Combined Analysis of VEGF and EGFR Predicts Complete Tumour Response in Rectal Cancer Treated with Preoperative Radiotherapy

Overview

Journal Br J Cancer

Specialty Oncology

Date 2008 Jan 10

PMID 18182986

Citations 25

Authors

I Zlobec

T Vuong

C C Compton

A Lugli

R P Michel

S Hayashi

J R Jass

Affiliations

Soon will be listed here.

Abstract

The ability to predict complete pathologic response or sensitivity to radiation before treatment would have a significant impact on the selection of patients for preoperative radiotherapy or chemo-radiation therapy schedules. The aim of this study was to determine the value of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53, Bcl-2 and apoptosis protease-activating factor-1 (APAF-1) as predictors of complete pathologic tumour regression in patients undergoing preoperative radiotherapy for advanced rectal cancer. Pretreatment tumour biopsies from predominantly cT3 patients undergoing a preoperative high-dose-rate brachytherapy protocol were immunostained for EGFR, VEGF, p53, Bcl-2 and APAF-1. Immunoreactivity was evaluated by three pathologists. Cut-off scores for tumour marker positivity were obtained by receiver-operating characteristic (ROC) curve analysis. The association of marker expression with complete pathologic response was analysed in univariate and multivariable analysis. Multi-marker phenotypes of the independent protein markers were evaluated. In multivariable analysis, loss of VEGF (P-value=0.009; odds ratio (OR) (95% CI)=0.24 (0.08-0.69)) and positive EGFR (P-value=0.01; OR (95% CI)=3.82 (1.37-10.6)) both demonstrated independent predictive value for complete pathologic response. The odds of complete response were 12.8 for the multi-marker combination of VEGF-negative and EGFR-positive tumours. Of the 34 EGFR-negative- and VEGF-positive cases, 32 (94.1%) had no complete pathologic response. The combined analysis of VEGF and EGFR is predictive of complete pathologic response in patients undergoing preoperative radiotherapy. In addition, the findings of this study have identified a subgroup of simultaneous EGFR-negative and VEGF-positive patients who are highly resistant to radiotherapy and should perhaps be considered candidates for innovative neoadjuvant combined modalities.

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References

Willett C, Duda D, Tomaso E, Boucher Y, Czito B, Vujaskovic Z . Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer. Nat Clin Pract Oncol. 2007; 4(5):316-21. PMC: 2686127. DOI: 10.1038/ncponc0813. View

Willett C, Kozin S, Duda D, Tomaso E, Kozak K, Boucher Y . Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice. Semin Oncol. 2006; 33(5 Suppl 10):S35-40. PMC: 2686124. DOI: 10.1053/j.seminoncol.2006.08.007. View

Vuong T, Devic S, Podgorsak E . High dose rate endorectal brachytherapy as a neoadjuvant treatment for patients with resectable rectal cancer. Clin Oncol (R Coll Radiol). 2007; 19(9):701-5. DOI: 10.1016/j.clon.2007.07.006. View

Jonker D, OCallaghan C, Karapetis C, Zalcberg J, Tu D, Au H . Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007; 357(20):2040-8. DOI: 10.1056/NEJMoa071834. View

Bertolini F, Bengala C, Losi L, Pagano M, Iachetta F, Dealis C . Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007; 68(5):1455-61. DOI: 10.1016/j.ijrobp.2007.02.018. View

Bewick V, Cheek L, Ball J . Statistics review 13: receiver operating characteristic curves. Crit Care. 2004; 8(6):508-12. PMC: 1065080. DOI: 10.1186/cc3000. View

Pore N, Jiang Z, Gupta A, Cerniglia G, Kao G, Maity A . EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res. 2006; 66(6):3197-204. DOI: 10.1158/0008-5472.CAN-05-3090. View

Zlobec I, Steele R, Michel R, Compton C, Lugli A, Jass J . Scoring of p53, VEGF, Bcl-2 and APAF-1 immunohistochemistry and interobserver reliability in colorectal cancer. Mod Pathol. 2006; 19(9):1236-42. DOI: 10.1038/modpathol.3800642. View

Larsen S, Wiig J, Dueland S, Giercksky K . Prognostic factors after preoperative irradiation and surgery for locally advanced rectal cancer. Eur J Surg Oncol. 2007; 34(4):410-7. DOI: 10.1016/j.ejso.2007.05.012. View

10.

Folkman J . Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971; 285(21):1182-6. DOI: 10.1056/NEJM197111182852108. View

11.

Zlobec I, Terracciano L, Jass J, Lugli A . Value of staining intensity in the interpretation of immunohistochemistry for tumor markers in colorectal cancer. Virchows Arch. 2007; 451(4):763-9. DOI: 10.1007/s00428-007-0466-8. View

12.

Cedermark B, Dahlberg M, Glimelius B, Pahlman L, Rutqvist L, Wilking N . Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med. 1997; 336(14):980-7. DOI: 10.1056/NEJM199704033361402. View

13.

Qiu H, Sirivongs P, ROTHENBERGER M, Rothenberger D, Garcia-Aguilar J . Molecular prognostic factors in rectal cancer treated by radiation and surgery. Dis Colon Rectum. 2000; 43(4):451-9. DOI: 10.1007/BF02237186. View

14.

Zlobec I, Steele R, Nigam N, Compton C . A predictive model of rectal tumor response to preoperative radiotherapy using classification and regression tree methods. Clin Cancer Res. 2005; 11(15):5440-3. DOI: 10.1158/1078-0432.CCR-04-2587. View

15.

Resnick M, Routhier J, Konkin T, Sabo E, Pricolo V . Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin Cancer Res. 2004; 10(9):3069-75. DOI: 10.1158/1078-0432.ccr-03-0462. View

16.

Zlobec I, Steele R, Terracciano L, Jass J, Lugli A . Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol. 2006; 60(10):1112-6. PMC: 2014838. DOI: 10.1136/jcp.2006.044537. View

17.

Kim J, Kim J, Li S, Yoon W, Song K, Kim K . Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2006; 66(1):195-200. DOI: 10.1016/j.ijrobp.2006.04.026. View

18.

Wolpin B, Meyerhardt J, Mamon H, Mayer R . Adjuvant treatment of colorectal cancer. CA Cancer J Clin. 2007; 57(3):168-85. DOI: 10.3322/canjclin.57.3.168. View

19.

Nozue M, Isaka N, Fukao K . Over-expression of vascular endothelial growth factor after preoperative radiation therapy for rectal cancer. Oncol Rep. 2001; 8(6):1247-9. DOI: 10.3892/or.8.6.1247. View

20.

Eriksen M, Wibe A, Haffner J, Wiig J . Prognostic groups in 1,676 patients with T3 rectal cancer treated without preoperative radiotherapy. Dis Colon Rectum. 2006; 50(2):156-67. DOI: 10.1007/s10350-006-0757-1. View