Oncotarget

Research Papers:

Liquid biopsy monitoring uncovers acquired RAS-mediated resistance to cetuximab in a substantial proportion of patients with head and neck squamous cell carcinoma

Friederike Braig, Minna Voigtlaender, Aneta Schieferdecker, Chia-Jung Busch, Simon Laban, Tobias Grob, Malte Kriegs, Rainald Knecht, Carsten Bokemeyer and Mascha Binder _

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Oncotarget. 2016; 7:42988-42995. https://doi.org/10.18632/oncotarget.8943

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Abstract

Friederike Braig1,*, Minna Voigtlaender1,*, Aneta Schieferdecker1, Chia-Jung Busch2, Simon Laban2,3, Tobias Grob4, Malte Kriegs5, Rainald Knecht2, Carsten Bokemeyer1 and Mascha Binder1

1 Department of Oncology and Hematology with Sections Bone Marrow Transplant and Pneumology, Hubertus Wald Tumorzentrum / University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany

2 Department of Otorhinolaryngology, Head and Neck Cancer Center of The University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany

3 Department of Otorhinolaryngology and Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany

4 Department of Pathology, University Medical Center Hamburg, Hamburg, Germany

5 Laboratory for Radiobiology and Experimental Radiooncology, Head and Neck Cancer Center of The University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany

* These authors have contributed equally to this work

Correspondence to:

Mascha Binder, email:

Keywords: head and neck squamous cell carcinoma (HNSCC), epidermal growth factor receptor (EGFR), RAS, resistance, cetuximab

Received: March 25, 2016 Accepted: March 29, 2016 Published: April 22, 2016

Abstract

Resistance to epidermal growth factor receptor (EGFR)-targeted therapy is insufficiently understood in head and neck squamous cell carcinoma (HNSCC), entailing the lack of predictive biomarkers.

Here, we studied resistance-mediating EGFR ectodomain and activating RAS mutations by next-generation sequencing (NGS) of cell lines and tumor tissue of cetuximab-naïve patients (46 cases, 12 cell lines), as well as liquid biopsies taken during and after cetuximab/platinum/5-fluorouracil treatment (20 cases). Tumors of cetuximab-naïve patients were unmutated, except for HRAS mutations in 4.3% of patients. Liquid biopsies revealed acquired KRAS, NRAS or HRAS mutations in more than one third of patients after cetuximab exposure. 46% of patients with on-treatment disease progression showed acquired RAS mutations, while no RAS mutations were found in the non-progressive subset of patients, indicating that acquisition of RAS mutant clones correlated significantly with clinical resistance (Chi square p=0.032). The emergence of mutations preceded clinical progression in half of the patients, with a maximum time from mutation detection to clinical progression of 16 weeks.

RAS mutations account for acquired resistance to EGFR-targeting in a substantial proportion of HNSCC patients, even though these tumors are rarely mutated at baseline. Liquid biopsies may be used for mutational monitoring to guide treatment decisions.


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