A new analysis approach of epidermal growth factor receptor pathway activation patterns provides insights into cetuximab resistance mechanisms in head and neck cancer

The pathways downstream of the epidermal growth factor receptor (EGFR) have often been implicated to play crucial roles in the development and progression of various cancer types. Different authors have proposed models in cell lines in which they study the modes of pathway activities after perturbation experiments. It is prudent to believe that a better understanding of these pathway activation patterns might lead to novel treatment concepts for cancer patients or at least allow a better stratification of patient collectives into different risk groups or into groups that might respond to different treatments. Traditionally, such analyses focused on the individual players of the pathways. More recently in the field of systems biology, a plethora of approaches that take a more holistic view on the signaling pathways and their downstream transcriptional targets has been developed. Fertig et al. have recently developed a new method to identify patterns and biological process activity from transcriptomics data, and they demonstrate the utility of this methodology to analyze gene expression activity downstream of the EGFR in head and neck squamous cell carcinoma to study cetuximab resistance. Please see related article: http://www.biomedcentral.com/1471-2164/13/16

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

BackgroundA 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 methodsWe 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.ResultsKRAS-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).ConclusionsThe TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients.Clinical trial registration numbersNCT00503997, NCT00425750, NCT00003809

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

BackgroundA 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 methodsWe 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.ResultsKRAS-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).ConclusionsThe TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients.Clinical trial registration numbersNCT00503997, NCT00425750, NCT00003809

Screening for Problem Drinking: Comparison of CAGE and AUDIT

OBJECTIVE: To compare self-administered versions of three questionnaires for detecting heavy and problem drinking: the CAGE, the Alcohol Use Disorders Identification Test (AUDIT), and an augmented version of the CAGE. DESIGN: Cross-sectional surveys. SETTING: Three Department of Veterans Affairs general medical clinics. PATIENTS: Random sample of consenting male outpatients who consumed at least 5 drinks over the past year (“drinkers”). Heavy drinkers were oversampled. MEASUREMENTS: An augmented version of the CAGE was included in a questionnaire mailed to all patients. The AUDIT was subsequently mailed to “drinkers.” Comparison standards, based on the tri-level World Health Organization alcohol consumption interview and the Diagnostic Interview Schedule, included heavy drinking (>14 drinks per week typically or ≥5 drinks per day at least monthly) and active DSM-IIIR alcohol abuse or dependence (positive diagnosis and at least one alcohol-related symptom in the past year). Areas under receiver operating characteristic curves (AUROCs) were used to compare screening questionnaires. MAIN RESULTS: Of 393 eligible patients, 261 (66%) returned the AUDIT and completed interviews. For detection of active alcohol abuse or dependence, the CAGE augmented with three more questions (AUROC 0.871) performed better than either the CAGE alone or AUDIT (AUROCs 0.820 and 0.777, respectively). For identification of heavy-drinking patients, however, the AUDIT performed best (AUROC 0.870). To identify both heavy drinking and active alcohol abuse or dependence, the augmented CAGE and AUDIT both performed well, but the AUDIT was superior (AUROC 0.861). CONCLUSIONS: For identification of patients with heavy drinking or active alcohol abuse or dependence, the self-administered AUDIT was superior to the CAGE in this population