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Background: For patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) palliative treatment options that improve overall survival are limited. The prognosis in this group remains poor and there is an unmet need for new therapeutic options. An emerging class of therapeutics, targeting tumor-specific antigens, are antibodies bound to a cytotoxic agent, known as antibody-drug conjugates (ADCs). The aim of this study was to prioritize ADC targets in HNSCC.Methods: With a systematic search, we identified 55 different ADC targets currently targeted by registered ADCs and ADCs under clinical evaluation. For these 55 ADC targets, protein overexpression was predicted in a dataset containing 344 HNSCC mRNA expression profiles by using a method called functional genomic mRNA profiling. The ADC target with the highest predicted overexpression was validated by performing immunohistochemistry (IHC) on an independent tissue microarray containing 414 HNSCC tumors.Results: The predicted top 5 overexpressed ADC targets in HNSCC were: glycoprotein nmb (GPNMB), SLIT and NTRK-like family member 6, epidermal growth factor receptor, CD74 and CD44. IHC validation showed combined cytoplasmic and membranous GPNMB protein expression in 92.0% of the cases. Strong expression was seen in 65.9% of the cases. In addition, 86.5% and 67.7% of cases showed ≥5% and >25% GPNMB positive tumor cells, respectively.Conclusions: This study provides a data-driven prioritization of ADCs targets that will facilitate clinicians and drug developers in deciding which ADC should be taken for further clinical evaluation in HNSCC. This might help to improve disease outcome of HNSCC patients. [ABSTRACT FROM AUTHOR]

Purpose: We sought to assess the effect of age on overall survival (OS), cancer-specific survival (CSS), and non-cancer-related death (NCRD) in elderly (aged ≥70 years) head and neck squamous cell carcinoma (HNSCC) patients treated with definitive radiation therapy. The results were compared with those of younger patients, and the most important prognostic factors for survival endpoints were determined. Treatments may be better justified based on identification of the main differences in survival between young and elderly patients.Methods and Materials: Data were analyzed from all consecutive HNSCC patients treated with definitive radiation therapy (66-70 Gy) in our department between April 2007 and December 2014. A total of 674 patients, including 168 elderly patients (24.9%), were included in the study. Multivariate association models were constructed to assess the effect of age on survival endpoints. Multivariate analysis was performed to identify potential prognostic factors for survival in elderly patients.Results: A total of 674 consecutive patients, including 168 elderly patients, were analyzed. The 5-year OS and NCRD rates were significantly worse for elderly patients than for young patients: 45.5% versus 58.2% (P=.007) and 39.0% versus 20.7% (P<.001), respectively. In the multivariate association analysis on the relationship between age and OS, lymph node involvement and worse World Health Organization (WHO) performance status were identified as significant confounders. Multivariate association analysis between age and NCRD identified Union for International Cancer Control stage as a significant confounder. After correction for confounders, the effect of age on OS and NCRD increased. Worse WHO performance status, lymph node involvement, and specific tumor site were independent prognostic factors for OS and CSS in the elderly patient group. Of the elderly patients, 80 (47%) died during follow-up; 45% of these deaths were ascribed to the index tumor. For elderly patients, radiation therapy combined with systemic forms of treatment was significantly associated with adverse NCRD rate (hazard ratio, 8.02; 95% confidence interval, 2.36-27.2; P=.001) after we performed a multivariate association analysis.Conclusions: Elderly HNSCC patients have worse survival outcomes than young HNSCC patients. Age is an independent prognostic factor for OS, mainly due to an increase in non-cancer-related mortality and comorbid diseases. The differences in CSS between young and elderly patients are negligible. [ABSTRACT FROM AUTHOR]

Purpose To assess the prevalence of EGFRvIII, a specific variant of EGFR (epidermal growth factor receptor), in 3 well-defined cohorts of head and neck squamous cell carcinoma (HNSCC). Methods and Materials Immunohistochemistry for the specific detection of EGFRvIII using the L8A4 antibody was optimized on formalin-fixed, paraffin-embedded tissue using glioblastoma tissue. It was compared with EGFR and EGFRvIII RNA expression using a specific reverse transcription–polymerase chain reaction also optimized for formalin-fixed, paraffin-embedded tissue. Tissue microarrays including 531 HNSCCs of various stages with complete clinicopathologic and follow-up data were tested for the presence of EGFRvIII. Results None of the 531 cases showed EGFRvIII protein expression. Using an immunohistochemistry protocol reported by others revealed cytoplasmic staining in 8% of cases. Reverse transcription–polymerase chain reaction for the EGFRvIII transcript of the 28 highest cytoplasmic staining cases, as well as 69 negative cases, did not show expression in any of the tested cases, suggesting aspecific staining by a nonoptimal protocol. Conclusions The EGFRvIII mutation is not present in HNSCC. Therefore, EGFRvIII does not influence treatment response in HNSCC and is not a usable clinical prognostic marker. [ABSTRACT FROM AUTHOR]

