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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1

Immunochistochemistry for AREG, EREG, Hif-1 α, VEGF-C, VEGF-D, VEGFR-3 and PTEN in tumour tissues obtained from patients with stage II/III CRC. According to the intensity and extend the stained tumor area samples were classified as positive or negative.

Figure 2

Survival analysis in patients receiving adjuvant treatment in relation to AREG- and EREG- expression. A. Disease-free survival rates. B. overall survival rates.

Figure 3

Survival analysis in patients under adjuvant 5-FU/FA/irinotecan in relation to AREG/EREG- expression. A. Disease-free survival in relation to AREG expression on tumor tissues. B. Disease-free survival in relation to EREG expression on tumor tissues. C. Disease-free survival in relation to AREG and EREG expression on tumor tissues.

Figure 4

Overall survival analysis for patients according to tumor PTEN-status. A. in the whole population B. in the subgroup treated with adjuvant 5-FU/FA/irinotecan.

Figure 5

Disease-free survival in patients under adjuvant 5-FU/FA versus 5-FU/FA/irinotecan in relation to VEGF-D expression. A. Disease-free survival rates in the total population, B. Patients under adjuvant 5-FU/FA, C. Patients under adjuvant 5-FU/FA/irinotecan.

Figure 6

Disease-free survival in patients under adjuvant 5-FU/FA versus 5-FU/FA/irinotecan in relation to Hif-1 α expression. A. Disease-free survival rates in the total population, B. Patients under adjuvant 5-FU/FA, C. Patients under adjuvant 5-FU/FA/irinotecan.

Figure 7

Survival analysis in relation to collective biomarker expression. Overall survival in patients treated with adjuvant 5-FU/FA versus 5-FU/FA/irinotecan in patients negative for AREG, EREG, Hif-1 α and positive for PTEN (A) and in patients negative for AREG, EREG and positive for PTEN (B).