Corinne M Doll1, Jennifer Moughan2, Alexander Klimowicz3, Clement K Ho3, Elizabeth N Kornaga3, Susan P Lees-Miller4, Jaffer A Ajani5, Christopher H Crane5, Lisa A Kachnic6, Gordon S Okawara7, Lawrence B Berk8, Kevin S Roof9, Mark J Becker10, David L Grisell11, Robert J Ellis12, Paul W Sperduto13, Gerald W Marsa14, Chandan Guha15, Anthony M Magliocco16. 1. Tom Baker Cancer Centre, Calgary, Alberta, Canada. Electronic address: Corinne.Doll@albertahealthservices.ca. 2. NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania. 3. Tom Baker Cancer Centre, Calgary, Alberta, Canada. 4. University of Calgary, Calgary, Alberta, Canada. 5. University of Texas M. D. Anderson Cancer Center, Houston, Texas. 6. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. 7. McMaster University Juravinski Cancer Center, Hamilton Health Sciences, Hamilton, Ontario, Canada. 8. Mount Sinai Comprehensive Cancer Center Community Clinical Oncology Program (CCOP), Miami Beach, Florida. 9. Southeast Cancer Control Consortium, Inc, CCOP, Winston-Salem, North Carolina. 10. Columbus CCOP, Columbus, Ohio. 11. Greenville CCOP, Greenville, South Carolina. 12. Cancer Research of the Ozarks, Springfield, Missouri. 13. Metro-MN CCOP, St. Louis Park, Minnesota. 14. Toledo Community Hospital Oncology Program CCOP, Toledo, Ohio. 15. Montefiore Medical Center, Bronx, New York. 16. H. Lee Moffitt Cancer Center, Tampa, Florida.
Abstract
PURPOSE: To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. METHODS AND MATERIALS: EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. RESULTS:A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. CONCLUSIONS: High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.
RCT Entities:
PURPOSE: To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancerpatients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. METHODS AND MATERIALS: EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. RESULTS: A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancerpatient cohort was performed and shows a very similar biomarker score distribution. CONCLUSIONS: High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.
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