Expression and prognostic significance of PDGF ligands (A, B, C, and D) and PDGFR (A, B, and L) in soft-tissue sarcomas and GIST.

Abstract

11067 Background: Sarcomas are a variety of rare connective tissue cancers. Doxorubicin and olaratumab (Ab against PDGFRA) improved survival in a recent Phase 1/2 study. Besides PDGFRA mutated gastrointestinal stroma tumor (GIST) and dermatofibrosarcoma protuberans, the role of PDGFR and the according ligands in the biology of sarcoma remain unclear. Methods: The expression levels of PDGF (A,B,C,D) and PDGFRs (A,B,L) were studied in a series of 255 sarcoma pts in localized phase using the Agilent 014850 platform. Data are available online (http://atg-sarc.sarcomabcb.org). Histologies were GIST (n = 60), myxoid liposarcoma (MLPS, n = 50), synovial sarcoma (SyS, n = 58), and sarcoma with complex genomics (SCG, n = 87). Expression levels were analyzed and tested for prognostic values for metastasis free survival (MFS) in uni- and multivariate analysis using SPSS 19.0. Results: Expression levels (ELs) of PDGFs and PDGFRs varied across histotypes: PDGFA levels were highest in SyS and lowest in MLPS (p < 0.0001). PDGFB and C levels were lower in GIST (p < 0.0001), while PDGFD ELs were similar across histological subtypes. PDGFRA ELs were highest in MLPS, while PDGFRB & L ELs were lowest in GIST and SyS (p < 0.0001 all). Complex patterns of correlation of expression between ligands and receptors were observed in each individual subtypes. PDGFA ELs above median were associated with a marginally higher risk of metastasis . Conversely, PDGFD ELs above median was associated with a reduced risk of metastasis in the whole cohort (p = 0.02). The ELs of the 3 receptors were not correlated to MFS. In multivariate analysis using Cox model on the non-GIST sarcoma cohort (histology, grade, depth, with size, PDGFA, PDGFD as continuous variables): histology, size, grade and PDGFA ELs were independent adverse prognostic factors (PF), while PDGFD ELs was a favorable PF for MFS. In the GIST cohort, testing AFIP score, PDGFA & D ELs as continuous variable, PDGFD ELs was also an independent favorable PF for MFS, in addition to AFIP score. Conclusions: The expression of PDGFs and the according receptors varies across sarcoma histological subtypes. PDGFA and D expression levels correlate independently to the risk of metastatic relapse.