title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  High Ki67ratio in EGFRhigh:lowis 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.
authors.affiliation: Tom Baker Cancer Centre, Calgary, Alberta, Canada. Electronic address: Corinne.Doll@albertahealthservices.ca.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Doll
authors.affiliation: NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moughan
authors.affiliation: Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Klimowicz
authors.affiliation: Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Clement K
authors.initials: CK
authors.lastname: Ho
authors.affiliation: Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Kornaga
authors.affiliation: University of Calgary, Calgary, Alberta, Canada.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Lees-Miller
authors.affiliation: University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Jaffer A
authors.initials: JA
authors.lastname: Ajani
authors.affiliation: University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Crane
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kachnic
authors.affiliation: McMaster University Juravinski Cancer Center, Hamilton Health Sciences, Hamilton, Ontario, Canada.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Okawara
authors.affiliation: Mount Sinai Comprehensive Cancer Center Community Clinical Oncology Program (CCOP), Miami Beach, Florida.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Berk
authors.affiliation: Southeast Cancer Control Consortium, Inc, CCOP, Winston-Salem, North Carolina.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Roof
authors.affiliation: Columbus CCOP, Columbus, Ohio.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Becker
authors.affiliation: Greenville CCOP, Greenville, South Carolina.
authors.forename: David L
authors.initials: DL
authors.lastname: Grisell
authors.affiliation: Cancer Research of the Ozarks, Springfield, Missouri.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ellis
authors.affiliation: Metro-MN CCOP, St. Louis Park, Minnesota.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sperduto
authors.affiliation: Toledo Community Hospital Oncology Program CCOP, Toledo, Ohio.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Marsa
authors.affiliation: Montefiore Medical Center, Bronx, New York.
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Magliocco
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001005:Anus Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D012737:Sex Factors; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D016685:Mitomycin; D066246:ErbB Receptors; D002945:Cisplatin; D005472:Fluorouracil