Soluble Fas (CD95) Is a Prognostic Factor in Patients with Metastatic Breast Cancer Undergoing High-Dose Chemotherapy and Autologous Stem Cell Transplantation

Abstract

The Fas/Fas ligand (FasL) system plays an important role in cellular apoptosis and is involved in cancer cell death induced by the immune system and anticancer drugs. Increased serum levels of soluble Fas (sFas) are associated with a number of different disease states and with tumor progression and metastasis in patients. In this study, we examined the plasma levels of sFas in 94 women with metastatic breast cancer undergoing high-dose chemotherapy (HDCT) treatment with autologous stem cell transplantation (ASCT) using a quantitative enzyme-linked immunosorbent assay (ELISA) method. Thirty-one patients (31/94, 33%) had plasma sFas levels greater than the optimum cut point of 1.90 ng/ml (median 2.47, range 1.98-13.54 ng/ml) and were designated as sFas positive. Sixty-three patients (63/94, 67%) had sFas levels below 1.90 ng/ml (median 1.14, range 0.47-1.89 ng/ml). In univariate analysis, patients with sFas-positive status, HER-2 overexpression, and the presence of liver metastases had a significantly shorter time to disease progression (PFS) and significantly decreased overall survival (OS). Multivariable analysis (Cox proportional hazards model) for PFS determined that sFas status significantly predicted disease progression (p = 0.004) with an adjusted hazard ratio (HR) of 2.0 (95% CI, 1.3-3.3). HER-2 status and liver metastases were also significant independent predictors of disease progression (p < 0.001) for both. sFas level was also an independent prognostic factor for OS with an adjusted HR of 2.0 (p = 0.006; 95% CI, 1.2-3.4). HER-2 status and liver metastases also remained highly significant independent prognostic factors for OS (HER-2: p < 0.001, HR 2.3, and liver metastases: p = 0.001, HR 2.7). In conclusion, these results suggest that plasma levels of sFas may be a valuable clinical prognostic factor in predicting outcome (PFS and OS) for patients with metastatic breast cancer undergoing HDCT with ASCT.

Prognostic Analysis of Early Lymphocyte Recovery in Patients with Advanced Breast Cancer Receiving High-Dose Chemotherapy with an Autologous Hematopoietic Progenitor Cell Transplant

“…Additionally, they observed that tumor-infiltrating lymphocytes in close proximity to breast cancer cells expressing Fas ligand were predominantly apoptotic. Further, Bewick et al (38) observed an adverse effect of high pretransplant serum levels of Fas in 94 metastatic breast cancer patients who received high-dose chemotherapy. Our observations suggest that day ϩ15 absolute lymphocyte count may be a valid surrogate of those immune subsets that might be involved in immunity.…”

Prognostic value of serum soluble Fas in patients with locally advanced unresectable rectal cancer receiving concurrent chemoradiotherapy

“…sFas inhibits the cell surface signal transduction by competitively binding and neutralizing FasL (Suda et al, 1993;Cascino et al, 1995;Natoli et al, 1995), which may correlate with cancer escaping immune surveillance and progression. Increased serum sFas level has been observed in patients with hepatocellular (Jodo et al, 1998), breast (Bewick et al, 2001), small cell lung cancer (SCLC) (Shimizu et al, 2005), esophageal (Gratas et al, 1998) and epithelial ovarian cancers (Chaudhry et al, 2008).…”

“…Zhu et al (2006) used immunohistochemistry and TdT-mediated dUTP nick end labeling (TUNEL) techniques to detect the changes of Fas, p53, Bcl-2, and apoptosis in 40 patients with uterine cervix carcinoma during radiotherapy, indicating a positive apoptosis rate, increased p53 and Fas expression, and significantly decreased Bcl-2 after radiotherapy. Several studies have demonstrated that apoptosis induced by chemotherapy involved the Fas/FasL system (Bewick et al, 2001;Shimizu et al, 2005;Naumnik et al, 2007;Chaudhry et al, 2008). Cytotoxic drugs lead to increasing FasL expression, which triggers tumor cells into apoptosis by binding Fas (Eichhorst et al, 2001).…”

Expression of AITR and AITR ligand in breast cancer patients

“…Gastro-intestinal tumors may escape FasL-dependent immune-cytotoxic attack by overexpressing DcR3 that blocks FasL (25). Serum sFas levels may be a valuable clinical prognostic factor in predicting an outcome of disease progression for patients with metastatic breast cancer (26). Soluble FasL was eluted from the surface of uveal melanomas specifically inhibited cytotoxic T lymphocyte lysis of tumor cells pretreated with an inhibitor of metalloproteases (27).…”