Chemotherapy in localized soft tissue sarcoma: will we soon have to treat grade 1 tumors? Update on CINSARC performances
Authors: T. Valentin, T. Lesluyes, S. Le Guellec, F. Chibon
Journal: Annals of Oncology (2018)

The debate concerning perioperative chemotherapy use in localized soft tissue sarcoma (STS) is mired in a dead-end, following the results of a dozen of randomized studies completed by two meta-analyses. In the current guidelines [1.Casali P.G. Abecassis N. Bauer S. et al.Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: iv51-iv67Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar], chemotherapy is not yet considered as a standard of care and may be proposed as an option in high-risk patients, currently imperfectly identified with classical factors as tumor size, depth and (Fédération Française des Centres de Lutte Contre le Cancer) FNCLCC grade [2.Coindre J.M. Terrier P. Bui N.B. Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group.J Clin Oncol. 1996; 14: 869-877Crossref PubMed Scopus (523) Google Scholar]. This uncertainty may reflect the limits of these factors (in particular FNCLCC grade) for the precise identification of the high-risk patients' population. When developed in 2010, CINSARC transcriptomic signature clearly appeared to be a promising way to overcome these limitations, as a tool able to identify high-risk STS patients independently of classical prognostic factors, in particular FNCLCC grade [3.Chibon F. Lagarde P. Salas S. et al.Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity.Nat Med. 2010; 16: 781-787Crossref PubMed Scopus (323) Google Scholar]. Initially incompatible with routine use (performed on frozen tumors analyzed by microarrays), CINSARC has been optimized [4.Lesluyes T. Pérot G. Largeau M.R. et al.RNA sequencing validation of the Complexity INdex in SARComas prognostic signature.Eur J Cancer. 2016; 57: 104-111Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 5.Le Guellec S. Lesluyes T. Sarot E. et al.Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed, paraffin-embedded, soft tissue sarcomas.Ann Oncol. 2018; 29: 1828-1835Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar] is now fully evaluable with FFPE tumors using NanoString technology (NanoCind®, patent number ≪EP18305190.3≫) [5.Le Guellec S. Lesluyes T. Sarot E. et al.Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed, paraffin-embedded, soft tissue sarcomas.Ann Oncol. 2018; 29: 1828-1835Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. This reproducible, low-cost array only needs small inputs of RNA, making perfectly feasible in core needle biopsies samples, gold standard for STS diagnosis. Following its technical optimization, CINSARC performances showed a remarkable constancy over successive works. Since its first development, CINSARC signature has indeed been applied to more than 600 STS samples, including 367 samples from the three pivotal studies, 195 samples from TCGA program, and a series of 44 synovial sarcoma samples. The pooled results of these analyses confirm that CINSARC perfectly splits STS patients into two separate prognostic groups (in term of Metastasis Free Survival) more accurately than FNCLCC grade [HR 2.7 (1.98; 3.69) versus 2.29 (1.17; 5.5)] (Figure 1). More interesting, this meta-analysis allows to demonstrate that CINSARC identifies, in each FNCLCC grade, a subgroup of high-risk patients. This feature has already been proposed as a way to overcome the classical limitation of FNCLCC grade in grade 2 patients. However, this meta-analysis reveals that CINSARC also identifies in patients with grade 1 STS, typically considered as low-risk patients, high-risk patients carrying poor prognosis. As many expert teams consider that high-risk STS patients are likely those supposed to take benefit from perioperative chemotherapy, we foresee CINSARC, able to identify them more accurately than the current histological evaluation, to be the key of this 'never-ending story'. Now applicable in routine settings, the next step is to evaluate the efficacy of perioperative chemotherapy in CINSARC high-risk STS patients. Several clinical trials based on CINSARC are about to begin with the French Sarcoma Group. Currently, chemotherapy is only offered as an option to patient with large, grade 3 STS! In the near-future, will chemotherapy be given as a standard treatment to patient with grade 1, CINSARC high-risk STS? Unthinkable nowadays, isn't it? None declared.