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).

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.

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Kaplan–Meier survival plots by KRAS-variant status (variant TG/GG versus non-variant TT). (A) Progression-free survival from HN0501 (phase II trial of docetaxel + bortezomib in R/M HNSCC patients); (B) overall survival from HN0501; (C) progression-free survival from E5397 (randomized phase III trial of cisplatin + placebo versus cisplatin + cetuximab in R/M HNSCC patients); (D) overall survival from E5397; (E) progression-free survival by KRAS-variant status (variant TG/GG versus non-variant TT) and E5397 treatment arms (cisplatin + placebo versus cisplatin + cetuximab); and (F) overall survival by KRAS-variant status (variant TG/GG versus non-variant TT) and E5397 treatment arms (cisplatin + placebo versus cisplatin + cetuximab).