A 30-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

Christine H. Chung, J. W. Lee, R. J. Slebos, J. D. Howard, J. Perez, H. Kang, E. J. Fertig, M. Considine, J. Gilbert, B. A. Murphy, S. Nallur, T. Paranjape, R. C. Jordan, J. Garcia, B. Burtness, A. A. Forastiere, J. B. Weidhaas

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2230-2236
Number of pages7
JournalAnnals of Oncology
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2014

Keywords

  • Cetuximab
  • Cisplatin
  • Head and neck squamous cell carcinoma
  • KRAS-variant
  • P16 expression

ASJC Scopus subject areas

  • Hematology
  • Oncology

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