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Abstract
There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and pharmacodynamic biomarkers of efficacy of afatinib, a pan-HER tyrosine kinase inhibitor, in a window-of-opportunity trial (NCT01415674). Multi-omics analyses were carried out on pre-treatment biopsy and surgical specimen for biological assessment of afatinib activity. Sixty-one treatment-naïve and operable HNSCC patients were randomised to afatinib 40 mg/day for 21–28 days versus no treatment. Afatinib produced a high rate of metabolic response. Responders had a higher expression of pERK1/2 (P = 0.02) and lower expressions of pHER4 (P = 0.03) and pRB1 (P = 0.002) in pre-treatment biopsy compared to non-responders. At the cellular level, responders displayed an enrichment of tumor-infiltrating B cells under afatinib (P = 0.02). At the molecular level, NF-kappa B signaling was over-represented among upregulated genes in non-responders (P < 0.001; FDR = 0.01). Although exploratory, phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy.
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1 Institut Curie, Department of Drug Development and Innovation (D3i), Paris, France (GRID:grid.418596.7) (ISNI:0000 0004 0639 6384)
2 Gustave Roussy, Department of Head and Neck Surgery, Villejuif, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388)
3 Gustave Roussy, Head and Neck Oncology Department, Villejuif, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388)
4 Centre Claudius Régaud, Department of Medical Oncology, Toulouse, France (GRID:grid.417829.1) (ISNI:0000 0000 9680 0846)
5 Institut Curie, Department of Head and Neck Surgery, Paris, France (GRID:grid.418596.7) (ISNI:0000 0004 0639 6384)
6 Institut de Cancérologie de Lorraine, Department of Head and Neck Surgery, Nancy, France (GRID:grid.452436.2) (ISNI:0000 0000 8775 4825)
7 Centre Hospitalier Universitaire, Department of Head and Neck Surgery, Nantes, France (GRID:grid.277151.7) (ISNI:0000 0004 0472 0371)
8 Centre Léon Bérard, Department of Medical Oncology, Lyon, France (GRID:grid.418116.b) (ISNI:0000 0001 0200 3174)
9 Centre Paul Papin, Department of Medical Oncology, Angers, France (GRID:grid.418191.4) (ISNI:0000 0000 9437 3027)
10 Institut Claudius Regaud, Department of Head and Neck Surgery, Toulouse, France (GRID:grid.417829.1) (ISNI:0000 0000 9680 0846)
11 Institut de Cancérologie de Lorraine, Department of Medical Oncology, Nancy, France (GRID:grid.452436.2) (ISNI:0000 0000 8775 4825)
12 Centre René Gauducheau, Department of Medical Oncology, Nantes, France (GRID:grid.418191.4) (ISNI:0000 0000 9437 3027)
13 Centre Léon Bérard, Department of Head and Neck Surgery, Lyon, France (GRID:grid.418116.b) (ISNI:0000 0001 0200 3174)
14 Centre Hospitalier Universitaire, Department of Head and Neck Surgery, Angers, France (GRID:grid.411147.6) (ISNI:0000 0004 0472 0283)
15 Centre Antoine Lacassagne, Department of Medical Oncology, Nice, France (GRID:grid.417812.9) (ISNI:0000 0004 0639 1794)
16 Centre François Baclesse, Department of Nuclear Medicine, Caen, France (GRID:grid.476192.f) (ISNI:0000 0001 2106 7843)
17 UNICANCER, Paris, France (GRID:grid.418189.d) (ISNI:0000 0001 2175 1768)
18 Institut Curie, Department of Pathology, Paris, France (GRID:grid.418596.7) (ISNI:0000 0004 0639 6384)
19 Institut Curie, Bioinformatics Core Facility, INSERM U900, Mines Paris Tech, Paris, France (GRID:grid.418596.7) (ISNI:0000 0004 0639 6384)
20 Institut Curie, Genetics Department, Paris, France (GRID:grid.418596.7) (ISNI:0000 0004 0639 6384)
21 PSL Research University, Department of Translational Research, Institut Curie, Paris, France (GRID:grid.440907.e) (ISNI:0000 0004 1784 3645)
22 Centre Antoine Lacassagne, Department of Biostatistics, Nice, France (GRID:grid.417812.9) (ISNI:0000 0004 0639 1794)
23 Institut Curie, Department of Drug Development and Innovation (D3i), Paris, France (GRID:grid.418596.7) (ISNI:0000 0004 0639 6384); Paris-Saclay University, INSERM U900, Institut Curie, Paris, France (GRID:grid.460789.4) (ISNI:0000 0004 4910 6535)