Proteins of the VEGFR and EGFR pathway as predictive markers for adjuvant treatment in patients with stage II/III colorectal cancer: results of the FOGT-4 trial

• Published in: Journal of experimental & clinical cancer research 2014-10, Vol.33 (1), p.83-83, Article 83
• Main Authors: Thomaidis, Thomas, Maderer, Annett, Formentini, Andrea, Bauer, Susanne, Trautmann, Mario, Schwarz, Michael, Neumann, Wiebke, Kittner, Jens Martin, Schad, Arno, Link, Karl-Heinrich, Rey, Johannes Wilhelm, Weinmann, Arndt, Hoffman, Arthur, Galle, Peter Robert, Kornmann, Marko, Moehler, Markus
• Format: Article
• Language: English
• Subjects: Acquisitions & mergers; Angiogenesis; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Cancer therapies; Care and treatment; Chemotherapy, Adjuvant; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Epidermal growth factor; Fluorouracil - administration & dosage; Health aspects; Humans; Hypoxia; Ligands; Metastasis; Neoplasm Staging; Patient outcomes; Receptor, Epidermal Growth Factor - metabolism; Receptors, Vascular Endothelial Growth Factor - metabolism; Rodents; Signal Transduction; Statistical analysis; Studies; Treatment Outcome; Tumors; Vascular endothelial growth factor
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-014-0083-8

Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients. The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 α, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators. Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 α, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 α (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination. The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 α negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/- irinotecan in stage II/III colorectal cancer.