title: Development of a hypoxia gene expression classifier with predictive impact for hypoxic modification of radiotherapy in head and neck cancer.
abstract: Hypoxia, a common feature of the microenvironment in solid tumors, is associated with resistance to radiotherapy, reduced therapeutic response, and a poorer clinical outcome. In head and neck squamous cell carcinomas (HNSCC), the negative effect of hypoxia on radiotherapy can be counteracted via addition of hypoxic modification to the radiotherapy. To predict which patients harbor hypoxic tumors and would therefore benefit from hypoxic modification, clinically applicable methods for pretherapeutic hypoxic evaluation and categorization are needed. In this study, we developed a hypoxia classifier based on gene expression. Through study of xenograft tumors from human squamous cell carcinoma cell lines, we verified the in vivo relevance of previously identified in vitro derived hypoxia-induced genes. We then evaluated a training set of 58 hypoxia-evaluated HNSCCs to generate a gene expression classifier containing 15 genes. This 15-gene hypoxia classifier was validated in 323 patients with HNSCC randomized for hypoxic modification or placebo in combination with radiotherapy. Tumors categorized as hypoxic on the basis of the classifier were associated with a significantly poorer clinical outcome than nonhypoxic tumors. This outcome was improved and equalized to the nonhypoxic tumors by addition of hypoxic modification. Thus, findings show that the classifier attained both prognostic and predictive impact, and its pretherapeutic use may provide a method to identify those patients who will benefit from hypoxic modification of radiotherapy.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital and Bioinformatics Research Centre, Aarhus University, Aarhus C, Denmark. kasper@oncology.dk
authors.forename: Kasper
authors.initials: K
authors.lastname: Toustrup
authors.forename: Brita Singers
authors.initials: BS
authors.lastname: Sørensen
authors.forename: Marianne
authors.initials: M
authors.lastname: Nordsmark
authors.forename: Morten
authors.initials: M
authors.lastname: Busk
authors.forename: Carsten
authors.initials: C
authors.lastname: Wiuf
authors.forename: Jan
authors.initials: J
authors.lastname: Alsner
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018307:Neoplasms, Squamous Cell / Q000235:genetics* / Q000532:radiotherapy*; D011379:Prognosis; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays