Does bevacizumab impact anti-EGFR therapy efficacy in metastatic colorectal cancer?
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Valentin Derangère1,*, Jean David Fumet2,*, Romain Boidot2, Leila Bengrine2, Emeric Limagne1, Angélique Chevriaux1,2, Julie Vincent2, Sylvain Ladoire1,2, Lionel Apetoh1, Cédric Rébé1,2, François Ghiringhelli1,2
1INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France
2Centre Georges-François Leclerc, Dijon, France
*These authors have contributed equally to this work
François Ghiringhelli, e-mail: [email protected]
Keywords: metastatic colon cancer, anti-EGFR therapy, bevacizumab, Stat-3, VEGFR
Received: July 24, 2015 Accepted: January 01, 2016 Published: January 25, 2016
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.
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