Liquid biopsy monitoring uncovers acquired RAS-mediated resistance to cetuximab in a substantial proportion of patients with head and neck squamous cell carcinoma.
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.
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.
Friederike
F
Braig
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.
Minna
M
Voigtlaender
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.
Aneta
A
Schieferdecker
Department of Otorhinolaryngology, Head and Neck Cancer Center of The University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany.
Chia-Jung
CJ
Busch
Department of Otorhinolaryngology, Head and Neck Cancer Center of The University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany.|Department of Otorhinolaryngology and Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany.
Simon
S
Laban
Department of Pathology, University Medical Center Hamburg, Hamburg, Germany.
Tobias
T
Grob
Laboratory for Radiobiology and Experimental Radiooncology, Head and Neck Cancer Center of The University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany.
Malte
M
Kriegs
Department of Otorhinolaryngology, Head and Neck Cancer Center of The University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany.
Rainald
R
Knecht
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.
Carsten
C
Bokemeyer
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.
Mascha
M
Binder
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage; D020558:GTP Phosphohydrolases / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D000073890:Liquid Biopsy / Q000379:methods*; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation / Q000187:drug effects; D010984:Platinum / Q000008:administration & dosage; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D008565:Membrane Proteins; D010984:Platinum; C512478:EGFR protein, human; D066246:ErbB Receptors; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D005472:Fluorouracil
RAS; cetuximab; epidermal growth factor receptor (EGFR); head and neck squamous cell carcinoma (HNSCC); resistance