Functional Genomics Uncover the Biology behind the Responsiveness of Head and Neck Squamous Cell Cancer Patients to Cetuximab

Abstract

Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent-metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median ¼ 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long-and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long-versus short-PFS patients (P range: <0.0022-1eÀ07).Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection.

Basal subtype is predictive for response to cetuximab treatment in patient-derived xenografts of squamous cell head and neck cancer

“…Bossi et al . recently showed that patients with a long progression‐free survival under cetuximab maintenance therapy can be predominantly found in the basal subtype group . This is very much in line with our findings and supports the notion of prospective evaluation of gene expression profiles in regard to patient stratification.…”

MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer

“…6,7 EGFR triggers multiple downstream signaling pathways linked to cell survival and proliferation, such as the STAT, SRC, PI3K and MAPK pathways [reviewed in Refs. [19][20][21][22] An additional common resistance mechanism to cetuximab is reactivation of signaling pathways due to upregulation and activation of alternative RTKs, which termed as a compensatory activation loop [reviewed in Ref. [3][4][5][12][13][14] Cetuximab inhibits tumor cell growth by preventing ligand binding to the extracellular domain of EGFR, thereby preventing the dimerization and auto-phosphorylation of this receptor and the subsequent activation of the signaling pathways downstream of EGFR.…”

Heads Up! Predictive Gene Signatures in Head and Neck Cancer May Be Coming Soon

“…In this issue of Clinical Cancer Research, Bossi and colleagues (1) report that pretreatment tumor gene expression profiles (GEP) of recurrent/metastatic head and neck squamous cell carcinomas (HNSCC) from patients who experience prolonged response [median progression-free-survival (PFS) of 19 months] to treatment with palliative cetuximab-chemotherapy are characterized by basal subtype traits, and significantly differ from GEP of patients with short responses, thus highlighting the potential opportunity for the future development of a predictive gene signature to select HNSCC patients for cetuximab-chemotherapy. Cetuximab, a chimeric immunoglobulin G1 antibody to the Epidermal Growth Factor Receptor (EGFR) is the only "molecularly targeted" therapy in HNSCC.…”