Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811

Int J Radiat Oncol Biol Phys. 2017 Mar 1;97(3):554-562. doi: 10.1016/j.ijrobp.2016.11.021. Epub 2016 Nov 23.

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 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 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.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Anus Neoplasms / metabolism*
  • Anus Neoplasms / mortality
  • Anus Neoplasms / pathology
  • Anus Neoplasms / therapy*
  • Chemoradiotherapy / methods*
  • Cisplatin / administration & dosage
  • ErbB Receptors / metabolism*
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Ki-67 Antigen / metabolism*
  • Male
  • Middle Aged
  • Mitomycin / administration & dosage
  • Neoplasm Proteins / metabolism*
  • Prognosis
  • Sex Factors
  • Treatment Failure
  • Treatment Outcome

Substances

  • Ki-67 Antigen
  • Neoplasm Proteins
  • Mitomycin
  • ErbB Receptors
  • Cisplatin
  • Fluorouracil