A 3'-UTR KRAS-variant Is Associated With Cisplatin Resistance in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Ann Oncol. 2014 Nov;25(11):2230-6. doi: 10.1093/annonc/mdu367. Epub 2014 Jul 31.

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).

Patients and 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.

Clinical trial registration numbers: NCT00503997, NCT00425750, NCT00003809.

Keywords: KRAS-variant; cetuximab; cisplatin; head and neck squamous cell carcinoma; p16 expression.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Cetuximab
  • Cisplatin / administration & dosage
  • Cisplatin / adverse effects
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genotype
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Squamous Cell Carcinoma of Head and Neck
  • ras Proteins / biosynthesis
  • ras Proteins / genetics*

Substances

  • 3' Untranslated Regions
  • Antibodies, Monoclonal, Humanized
  • Cyclin-Dependent Kinase Inhibitor p16
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab
  • Cisplatin

Associated data

  • ClinicalTrials.gov/NCT00003809
  • ClinicalTrials.gov/NCT00425750
  • ClinicalTrials.gov/NCT00503997