Abstract 4499: Loss of ATM (distal chromosome 11q) as a prognostic marker in HPV-negative head and neck squamous cell carcinomas

Abstract

Abstract Introduction: HPV-negative head and neck squamous cell carcinomas (HNSCC) represent a subset of head and neck cancers with poor response to treatment and worse prognosis compared to HPV-positive HNSCC. In our prior pre-clinical experiments with HNSCC cell lines, we demonstrated that copy number loss of ATM as a marker for loss of distal chromosome 11q loss leads to defectiveγ-H2AX focus formation, increased chromosomal instability, and reduced sensitivity to ionizing radiation. We hypothesize that in HPV-negative HNSCC, ATM loss is a biomarker for poor outcome. Methods: We performed a single center, retrospective analysis of 42 HNSCC patients to determine if ATM loss is associated with poor overall survival in HPV-negative HNSCC. We performed fluorescence in situ hybridization using probes to cyclin D1 (CCND1) and ATM to assess copy number changes in paraffin sections from HNSCC tumors. Disease-specific survival was defined as time from the date of tissue procurement (surgery or biopsy) until death from disease (HNSCC). Patients who were alive at last follow-up or had died from causes unrelated to their disease were censored. Disease-specific survival by ATM loss status was estimated by the Kaplan-Meier method and tested for a difference by a two-tailed log rank test. Three covariates, age, T stage and N stage were investigated and the effect of ATM loss upon disease-specific survival was assessed with proportional hazards regression by adjusting for these covariates as needed to determine if ATM loss could be considered independently associated with cancer mortality. Results and Conclusions: HPV-negative HNSCC patients with ATM copy number loss have a median disease-specific survival of only 19 months compared to 65 months for patients without ATM loss (log rank p = .0401). We investigated whether the association between ATM loss and disease-specific survival was due to the confounding influence of other clinical variables. Age and T stage were modestly associated with survival, but neither covariate was correlated with ATM loss. We estimated the hazard ratio for ATM loss alone and conditional upon age and T stage was unchanged (.040 alone vs .047 adjusting for age and T stage). Therefore, distal 11q loss, marked by copy number loss of ATM appears to increase the risk of disease-specific mortality independently of age, N stage and T stage. Our results demonstrate that ATM loss in HPV-negative HNSCC may be prognostic of poor outcome and novel therapeutic strategies may be required in this subset of patients. Further studies to elucidate the mechanisms of distal 11q loss and study potential treatment options are underway in our laboratory. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4499. doi:1538-7445.AM2012-4499