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Purpose: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), has shown clinical efficacy in squamous cell carcinoma of the head and neck with prolonged progression-free (PFS) and overall survival (OS). In this study, we analyzed whether cetuximab-induced skin rash was correlated with distinct polymorphisms within the EGFR gene known to modulate EGFR expression, ligand binding, or signaling activity. Experimental Design: Fifty-one patients enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with cetuximab/docetaxel were genotyped for two genetic variations in the EGFR gene, a point substitution G→A in exon 13 resulting in an amino acid substitution in position 521 (EGFR-R521K) and a CA repeat (CA-SSR) polymorphism in intron 1. Association between genotypes and incidence/grade of skin rash was determined by Fisher's exact test. The predictive value of genotypes for PFS and OS was determined using the log-rank test. Results: Overall, 21 patients (41%) developed skin rash with grade >1 within 6 weeks of treatment. The common EGFR-R521K genotype (G/G) was significantly associated with increased skin toxicity (P = 0.024) and showed a trend toward reduced risk of tumor progression (hazard ratio, 0.55; 95% confidence interval, 0.27-1.08; P = 0.08), whereas no correlation of the EGFR-R521K genotype with OS could be observed (P = 0.20). No significant interaction between CA-SSR polymorphism and skin toxicity, PFS, or OS could be detected. Conclusions: Our study revealed an influence of the EGFR-R521K genotype on skin toxicity and suggested its relation to clinical activity of cetuximab/docetaxel treatment. Clin Cancer Res; 16(1); 304–10

Introduction Despite recent advances in radiochemotherapy, the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) is still challenging with 5-year survival rates less than 60% resulting from a high frequency of local and/or regional tumor recurrence. Hence, the investigation on molecular mechanisms that influence treatment efficacy and the identification of predictive molecular markers, which could improve patient selection for optimized treatment, are therefore of high clinical relevance. MicroRNAs (miRNA) as key regulators of gene expression and modulators of cancer progression are of rising interest as a source of such biomarkers. In this study we evaluated the impact of miRNA expression on the efficacy of radiochemotherapy on HNSCC. Methods Formalin-fixed, paraffin-embedded archival tumor material was collected from patients with locally advanced HNSCC, who had been treated with hyperfractionated accelerated radiotherapy in combination with either 5-fluorouracil/cisplatin (5-FU/CDDP) or 5-fluorouracil/mitomycin C (5-FU/MMC) within the ARO0401 phase III trial. Using samples from a test cohort of 50 patients (tumor site only oropharynx) the microRNA profiles of tumor cells were established by Affymetrix miRNA microarrays. Results were validated in samples from 149 HNSCC patients (oropharynx and hypopharynx) by quantitative real-time PCR (qRT-PCR). Results The expression levels of 15 miRNAs were identified to correlate with overall survival of patients treated with MMC-based chemoradiation, whereas the expression levels of 10 other microRNAs were correlated with overall survival of patients treated with CDDP-based chemoradiation. The expression pattern of miR-200b and miR-146a were validated by qRT-PCR, each of them being a significantly correlated miRNA in the respective study arm. Our results revealed that the correlation of the expression levels of these microRNAs was dependent on the tumor subsite, as a significant correlation was only observed in patients with oropharyngeal but not hypopharyngeal carcinomas. Interestingly, expression of miR-146a correlated with local recurrence, whereas miR-200b was associated with the occurrence of distant metastases. Conclusion miRNA expression levels can be used as predictive markers for the efficacy of chemoradiation. The biological function of the candidate miRNAs identified in this study will be further investigated in HNSCC cell line models.

Background and Purpose: Mutations in the p53 gene are frequently observed in squamous cell carcinoma of the head and neck region (SCCHN) and have been associated with drug resistance. The potential of arsenic trioxide (ATO) for treatment of p53-deficient tumor cells and those with acquired resistance to cisplatin and cetuximab was determined. Material and Methods: In a panel of 10 SCCHN cell lines expressing either wildtype p53, mutated p53 or which lacked p53 by deletion the interference of p53 deficiency with the growth-inhibitory and radiosensitizing potential of ATO was determined. The causal relationship between p53 deficiency and ATO sensitivity was evaluated by reconstitution of wildtype p53 in p53-deficient SCCHN cells. Interference of ATO treatment with cell cycle, DNA repair and apoptosis and its efficacy in cells with acquired resistance to cisplatin and cetuximab was evaluated. Results: Functional rather than structural defects in the p53 gene predisposed tumor cells to increased sensitivity to ATO. Reconstitution of wt p53 in p53-deficient SCCHN cells rendered them less sensitive to ATO treatment. Combination of ATO with irradiation inhibited clonogenic growth in an additive manner. The inhibitory effect of ATO in p53-deficient tumor cells was mainly associated with DNA damage, G2/M arrest, upregulation of TRAIL (tumor necrosis factor-related apoptosisinducing ligand) receptors and apoptosis. Increased activity of ATO was observed in cetuximab-resistant SCCHN cells whereas cisplatin resistance was associated with cross-resistance to ATO. Conclusions: Addition of ATO to treatment regimens for p53-deficient SCCHN and tumor recurrence after cetuximabcontaining regimens might represent an attractive strategy in SCCHN.

Background Treatment of locally advanced squamous cell carcinomas of the head and neck (SCCHN) remains unsatisfactory. Although the addition of concurrent radiochemotherapy (RCT) or the combination of radiotherapy with blockade of the epidermal growth factor receptor (EGFR) have improved outcomes over radiotherapy alone, further optimization is urgently needed. The introduction of immune checkpoint inhibitors is currently revolutionizing cancer treatment. Clinical evidence has recently been provided in melanoma that immune checkpoint blockade may cooperate with radiation. Therefore, we searched in the literature for the evidence of combining immune checkpoint inhibitors with radiotherapy in primary treatment of SCCHN. Discussion A substantial amount of previous studies has dissected the molecular mechanisms of immune evasion in SCCHN. The biological effects of radio- and chemotherapy in tumor cells and the immune cell microenvironment were characterized in detail, revealing significant interference of both types of treatment with anti-tumor immunity. This extensive review of the literature revealed considerable amount of evidence that addition of immune checkpoint inhibitors might boost the immunomodulatory potential of radiotherapy and RCT regimens in SCCHN. Summary Promising activity of immune checkpoint inhibitors has already been reported for metastatic/recurrent SCCHN. Given the immunogenic effect of radiotherapy and its enhancement by chemotherapy, combination of radiotherapy or RCT with this new type of immunotherapy might represent a valuable option for improvement of curative treatment modalities in SCCHN.

The introduction of next-generation sequencing (NGS) in the field of cancer research has boosted worldwide efforts of genome-wide personalized oncology aiming at identifying predictive biomarkers and novel actionable targets. Despite considerable progress in understanding the molecular biology of distinct cancer entities by the use of this revolutionary technology and despite contemporaneous innovations in drug development, translation of NGS findings into improved concepts for cancer treatment remains a challenge. The aim of this article is to describe shortly the NGS platforms for DNA sequencing and in more detail key achievements and unresolved hurdles. A special focus will be given on potential clinical applications of this innovative technique in the field of radiation oncology.