Molecular Prognostication for Soft Tissue Sarcomas: Are We Ready Yet?

Since the discovery more than a decade ago of the EWS-FLI1 fusion gene resulting from the chromosomal translocation(11;22) in the Ewing’s sarcoma family of tumors, major advances in our understanding of the molecular biology of several sarcomas have taken place at an impressively fast pace. Following the example of hematologic malignancies, in which simple reciprocal chromosomal translocations are also common, the new molecular era is opening not only novel investigative pathways with the cloning of multiple fusion genes and the identification of gene expression signatures in sarcomas, but is also stimulating a desire to quickly translate these achievements into better patient care through either enhanced prognostication or identification of new therapeutic targets. At the same time that the appearance of molecular markers promises highly accurate predictive frameworks for sarcoma diagnosis, prognosis, and therapeutic tailoring, some of these data are also generating controversial and, not uncommonly, contradictory findings. The recent debate around the prognostic value of synovial sarcoma fusion genes is an example of many of the issues encountered in studies of molecular prognostic markers in cancer. Synovial sarcoma is an aggressive tumor of uncertain cellular differentiation that predominantly affects young adults; although having a wide anatomic distribution, it shows a predilection for the limbs. Cytogenetically, synovial sarcoma is characterized in almost all cases by the chromosomal translocation t(X;18)(p11;q11). This chromosomal rearrangement typically leads to fusion of the SYT gene on chromosome 18 with either the SSX1 or SSX2 genes on chromosome X. In a ground-breaking retrospective pilot study published in 1998, Kawai et al found that patients with localized tumors harboring SYT-SSX1 fusion transcripts had decreased metastasis-free survival. Similar results were later obtained in four other retrospective studies and were further supported by a large multicenter study involving more than 200 patients, published in 2002 by Ladanyi et al. In this issue of the Journal of Clinical Oncology, the same question has been readdressed in another multi-institutional study by Guillou et al of 165 patients with synovial sarcoma from the French sarcoma group. In contrast to the previous series, these authors found no association between the type of fusion gene and clinical outcome. Moreover, they also report that histologic grade was the strongest predictor for survival in a multivariate model. So what factors can account for these differing results, and what valuable lessons can be taken from these studies? One explanation for the discordant results of this study compared with previous reports is the retrospective design of these studies and their unavoidable shortcomings, including missing data and the possibility of several selection biases. Despite the fact that known patient and tumor characteristics were apparently similar (such as age, sex, or tumor size), the use of different therapeutic approaches and the presence of other potential confounders (such as comorbidities, access to medical care, or varying size and expertise of treatment centers) should not easily be disregarded. As pointed out by others, unavailability of clinical data in retrospective studies is unlikely to be random in nature and may have different causes among different studies. Although the various published studies in synovial sarcoma seem to have accrued cases over a similar time period and most likely have used comparable therapeutic approaches, the understandably limited information available, particularly regarding precise details of treatment, make it impossible to exclude with certainty the possibility that therapy, for example in the French study, might have JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 20 OCTOBER 15 2004