Serum soluble Fas levels and prediction of response to platinum‐based chemotherapy in epithelial ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is treated mainly by platinumbased combination chemotherapy. Chemotherapy induces apoptosis in which the Fas/Fas ligand pathway is important. Serum soluble Fas (sFas) is a biomarker of this pathway and functionally inhibits Fas-/FasL-mediated apoptosis. In this study, we have investigated the role of sFas in prediction of response to chemotherapy in EOC. Thirty-five patients were recruited and their serum sFas levels were estimated by ELISA at 4 time points-preoperative (sFas1), postoperative (sFas2), midchemotherapy (sFas3) and at the end of chemotherapy (sFas4). The response to chemotherapy was documented clinically, radiologically and by CA-125 levels, based on which, 2 groups were identified: primary chemosensitive (n 5 24) and primary chemoresistant (n 5 11). Based on the disease status at last follow-up, 2 groups were identified: No Evidence of Disease (n 5 15) and Evidence of Disease (n 5 20). The primary chemoresistant tumors showed significantly higher median sFas2 levels (p 5 0.033) with the sFas2/sFas1 ratio ‡1 (p 5 0.001). A multivariate Cox proportional hazards regression model identified sFas2/sFas1 ratio as a significant factor for the prediction of response to platinum-based chemotherapy (p 5 0.011). Receiver operating characteristic (ROC) analysis showed that at a ratio of 1.2, sFas2/sFas1 achieved a sensitivity of 82% and specificity of 100% for prediction of chemotherapeutic response. sFas2/ sFas1 and sFas3/sFas1 ratio was also higher in patients with evidence of disease (p 5 0.018 and p 5 0.028, respectively). Progression-free survival rates in patients with sFas2/sFas1 ratio <1 exceeded those with ratio ‡1 (p 5 0.004). In conclusion, serum sFas is a useful biomarker for predicting response to platinumbased chemotherapy in EOC. ' 2007 Wiley-Liss, Inc.

High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma

“…However, the treatment can still be viewed largely as a 'shot in the dark' and the tools available to help predict who will respond optimally to which treatment are still relatively crude. Some molecules, such as BRCA1 (Quinn et al, 2007), soluble Fas levels (Chaudhry et al, 2008), Death Receptor 4 and TNF receptor 2 (TNFR2) (Dong et al, 2008), EF24 (Selvendiran et al, 2007), and trophinin (Baba et al, 2007), have been shown to correlate with cisplatin resistance in human ovarian cancer. The molecular markers involved in the activity of chemotherapeutic agents can shed light on the successes and failures of treatment in ovarian cancer patients and can also provide a basis for individualised therapy.…”

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

“…Debatin and Krammer (2004) expressed a different view that the Fas/FasL system may amplify the mitochondrial pathway to induce apoptosis. Many studies have confirmed that chemotherapy decreases serum sFas (Shimizu et al, 2005;Naumnik et al, 2007;Chaudhry et al, 2008), which relieves the inhibition of Fas/FasL system, and amplifies the apoptotic signal leading to tumor shrinkage.…”

“…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).…”

“…Fas is a key receptor triggering apoptosis in cells. Studies have reported that soluble Fas (sFas), to a certain extent, reflects the biological behavior of tumors (Liang et al, 2002), and it can be a predictive factor during radiotherapy (Zhu et al, 2006) and chemotherapy (Shimizu et al, 2005;Chaudhry et al, 2008), but there is still little evidence confirming whether concurrent chemoradiotherapy declines sFas levels and whether sFas levels have a prognostic value in LAURC. Thus, the aim of our study was to detect the changes of serum sFas level in patients with LAURC, and to explore its prognostic value of response.…”