Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study

Abstract

Background: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients.Patients and methods: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU.Results: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU.Conclusion: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.

The molecular pathogenesis of head and neck squamous cell carcinoma

“…Although it is often considered to be among the most important therapeutic targets in HNSCC (81), our understanding of the role of EGFR is evolving with the appreciation that EGFR activating mutations are rare in HNSCC and that the reported frequency of EGFR gene amplification in HNSCC varies widely, in part due to varying definitions of the degree and size of copy number gain that constitute amplification (82,83). Furthermore, although copy number gain of EGFR has been suggested to correlate with poor prognosis in HNSCC (83,84), in general gain of EGFR has not been clearly demonstrated to predict improved outcomes following EGFR-directed therapy (85,86). Similarly, therapeutic agents that inhibit EGFR, including the small molecule inhibitors gefitinib and erlotinib and the therapeutic antibody cetuximab, have modest activity in HNSCC, with little or no correlation with EGFR status (87)(88)(89)(90)(91).…”

“…This agent has generally modest efficacy, and efforts to identify a subset of patients whose tumors are "addicted" to EGFR signaling have not been successful (86,87). One intriguing possibility is that production of EGFR activating ligands by tumor cells or tumor-associated stroma may increase sensitivity to EGFR inhibitors in HNSCC (114).…”

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

“…Although anti-EGFR agents such as cetuximab and erlotinib are used in the treatment of HNSCC, responses to therapy are inconsistent, and the molecular determinants of response are still not well defined (22,46,47). Because PTPRS can directly regulate EGFR activity, we sought to determine whether PTPRS loss affects the sensitivity of cancer cells to EGFR inhibition.…”

Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum

“…This occurs through the amplification of EGFR or HER2 as seen in cancers of the breast, lung, stomach, endometrium, head & neck, or brain 28,30,38,44,50 , or through mutational activation of the extracellular domain of EGFR in gliomas 12 , or the kinase domain of EGFR in lung cancers 41 , or the kinase domain of HER2 in cancers of the lung or breast 8,43 . In many of these cancers, EGFR or HER2 are disease-driving oncogenes and agents that target them show considerable efficacy in the treatment of these cancers 4,18,31,45 .…”