title: Does bevacizumab impact anti-EGFR therapy efficacy in metastatic colorectal cancer?
abstract: Anti-EGFR therapy and antiangiogenic therapies are used alone or in combination with chemotherapies to improve survival in metastatic colorectal cancer. However, it is unknown whether pretreatment with antiangiogenic therapy could impact on the efficacy of anti-EGFR therapy. We selected one hundred and twenty eight patients diagnosed with advanced colorectal cancer with a KRAS and NRAS unmutated tumor. These patients were treated with cetuximab or panitumumab alone or with chemotherapy as second or third-line. Univariate and multivariate Cox model analysis were performed to estimate the effect of a previous bevacizumab regimen on progression free survival and on overall survival during anti-EGFR therapy. In vitro studies using wild type KRAS and NRAS colon cancer cells were performed to evaluate the impact of VEGF-A on cetuximab-induced cell death. The median progression free survival (PFS) during anti-EGFR treatment was significantly different between the bevacizumab group and the non-bevacizumab group (2.8 and 4 months respectively; p = 0.003). The median overall survival from the beginning of the metastatic disease was similar in the two groups (41.3 and 42 months respectively; p = 0.7). In vitro, VEGF-A induced a resistance toward cetuximab cytotoxicity on three KRAS and NRAS wild type colon cancer cell lines in a VEGFR2 and Stat-3-dependent manner. All in all, our clinical data, supported by in vitro procedures, suggest that a previous anti-VEGF therapy decreases anti-EGFR efficacy. Although these results are observed in a limited cohort, they could be taken into consideration for a better strategy of care for patient suffering from metastatic colorectal cancer.
authors.affiliation: INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Derangère
authors.affiliation: Centre Georges-François Leclerc, Dijon, France.
authors.forename: Jean David
authors.initials: JD
authors.lastname: Fumet
authors.affiliation: Centre Georges-François Leclerc, Dijon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Boidot
authors.affiliation: Centre Georges-François Leclerc, Dijon, France.
authors.forename: Leila
authors.initials: L
authors.lastname: Bengrine
authors.affiliation: INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.
authors.forename: Emeric
authors.initials: E
authors.lastname: Limagne
authors.affiliation: INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.|Centre Georges-François Leclerc, Dijon, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Chevriaux
authors.affiliation: Centre Georges-François Leclerc, Dijon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Vincent
authors.affiliation: INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.|Centre Georges-François Leclerc, Dijon, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.affiliation: INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.affiliation: INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.|Centre Georges-François Leclerc, Dijon, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Rébé
authors.affiliation: INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.|Centre Georges-François Leclerc, Dijon, France.
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004347:Drug Interactions; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
keywords: Stat-3; VEGFR; anti-EGFR therapy; bevacizumab; metastatic colon cancer
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