title: The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial.
abstract: OBJECTIVE
  There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment.
  
  
  OBJECTIVE
  To examine whether the Kirsten rat sarcoma viral oncogene homolog (KRAS)-variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS-variant with p16 status and blood-based transforming growth factor β1 (TGF-β1).
  
  
  METHODS
  A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS-variant. Genomic DNA was tested for the KRAS-variant in a CLIA-certified laboratory. Correlation of the KRAS-variant, p16 positivity, outcome, and TGF-β1 levels was evaluated. Hazard ratios (HRs) were estimated with the Cox proportional hazards model.
  
  
  METHODS
  The correlation of KRAS-variant status with cetuximab response and outcome, p16 status, and plasma TGF-β1 levels was tested.
  
  
  RESULTS
  Of 891 patients eligible for protocol analyses (786 male [88.2%], 105 [11.2%] female, 810 white [90.9%], 81 nonwhite [9.1%]), 413 had biological samples for KRAS-variant testing, and 376 had plasma samples for TGF-β1 measurement. Seventy patients (16.9%) had the KRAS-variant. Overall, for patients with the KRAS-variant, cetuximab improved both progression-free survival (PFS) for the first year (HR, 0.31; 95% CI, 0.10-0.94; P = .04) and overall survival (OS) in years 1 to 2 (HR, 0.19; 95% CI, 0.04-0.86; P = .03). There was a significant interaction of the KRAS-variant with p16 status for PFS in patients treated without cetuximab. The p16-positive patients with the KRAS-variant treated without cetuximab had worse PFS than patients without the KRAS-variant (HR, 2.59; 95% CI, 0.91-7.33; P = .07). There was a significant 3-way interaction among the KRAS-variant, p16 status, and treatment for OS (HR, for KRAS-variant, cetuximab and p16 positive, 0.22; 95% CI, 0.03-1.66; HR for KRAS-variant, cetuximab and p16 negative, 1.43; 95% CI, 0.48-4.26; HR for KRAS-variant, no cetuximab and p16 positive, 2.48; 95% CI, 0.64-9.65; and HR for KRAS-variant, no cetuximab and p16 negative, 0.61; 95% CI, 0.23-1.59; P = .02). Patients with the KRAS-variant had significantly elevated TGF-β1 plasma levels (median, 23 376.49 vs 18 476.52 pg/mL; P = .03) and worse treatment-related toxic effects.
  
  
  CONCLUSIONS
  Patients with the KRAS-variant with HNSCC significantly benefit from the addition of cetuximab to radiotherapy and cisplatin, and there is a significant interaction between the KRAS-variant and p16 status. Elevated TGF-β1 levels in patients with the KRAS-variant suggests that cetuximab may help these patients by overcoming TGF-β1-induced suppression of antitumor immunity.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00265941.
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at UCLA (University of California, Los Angeles), Los Angeles, California.
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Weidhaas
authors.affiliation: NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Harris
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at UCLA (University of California, Los Angeles), Los Angeles, California.
authors.forename: Dörthe
authors.initials: D
authors.lastname: Schaue
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at UCLA (University of California, Los Angeles), Los Angeles, California.
authors.forename: Allen M
authors.initials: AM
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at UCLA (University of California, Los Angeles), Los Angeles, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Chin
authors.affiliation: Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Rita
authors.initials: R
authors.lastname: Axelrod
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Anurag K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Galloway
authors.affiliation: Department of Radiation Oncology, University of Colorado at Denver, Aurora.
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee.
authors.forename: Dian
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Oklahoma University Health Sciences Center, Oklahoma City.
authors.forename: Chance
authors.initials: C
authors.lastname: Matthiesen
authors.affiliation: Department of Radiation Oncology, Intermountain Medical Center, Salt Lake City, Utah.
authors.forename: Vilija N
authors.initials: VN
authors.lastname: Avizonis
authors.affiliation: University of Florida Health Cancer Center, Orlando Health, Orlando.
authors.forename: Rafael R
authors.initials: RR
authors.lastname: Manon
authors.affiliation: Department of Radiation Oncology, Geisinger Medical Center CCOP, Danville, Pennsylvania.
authors.forename: Omar
authors.initials: O
authors.lastname: Yumen
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de l'Université de Montreal, Montreal, Quebec, Canada.
authors.forename: Phuc Felix
authors.initials: PF
authors.lastname: Nguyen-Tan
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Andy
authors.initials: A
authors.lastname: Trotti
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Heath
authors.initials: H
authors.lastname: Skinner
authors.affiliation: NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Cancer Immunology Program and Tumor Microvenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D000068818:Cetuximab / Q000008:administration & dosage*; D059248:Chemoradiotherapy / Q000379:methods; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002945:Cisplatin