3405 The role of pharmacogenetics in osteosarcoma

Abstract

Prof. dr. F.G.M. RusselThe research described in this thesis was financially supported by Stichting Kinderen Kankervrij (KiKa). 7 Contents CONTENTS Chapter 1 IntroductionChapter 2 Age as prognostic factor in patients with osteosarcoma Bone. 2011;49:1173-1177 Chapter 3 Survival trends and long term toxicity in pediatric patients with osteosarcoma Sarcoma. 2012;636405Chapter 4 Taqman genotyping assays can be used on decalcified and paraffin embedded tissue from patients with osteosarcomaPediatr Blood Cancer. 2011;56:35-38 Chapter 5 A pilot study: Genetic variants may influence methotrexate plasma concentrations in pediatric malignancies Chapter 6The role of the MTHFR 677C>T polymorphism in methotrexate -induced liver toxicity: a meta-analysis in patients with cancer J. 2014;14:115-119 Chapter 6B Is there a role for the MTHFR 677C>T and the 1298 A>C polymorphism methotrexate induced liver toxicity? . 2014;15:1401-1403 . Treatment with bisphosphonates such as pamidronate or zoledronic acid in addition to chemotherapy is only applied to a hand full of patients and the clinical benefit of these agents need to be studied in a prospective randomized trial 21,22 . As the incidence of osteosarcoma is between 3 and 4.5 cases per million, it will take several years to include a large number of patients in a prospective trial to study the efficacy of these new agents. Furthermore, the a priori knowledge of which patients will benefit from new agents will help to define new strategies in order to improve outcome and decrease the burden of late effects. We hypothesized that pharmacogenetics may help to stratify patient into good responders and bad responders. More insight in the genetic determinants involved in drug response may help in designing more effective therapeutic approaches, e.g. targeted cancer therapy for patients not responding on standard therapy ( Figure I). Pharmacogenomics Pharmacogenomics O s t e o s a r c o m aOsteosarcoma is the most common primary tumor of the bone, which may occur at all ages but is seen predominantly in adolescents. Nevertheless, it is still a rare disease with a worldwide incidence rate of 3-4 cases per million per year 1 . Untreated, osteosarcoma is fatal. Aggressive local growth and the tendency to metastasize mark its course. In the 1970s when surgery was the only treatment option, the prognosis for patients with osteosarcoma was poor, with long-term survival rates of less than 20% 2 . Today, therapy is changed to a multi-disciplinary approach, focusing on both local and systemic manifestations of osteosarcoma, incorporating surgery and chemotherapy. The use of this multi-disciplinary approach has resulted in survival rates of 60-65% since the late 1980s Drug related phenotypeThe candidate gene approach is a hypothesis driven method that investigates genetic variants in genes known to be associated with the trait of interest e.g. metabolism of the used medication. However, replication studies often show inconsistent results making it difficult to interpret the clinical v...