Abstract
Despite the recent progress, non-metastatic pediatric osteosarcomas have now a 5-year overall survival (OS) around 75% and the metastatic forms are decreasing to 20–30%. To increase these survival rates, new molecular approaches are on development to understand and highlight new candidates for targeted therapies. Tyrosine kinase receptors (TKR) are one of this target class, where new drugs were especially developped, screening now a large spectrum of TKR. After the demonstration among cancers of TKR’s clinical utility as surrogate markers to guide the selection of patients susceptible to respond to these treatments, this success was recently tempered in part because of cancers developping resistance mechanisms to these drugs. A study was conducted to evaluate the interest of these molecular targets among pediatric osteosarcomas.
Materiel and methods: 91 pediatric patients treated homogeneously with the French OS94 protocol were included in this analysis. Allelotyping, real-time quantitative PCR (QPCR), sequencing and immunhistochemistry were performed to analyse the following targets: EGFR, MET, PDGFRA, KIT and ERBB2.
Results and discussion: Most of these targets were rearranged in more than 45% of the population and mainly deleted. Only 11.4% were amplified at MET and 8.6% at PDGFRA. By QPCR, ERBB2 was normal in 78 out of 81 informative patients. Surprinsingly, wild-type KIT protein was amplified in 37%. EGFR was rearranged by allelotyping in 48% and QPCR evaluation just started. MET amplified subgroup is linked to a worst OS than normal and deleted subgroups (p=0.04) whereas PDGFRA amplified tumors tend to be significantly linked to a better patient OS (p=0.08). Considering all amplified subgroups, no ovelap was found as if an osteosarcoma could only be amplified for one gene. This observation could be considered as a way to increase the potential targeted populations where the use of large spectrum TKR inhibitors would be useful in osteosarcoma treatment.
Correspondence should be addressed to Professor Stefan Bielack, Olgahospital, Klinikum Stuttgart, Bismarkstrasse 8, D-70176 Stuttgart, Germany. Email: s.bielack@klinikum_stuttgart.de
