83IN - Evolving biology of sarcoma

Date 29 September 2014
Event ESMO 2014
Session Controversies in the neo-adjuvant treatment of localised soft tissue sarcomas (STS)
Topics Soft Tissue Sarcomas
Pathology/Molecular Biology
Basic Scientific Principles
Presenter Jean-Yves Blay
Citation Annals of Oncology (2014) 25 (suppl_4): iv31-iv32. 10.1093/annonc/mdu309
Authors J. Blay
  • University Claude Bernard Lyon I, Centre Léon Bérard, 69008 - Lyon CEDEX/FR




The biology of soft tissue sarcomas and locally aggressive connective tissue tumors evolves rapidly. At least seven molecular subgroups of connective tissue tumors may be distinguished: 1) sarcoma with specific translocations generating fusion transcription factors or growth factors; 2) sarcomas with mutated activated kinases (KIT in GIST); 3) sarcomas with deletion of tumor suppressor genes such as NF1 sarcomas; 4) Sarcomas with simple genetic alterations (MDM2/CDK4 gene amplification in WD/DD liposarcomas;); 5) Tumors with alterations of the intercellular adhesion pathways (aggressive fibromatosis with APC deletion or beta catenin mutations); 6) tumors with histone protein mutations such as giant cell tumor of the bone; 5) Finally, sarcomas with gross genetic alterations (e.g. leiomyosarcomas, UPS) represent a mixed bag for which the CINSARC expression profile distinguishes subgroups with very different prognosis This biological classification is therefore rapidly evolving and guides in real time the development of novel treatment. The identification of the “driver” mutation paved the way for the selection of efficient targeted therapies, following the paradigm of KIT and PDGFRA kinase mutations in GIST. Other examples are currently identified, in DFSP, a PDGF driven tumor and in PVNS, an M-CSF driven tumor. For this later group, 2 novel MCSFR inhibitors have been shown to have an outstanding clinical activity in phase I in ASC O 2014. This concept has therefore been fruitful, but now shows limitations, as observed with IGF1R Ab, or may be associated with a less dramatic activity in some pathways such as MDM2 inhibitors or CDK4 inhibitors. In addition, tumor heterogeneity, in the primary tumor, in the metastases, and following exposure to a TKI are now frequently observed, calling for innovative strategies to overcome this common phenomenon. During this presentation, we will review how the understanding of the driver molecular alterations of these tumors paved the way for the development of targeted treatment inhibiting driver mutations, and discuss the next steps to be explored.


JY Blay: Research support and honoraria from Novartis, Roche, Bayer, Pharmamar and GSK.