TP53 Mutations and Outcome in Osteosarcoma: A Prospective, Multicenter Study Jay S. Wunder, Nalan Gokgoz, Robert Parkes, Shelley B. Bull, Sasha Eskandarian, Aileen M. Davis, Chris P. Beauchamp, Ernest U. Conrad, Robert J. Grimer, John H. Healey, David Malkin, D.C. Mangham, Michael J. Rock, Robert S. Bell, and Irene L. Andrulis A B S T R A C T Purpose Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma. Patients and Methods One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoad- juvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. Results Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P  .10). In multivariate analysis, large ( 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response ( 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. Conclusion We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemo- therapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes. J Clin Oncol 23:1483-1490. © 2005 by American Society of Clinical Oncology INTRODUCTION Recent advances in the treatment of osteo- sarcoma have led to significant improve- ments in patient outcome. Because of better radiographic imaging combined with the benefits of preoperative chemotherapy, few patients require amputation. 1-3 Introduc- tion of intensive multiagent chemotherapy has also contributed to major improvements in patient survival. Long-term cure rates for patients with high-grade osteosarcoma pre- senting without metastases have been reported at between 50% and 75%. 4-7 However, 25% to 50% of patients will relapse, and only a minor- ity of these will be salvaged. One of the major difficulties in treating patients with osteosarcoma is the lack of From the Samuel Lunenfeld Research Institute, and the University Musculo- skeletal Oncology Unit, Mount Sinai Hospital; Departments of Surgery, Public Health Sciences, Medical Genetics and Microbiology, Pathology and Laboratory Medicine, University of Toronto; Division of Hematology- Oncology, Hospital for Sick Children, Toronto, Ontario; University of British Columbia, Vancouver, British Columbia, Canada; University of Washington Medical Center, Seattle, WA; Royal Orthopaedic Hospital, Birmingham, England; Memorial Sloan-Kettering Cancer Center, NY, New York; and Mayo Clinic, Rochester, MN. Submitted April 8, 2003; accepted November 29, 2004. Supported by grants from the National Cancer Institute of Canada and Cana- dian Institutes of Health Research (J.S.W., A.M.D., D.M., R.S.B., I.L.A.). J.S.W. and N.G. contributed equally to this work. Authors’ disclosures of potential con- flicts of interest are found at the end of this article. Address reprint requests to Jay S. Wunder, MD, 476E-600 University Ave, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5; e-mail: wunder@mshri.on.ca. © 2005 by American Society of Clinical Oncology 0732-183X/05/2307-1483/$20.00 DOI: 10.1200/JCO.2005.04.074 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 23  NUMBER 7  MARCH 1 2005 1483 Downloaded from ascopubs.org by 34.239.169.225 on June 16, 2022 from 034.239.169.225 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.