TRIAL IN RARE SARCOMAS REMAIN DIFFICULT OR NON FEASIBLE

Sarcomas are altogether rare cancers, with an overall incidence of 6/100.000/year, including more than 50 subtypes, and over 150 molecular subtypes. Thus, the incidence of individual rare sarcomas subtypes is often less than 0.5/100.0000/year, thus making the accrual of patients in specific trials very difficult even for cooperative groups or large constituted networks to accrue sufficient numbers of patients in specific clinical trials.Apart from the 10 most frequent histological subtypes (GIST, Leiomyosarcomas, Liposarcomas, synovial sarcomas, Rabdhomyosarcomas, Osteosarcomas, Ewing sarcomas, angiosarcomas, DFSP), no prospective clinical trials testing systemic treatments has ever been performed because of difficulties in trial accrual.This occurs while the clinical research in sarcoma is well organized worldwide, with national sarcoma groups in most large EU countries, working in close collaboration with the international EORTC soft tissue and bone sarcoma group, and sometimes with US and Canadian groups.

This is why a more global and more systematic intergroup approach is needed in rare sarcomas.

A STRONG NETWORKS TO TAKE THE LEADERSHIP IN ORGANIZING THE RESEARCH IN THIS FIELD WORLDWIDE

In addition, the efficacy, and feasibility of these trials can be increased when their rationale is based on solid preclinical biological mechanisms, such as in the cases of imatinib and sunitinib for GIST and DFSP. However, these are still unusual examples, in two subtypes of tumors that represent relatively frequent sarcomas.

Today, there is an urgent need to improve the level of collaboration between research groups to enable the feasibility of clinical trials in rare subtypes of sarcomas:

• The 10-15 largest sites and networks worldwide could be associated within single clinical trials
• Trials would be designed for the testing of specifically targeted agents, in given molecular subtypes

Sarcomas are favourable models for targeted oncogene therapies

Sarcomas have been found to be very good models for the development of novel agents targeting specific molecular alterations, since several primary genetic alterations driving the tumour were identified in a relatively large proportion of sarcoma subsets:

• Sarcomas with specific translocations (15% of sarcomas)
• Sarcoma with activation mutations of tyrosine kinase receptors (GIST, 20% of sarcomas)
• Sarcomas with inactivation of specific tumour suppressor genes (NF1 in MPNST, INI1 in rhabdoid tumours, 5-7% of sarcomas)
• Sarcomas -liposarcomas- with amplification of MDM2 and CDK4, along with additional amplifications of Jun, or Ask1 in well differentiated dedifferentiated liposarcomas (15-20%)

This molecular characterisation is now used in routine clinical settings for diagnosis purpose in sarcoma reference centers. Molecular characterization is also used to identify mutated activated targets to guide targeted oncogene treatments such as imatinib for GIST, or DFSP. Sarcomas are therefore very good models for the development of rationally based targeted oncogene therapies, but the limitations often lies in the rarity of these diseases that complicates the feasibility of clinical trials.

A NEED FOR GLOBAL COOPERATION

Given these specificities, a wide and global cooperation among the main sarcoma reference centres around the World – driving a global network worldwide – will be extremely useful to develop novel research strategies, on the example of what has been achieved with extremely rare infant leukaemia recently.

In this perspective, the “World Sarcoma Network” (WSN) is aiming at facilitating collaboration between the different sarcoma research groups on a global scale.