ERCC1 is a prognostic biomarker in locally advanced head and neck cancer: results from a randomised, phase II trial.
BACKGROUND
Cisplatin-radiotherapy is a preferred standard for locally advanced, head and neck squamous cell carcinoma (HNSCC). However, the cisplatin-attributable survival benefit is small and toxicity substantial. A biomarker of cisplatin resistance could guide treatment selection and spare morbidity. The ERCC1-XPF nuclease is critical to DNA repair pathways resolving cisplatin-induced lesions.


METHODS
In a phase II trial, patients with untreated Stage III-IVb HNSCC were randomised to cisplatin-radiotherapy with/without erlotinib. Archived primary tumours were available from 90 of 204 patients for this planned substudy. Semi-quantitative ERCC1 protein expression (H-score) was determined using the FL297, 4F9, and 8F1 antibodies. The primary analysis evaluated the relationship between continuous ERCC1 protein expression and progression-free survival (PFS). Secondary analyses included two pre-specified ERCC1 cutpoints and performance in HPV-associated disease.


RESULTS
Higher ERCC1 expression was associated with inferior PFS, as measured by the specific antibodies FL297 (HR=2.5, 95% CI=1.1-5.9, P=0.03) and 4F9 (HR=3.0, 95% CI=1.2-7.8, P=0.02). Patients with increased vs decreased/normal ERCC1 expression experienced inferior PFS (HR=4.8 for FL297, P=0.003; HR=5.5 for 4F9, P=0.007). This threshold remained prognostic in HPV-associated disease.


CONCLUSIONS
ERCC1-XPF protein expression by the specific FL297 and 4F9 antibodies is prognostic in patients undergoing definitive cisplatin-radiotherapy for HNSCC, irrespective of HPV status.
Departments of Medicine, Biostatistics and Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
J E
JE
Bauman
M C
MC
Austin
R
R
Schmidt
B F
BF
Kurland
A
A
Vaezi
D N
DN
Hayes
E
E
Mendez
U
U
Parvathaneni
X
X
Chai
S
S
Sampath
R G
RG
Martins
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D000918:Antibody Specificity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000096:biosynthesis*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy / Q000628:therapy*; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D004720:Endonucleases / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D011799:Quinazolines; C095888:xeroderma pigmentosum group F protein; D000069347:Erlotinib Hydrochloride; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin