ANGPT2. We detected that ANGPT2 was highly expressed in GC, which correlated with a worse prognosis. Our findings indicated that ANGPT2 encourages growth, invasion, and epithelial-mesenchymal transition (EMT) in GC. Importantly, miR-145 inhibits ANGPT2 and abrogates its effects. Furthermore, LINC00184, a ceRNA, blocks miR-145, thereby improving ANGPT2-mediated carcinogenesis. Conclusions: Our findings indicate that the LINC00184/miR-145/ANGPT2 pathway has a crucial function in the development of GC and can act as a possible biomarker and targets for GC therapy.

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Prognostic Value of Angiopoietin-2 for Death Risk Stratification in Patients with Metastatic Colorectal Carcinoma

Cited by 13 publications

References 45 publications

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

Prognostic value of baseline seric Syndecan‐1 in initially unresectable metastatic colorectal cancer patients: a simple biological score

LINC00184 involved in the regulatory network of ANGPT2 via ceRNA mediated miR-145 inhibition in gastric cancer

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