Proffered Papers— Medical Oncology

EXPRESSION OF THE TRAIL RECEPTOR DR4 IN HUMAN SOFT TISSUE SARCOMAS

Komdeur R, de Jong S, Hoekstra HJ, Molenaar WM, Plaat BEC, Van den Berg E, Van der Graaf WTA (University Hospital Groningen, 9700 RB, the Netherlands)

Introduction. Nowadays limb salvage is feasible in more than 75% of patients with a primarily irresectable soft tissue sarcoma (STS) of the extremity after treatment with hyperthermic isolated limb perfusion with TNF” and melphalan (HILP-TM). TNF Related Apoptosis Inducing Ligand (TRAIL) is a recently described member of the TNF family of cytokines that rapidly induces apoptosis in tumor cells. TRAIL appears to be non-toxic to normal tissues when administered in non-human primates. Six distinct receptors for TRAIL have been identified of which only DR4 and DR5 can initiate cell-death. Adding TRAIL to the treatment schedule might further improve limb salvage rate for locally advanced extremity STS. HILP offers the unique possibility to introduce TRAIL in humans since unforeseen toxicity would be limited. The objectives of the current study are (1.) to investigate the expression of DR4 in human STS, and (2.) to determine whether the expression of DR4 is changed after HILP-TM.

Patients and methods. 25 patients with a primarily irresectable extremity STS underwent HILP with TNF” (3-4 mg) and melphalan (10-13 mg/L limb volume), followed by a delayed resection. The median period between HILP and resection of the tumor remnant was 61 days (range 12 - 81 days). Tumor-samples were obtained from the diagnostic pre-HILP specimen and from the post-HILP resection specimen. Immunohistochemical detection of DR4 was scored as described in Table 1.

Results. Of the 25 samples obtained before HILP-TM, 16 scored positive for DR4 expression (64%) (Figure 1). After HILP 18 samples were evaluable: 12 scored positive (76%) (Figure 2). Statistical analysis of paired (pre- and post-HILP) samples revealed no significant change in DR4 expression. Interestingly, all synovial sarcomas (n=4) were scored negative before HILP-TM, whereas 3 were positively stained afterwards.

Conclusions. The majority of these human STS expresses the DR4 receptor. Of interest, all 4 synovial sarcomas scored DR4-negative before HILP; 3 of them were positive afterwards. DR4 expression did not significantly change in paired samples after HILP. However, acute effects may be missed due to the long period between HILP and tumor resection. The high percentage of initial DR4 positive tumors make TRAIL an interesting agent for STS when it becomes available for clinical studies.