Summary: Detection of distant metastases and second primary tumors in patients with head and neck squamous cell carcinoma (HNSCC) is of importance because of the impact on treatment and prognosis. The aim of this study was to assess the value of whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET) in detecting distant metastases and second primary tumors below clavicular level in HNSCC compared to chest CT and chest radiography (CXR). Patient records of 149 consecutive patients with a primary HNSCC in whom a whole-body FDG-PET for initial staging was performed were reviewed. FDG-PET showed a sensitivity and specificity for detecting distant disease of 92% and 93%, respectively. Chest CT (n =82) showed a sensitivity and a specificity of 74% and 61% respectively. CXR (n =106) showed a sensitivity and a specificity of 41% and 91%, respectively. FDG-PET was shown to be able to detect distant metastases and second primary tumors in HNSCC with a high sensitivity and specificity. The higher sensitivity of PET compared to chest CT is mainly due to the detection of extrapulmonary malignancy. Sensitivity of PET and CT were similar in detecting intrapulmonary malignancy, but PET specificity was significantly higher. FDG-PET helps to determine the nature of pulmonary lesions and might be considered as a first diagnostic modality for detecting distant disease in advanced HNSCC. [Copyright &y& Elsevier]

Abstract: Background and purpose: The aim of the study was to define the added value of whole body FDG-PET in screening for distant metastases in patients with head and neck squamous cell carcinoma and risk factors. Materials and methods: In a multi-center prospective study between 1998 and 2003, 145 consecutive HNSCC patients with risk factors for distant metastases underwent chest CT and whole body FDG-PET for screening of distant metastases. The data of 92 evaluable patients who developed distant metastases or who had a follow-up of at least 12 months were analyzed. Besides their performance in clinical practice, the operational characteristics of PET and CT using ROC analyses were investigated. Results: Pretreatment screening identified distant metastases in 19 patients (21%). FDG-PET had a higher sensitivity (53% vs. 37%) and positive predictive value (80% vs. 75%) than CT. The combination of CT and FDG-PET had the highest sensitivity (63%). The ROC analyses of the five point ordinal scales revealed that the “area under the curve” (AUC) of FDG-PET was significantly higher as compared to CT. Conclusion: In HNSCC patients with risk factors, pretreatment screening for distant metastases by chest CT is improved by FDG-PET. [Copyright &y& Elsevier]

Summary: Treatment of the clinical N0 neck in squamous cell carcinoma (SCC) of oral cavity and oropharynx remains a dilemma. None of the current imaging modalities are able to detect the presence of micrometastases in the lymph nodes of clinical N0 necks reliably. The aim of this study was to determine the diagnostic properties of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) in patients clinically staged as N0. FDG PET results of 38 patients were compared to histologic specimens obtained with neck dissections or to follow-up. FDG PET performance was compared to computed tomography (CT), magnetic resonance imaging (MRI) or ultrasonography-guided fine needle aspiration cytology (USgFNAC). Sensitivity and specificity of FDG PET in detecting occult cervical metastases were 50% and 97% respectively. Although FDG PET performed better than conventional imaging modalities, sensitivity was lower than desired. As a consequence, clinical application of FDG PET in the patient staged as N0 is limited. [Copyright &y& Elsevier]

About halve of all oral squamous cell carcinoma (OSCC) patients have occult nodal metastases (N-status) due to the inaccuracy of current detection methods. The aim of our study is to find DNA methylation markers in the DNA of the primary tumor that predict N-status. For biomarker discovery we used a new approach combining a global DNA methylation screen, next generation sequencing, quantitative methylation detection and microarray expression profiling. Here we report the success of this new approach and the further validation of novel methylation markers. We assessed global methylation levels on DNA extracted from 6 oral squamous cell carcinomas (OSCC) with nodal metastases (N+) and 6 OSCC without nodal metastases (N0) by MethylCap-Seq. Isolated methylated DNA fragments were sequenced by Illumina GA II and computationally mapped back to the genome. A list was composed of the 5000 most differentially methylated genes between the N+and the N0 group. The most significantly differentially methylated genes were selected for further validation by Quantitative Methylation Specific PCR and Pyrosequencing on an independent series of 20N+and 20 N0 OSCC. In addition the MethylCap-Seq methylation data was combined with microarray expression data of 696 genes for a N-status validation cohort containing 222 OSCC (Hoof et al., 2012, J. Clin. Oncol.). The effect of DNA methylation on gene expression will be measured by (Q)RT-PCR and immunohistochemistry on genes differently hypermethylated and downregulated. The most promising methylation markers will be further validated on a N-status validation cohort containing 463 cases for which complete clinicopathological and follow-up data are available. These markers might contribute to better diagnosis, improved quality of life and may be associated with increased survival. [Copyright &y& Elsevier]