Abstract 3545: ATM, TS and RRM1 protein expression in nasopharyngeal carcinomas (NPC) treated with curative intent.
Authors: Klimowicz Alexander C. , Jagdis Amanda , Phan Tien , Laskin Janessa J. , Lau Harold Y. , Siever Jodi E. , Petrillo Stephanie K. , Thomson Thomas A. , Rose M. Sarah , Magliocco Anthony M. , Hao Desirée 
Published: August 2014

Abstract
Background: Although NPC is a radiation and chemotherapy sensitive tumour, some patients still relapse with distant metastatic disease. Biomarkers are needed to help identify which patients are at higher risk of relapse and/or who will respond to therapy. Ataxia telangiectasia mutated (ATM) is a putative marker for radiation sensitivity while, thymidylate synthetase (TS), and ribonucleotide reductase subunit M1 (RRM1) levels have been associated with response to 5FU and gemcitabine, two chemotherapy agents often used in NPC. We characterized the protein expression of ATM, TS, and RRM1 in tumours from 146 patients with non-metastatic NPC treated at two Canadian institutions between Jan 2000-Dec 2007 and explored the relationship of each marker with clinical outcomes. Methods: Pre-treatment, formalin-fixed, paraffin-embedded NPC tumour specimens were assembled in a tissue microarray. ATM, TS and RRM1 protein expression were evaluated by quantitative fluorescence immunohistochemistry and with automated quantitative digital image analysis (AQUA) using the Y170, TS106 and 60073-2-Ig monoclonal antibodies respectively. Protein expression levels were assessed in tumour, tumour cytoplasm, tumour nuclear, and non-malignant tumour stroma compartments. The effect of protein expression levels on overall survival (OS) and disease-free survival (DFS) was examined using Cox regression. For all biomarkers, AQUA scores were analyzed in quartiles. Results: Patient characteristics were: mean age=52 years (SD=12.2; range 18 to 85), 67% male, 73% KPS ≥ 90%, WHO type 1/2/3=11%/28%/61%, stage III/IV=65%. Fifty-eight (40%) patients received platinum-based CRT; the remainder was treated with RT alone. With a median follow-up of 50 months (range 3 to 120), the 5 year survival rates were 71% (95% CI=62%-78%) for OS and 48% (95% CI=39%-57%) for DFS. After adjusting for KPS, stage, and WHO type, OS was worse for the group with tumour:stromal (T/S) ATM ratios in the top quartile versus those in the lowest quartile (p=0.049). OS was also worse for tumours with TS levels in the lowest quartile versus the top quartile (p=0.033). RRM1 was not associated with outcomes (p=0.748). There was no significant effect of any of the biomarkers on disease-free survival (ATM T/S p=0.708; TS p=0.978; RRM1 p=0.918). Conclusions: In our cohort of non-metastatic NPC patients, relative overexpression of ATM and low TS protein levels were associated with worse outcomes suggesting further investigation of these potential biomarkers is warranted.
Citation Format: Alexander C. Klimowicz, Amanda Jagdis, Tien Phan, Janessa J. Laskin, Harold Y. Lau, Jodi E. Siever, Stephanie K. Petrillo, Thomas A. Thomson, M. Sarah Rose, Anthony M. Magliocco, Desirée Hao. ATM, TS and RRM1 protein expression in nasopharyngeal carcinomas (NPC) treated with curative intent. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3545. doi:10.1158/1538-7445.AM2013-3545