Metastatic Renal Cell Carcinoma: Use of Bcl-2 and Fas to Predict Responses to Immunotherapy

Abstract

Because conventional chemotherapy, ­radiotherapy, and hormonal therapy have no benefit in terms of prolonging survival in patients with metastatic renal cell cancer (mRCC), almost all mRCC patients eventually succumb to disease. Intriguingly metastatic lesions have been known to disappear after the resectioning of the primary RCC although such cases are very rare (Kavoussi et al. 1986). In addition, immunotherapy, such as the administration of interferon-alpha (IFN-alpha) or interleukin-2 (IL-2), has shown ­promise, although the efficacy varies among cases and the total response rate reaches only approximately 20% (Krown 1987; Fyfe et al. 1995). Immunotherapy should be performed only in selected responders, because the treatment is sometimes accompanied by severe adverse effects especially with IL-2 (Fyfe et al. 1995). The demography favoring a response to immunotherapy includes a good performance status, prior nephrectomy, metastasis predominantly to the lung (Atkins et al. 1993; Fyfe et al. 1995; Figlin et al. 1997; Rosenberg et al. 1998), and only one site of metastatic disease (Negrier et al. 1998), with a clear cell histological variant (Wu et al. 1998). To date, however, no reliable molecular markers have been identified that can predict susceptibility to immunotherapy.

The present study was performed to ­elucidate the potential role of the apoptosis-related molecules Bcl-2 and Fas as predictors of the susceptibility of metastatic RCC to immunotherapy. An immunohistochemical examination of tumor tissue from 40 patients with metastatic RCC undergoing postoperative immunotherapy after radical nephrectomy was performed. Patients with progressive disease after immunotherapy had a decreased rate of survival (p = 0.006). Progressive disease correlated with a higher proliferation index (PI) in the primary tumor. All primary tumors in cases of complete response or partial response were negative for Bcl-2, while 40.6% of no change + progressive disease patients, were positive for Bcl-2 (p = 0.0373). Patients in whom the primary tumors were both Bcl-2 and Fas-negative showed significantly better responses to immunotherapy than the remaining group (p = 0.0022). The Bcl-2 and Fas status of the primary lesion may become useful for the selection of patients with metastatic RCC for immunotherapy.