EGFR and K-ras gene mutation status in squamous cell anal carcinoma: a role for concurrent radiation and EGFR inhibitors?

Abstract

Background:There is a growing appreciation for radio-sensitiser use in multi-modal cancer treatment models. Squamous cell anal carcinoma (SCAC) is a rare gastrointestinal tumour traditionally treated with concurrent chemotherapy and radiation. Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, has demonstrated significant efficacy when combined with radiation in squamous cell carcinoma of the head and neck (SccH&N). We wanted to assess EGFR and Kirsten-ras (K-ras) status in SCAC to see whether it compares with SccH&N.Methods:Over 90 SCAC paraffin-embedded biopsies were mounted onto a tissue microarray and were assessed for EGFR expression by immunohistochemistry. These samples were also assessed for the most frequently mutated K-ras and EGFR exons by high-resolution melting analysis.Results:The EGFR was present in over 90% of samples tested. The K-ras and EGFR mutations were absent in all samples tested, although a synonymous single-nucleotide polymorphism was found in 3 out of 89 samples tested for EGFR exon 19.Conclusion:The low rate of K-ras and EGFR mutations, coupled with the high surface expression of EGFR, suggests similarity in the EGFR signalling pathway between SCAC and SccH&N, and thus a potential role for EGFR inhibitors in SCAC. To our knowledge this is the largest cohort of invasive SCAC samples investigated for EGFR and K-ras mutations reported to date.

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

“…4 EGFR is often overexpressed and/or abnormally activated in almost all squamous cell carcinomas (SCCs), including anal carcinomas (in up to 90%). 5 Cetuximab (Erbitux; Merck KgaA, Darmstadt, Germany) is an immunoglobulin G1 monoclonal antibody that specifically targets EGFR, competitively inhibiting ligand binding and ligand-dependent downstream signaling. 6 Phase 1 clinical trials demonstrated the safety of cetuximab combined with CP 7 and cetuximab combined with radiation therapy 8 in SCCs other than anal carcinoma.…”

The prognostic significance of epidermal growth factor receptor expression in patients with anal carcinoma

“…Three studies evaluated the determination of K-RAS mutation in 146 patients in total. None of the assessments showed the presence of the mutated K-RAS form [25,35]. A larger study evaluated 193 biopsies, demonstrating the K-RAS mutation in only 3 cases [36].…”

Ras and Ras mutations in cancer

“…EGFR-TKIs (EGFR-tyrosine kinase inhibitors), erlotinib and gefitinib are the other proficient drugs in clinical trials with antitumor activity (Table 2). Recent studies on squamous cell anal carcinoma (SCAC) showed significantly less prevalence of EGFR and K-ras mutations in head and neck cancer [116] with cetuximab showing appreciable anticancer effect when administered in synergy with radiation.…”