XPF Expression Correlates with Clinical Outcome in Squamous Cell Carcinoma of the Head and Neck

Abstract

Purpose Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC). Experimental Design Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms in the XPF gene using a custom array. The primary endpoint was progression-free survival (PFS). Results XPF expression was higher in tumors from the oral cavity than from the other sites (p<0.01). High XPF expression correlated with early time to progression both by univariate (HR =1.87, p=0.03) and multivariate analysis (HR =1.83, p=0.05). The one year PFS for high expressers was 47% (95% CI = 31% – 62%) compared to 72% (95% CI = 55% – 83%) for low expressers. In addition, we identified four XPF single nucleotide polymorphisms (SNPs) that demonstrated marginal association with treatment failure. Conclusions Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next-generation personalized cancer therapy.

Single nucleotide polymorphisms in nucleotide excision repair genes, cancer treatment, and head and neck cancer survival

“…Although no previous HNC studies examined rs3136038 or rs3136130 on ERCC4 , two studies assessed nine other ERCC4 SNPs (rs1799799, rs1799801, rs3136105, rs3136146, rs3136152, rs3136155, rs3136166, rs3136189, rs3136202), many of which were in LD with the SNPs in our study ( r 2 >0.80, CEU population) [10, 16, 33]. While five of these SNPs were not associated with progression-free survival among HNC cases, four SNPs appeared to be associated with worse progression-free survival contrary to our study [10, 16].…”

Pulsed Radiation Therapy With Concurrent Cisplatin Results in Superior Tumor Growth Delay in a Head and Neck Squamous Cell Carcinoma Murine Model

“…Tumor hypoxia was measured non-invasively by 18 The majority of cisplatin-induced DNA adducts are repaired by the NER pathway (19,20), and the expression of the ERCC1 NER gene is associated with tumor resistance to CDDP cytotoxicity. Higher expression of ERRC1 was associated with inferior progression free survival for HNSCC after cisplatin radiotherapy (21,22), and ERCC1 expression has good prognostic value in patients with HPV-negative tumors (21). The percent of ERCC1-positive cell nuclei in viable regions of the tumor was measured after the CDDP containing regimens.…”

Smoking at Diagnosis Is an Independent Prognostic Factor for Cancer-Specific Survival in Head and Neck Cancer: Findings from a Large, Population-Based Study

“…Although a few small studies have reported associations between levels of expression of proteins involved in DNA repair and survival in head and neck cancer patients (52)(53)(54), none appear to have explored the influence of smoking on these relationships.…”