title: A 3'-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
abstract: BACKGROUND
  A germline mutation in the 3'-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  We conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings.
  
  
  RESULTS
  KRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04).
  
  
  CONCLUSIONS
  The TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients.
  
  
  BACKGROUND
  NCT00503997, NCT00425750, NCT00003809.
authors.affiliation: Department of Oncology; Department of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore. Electronic address: cchung11@jhmi.edu.
authors.forename: C H
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston.
authors.forename: J W
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology.
authors.forename: R J
authors.initials: RJ
authors.lastname: Slebos
authors.affiliation: Department of Oncology.
authors.forename: J D
authors.initials: JD
authors.lastname: Howard
authors.affiliation: Department of Oncology.
authors.forename: J
authors.initials: J
authors.lastname: Perez
authors.affiliation: Department of Oncology.
authors.forename: H
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Oncology.
authors.forename: E J
authors.initials: EJ
authors.lastname: Fertig
authors.affiliation: Department of Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Considine
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville.
authors.forename: J
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville.
authors.forename: B A
authors.initials: BA
authors.lastname: Murphy
authors.affiliation: Department of Therapeutic Radiology.
authors.forename: S
authors.initials: S
authors.lastname: Nallur
authors.affiliation: Department of Therapeutic Radiology.
authors.forename: T
authors.initials: T
authors.lastname: Paranjape
authors.affiliation: Department of Pathology, University of California, San Francisco.
authors.forename: R C
authors.initials: RC
authors.lastname: Jordan
authors.affiliation: Mayo Clinic, Rochester, USA.
authors.forename: J
authors.initials: J
authors.lastname: Garcia
authors.affiliation: Section of Medical Oncology, Department of Internal Medicine, Yale University School of Medicine, New Haven.
authors.forename: B
authors.initials: B
authors.lastname: Burtness
authors.affiliation: Department of Oncology.
authors.forename: A A
authors.initials: AA
authors.lastname: Forastiere
authors.affiliation: Department of Therapeutic Radiology; Department of Radiation Oncology, University of California, Los Angeles.
authors.forename: J B
authors.initials: JB
authors.lastname: Weidhaas
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D000077195:Squamous Cell Carcinoma of Head and Neck; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D061067:Antibodies, Monoclonal, Humanized; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002945:Cisplatin
keywords: KRAS-variant; cetuximab; cisplatin; head and neck squamous cell carcinoma; p16 expression
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