title: DNA repair pathways to regulate response to chemoradiotherapy in patients with locally advanced head and neck cancer.
abstract: Platinum-based chemoradiotherapy (CRT) is a preferred standard of care for locally advanced head and neck cancer (HNC). However, survival benefit is small, with substantial toxicity and biomarkers of CRT resistance that could guide treatment selection and spare morbidity. Increased DNA repair in solid tumors may contribute to cancer cells' ability to survive in genotoxic stress environments afforded by therapy. We assessed mRNA expression levels of DNA repair-related genes BRCA1, RAP80, 53 binding protein 1 (53BP1), mediator of DNA damage checkpoint 1 (MDC1), and RNF8. We correlated our findings with response and overall survival in 72 head and neck patients treated with weekly carboplatin AUC 2 and radiotherapy. Complete response (CR) to CRT was 50 % in patients with low levels of 53BP1 compared to 6.3 % in patients with high levels (p = 0.0059). Of high BRCA1 mRNA expressors, 41.2 % had CR compared to 29.4 % of low expressors (p = 0.72). For a small group of patients with low 53BP1 and either high BRCA1 or RAP80, CRs were 66.7 and 71.4 %, respectively. A trend for better overall survival (OS) was found for patients with low 53BP1 (15 vs 8 m; p = 0.056). Our findings highlight the potential usefulness of 53BP1 mRNA as a predictive biomarker of response and overall survival in HNC patients treated with chemoradiotherapy. Those with high 53BP1 expression could derive only a meager benefit from treatment. Analysis of BRCA1 and RAP80 could further reinforce the predictive value of 53BP1. Although this was a retrospective study with small sample size, it could inform larger translational studies in HNC.
authors.affiliation: Medical Oncology, Institut Català d'Oncologia Badalona-HU Germans Trias i Pujol, Autonomous University of Barcelona, Badalona, Barcelona, Spain. bcirauqui@iconcologia.net.
authors.forename: B
authors.initials: B
authors.lastname: Cirauqui
authors.affiliation: Medical Oncology, Institut Català d'Oncologia Badalona-HU Germans Trias i Pujol, Autonomous University of Barcelona, Badalona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Margelí
authors.affiliation: Medical Oncology, Institut Català d'Oncologia Badalona-HU Germans Trias i Pujol, Autonomous University of Barcelona, Badalona, Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Quiroga
authors.affiliation: Pathological Anatomy, HU Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Quer
authors.affiliation: Quirón Dexeus University Institute, Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Karachaliou
authors.affiliation: Laboratory of Molecular Biology, Institut Català d'Oncologia Badalona, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Chaib
authors.affiliation: Laboratory of Molecular Biology, Institut Català d'Oncologia Badalona, Barcelona, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Ramírez
authors.affiliation: Pathological Anatomy, HU Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Muñoz
authors.affiliation: Otolaryngology, HU Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Pollán
authors.affiliation: Radiation Oncology, Institut Català d'Oncologia Badalona-HU Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Planas
authors.affiliation: Pivotal, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Drozdowsky
authors.affiliation: Quirón Dexeus University Institute, Barcelona, Spain.|Laboratory of Molecular Biology, Institut Català d'Oncologia Badalona, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Rosell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D018797:Cell Cycle Proteins; D059248:Chemoradiotherapy; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D015996:Survival Rate; D015534:Trans-Activators / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; C486521:RNF8 protein, human; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases; D045643:DNA Repair Enzymes
keywords: 53BP1; BRCA1; Chemoradiotherapy; DNA-repair; Head and neck cancer; RAP80