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

A 3'-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Author information

1
Department of Oncology Department of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore cchung11@jhmi.edu.
2
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston.
3
Department of Cancer Biology.
4
Department of Oncology.
5
Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville.
6
Department of Therapeutic Radiology.
7
Department of Pathology, University of California, San Francisco.
8
Mayo Clinic, Rochester, USA.
9
Section of Medical Oncology, Department of Internal Medicine, Yale University School of Medicine, New Haven.
10
Department of Therapeutic Radiology Department of Radiation Oncology, University of California, Los Angeles.

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

PMID:
25081901
PMCID:
PMC4207729
DOI:
10.1093/annonc/mdu367
[Indexed for MEDLINE]
Free PMC Article

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