Altered Expression of FAS System Is Related to Adverse Clinical Outcome in Stage I-II Breast Cancer Patients Treated with Adjuvant Anthracycline-Based Chemotherapy

Abstract

Purpose: To determine the prognostic value of Fas receptor and Fas ligand (FasL) as apoptosis-related biomarkers in the context of chemoresponsiveness in breast cancer (BC) patients submitted to anthracycline-based adjuvant therapy.Experimental Design: Fas and FasL were investigated by immunohistochemistry in surgical samples collected from 167 stage I-IIa-b BC patients enrolled in a prospective clinical trial using epirubicin plus cyclophosphamide in the adjuvant setting.Results: Fas and FasL were significantly associated with tumor stage (P < 0.0001). Multivariate analysis indicated that stage, loss of Fas (relative risk, 8.5 and 9.12; P < 0.0001) and FasL up-regulation (relative risk, 2.38 and 2.88; P ‫؍‬ 0.01) were independent prognostic variables influencing both disease-free survival (DFS) and overall survival (OS). A Cox analysis using a four-category Fas/FasL phenotype (؉/؊, ؉/؉, ؊/؉, ؊/؊) as a stratification factor evidenced a highly positive association between Fas/FasL phenotype and the cumulative hazard of relapse and death in the entire series of patients. We also estimated the DFS and OS for different combinations of the pathological-tumor-nodemetastasis (TNM) stage and Fas/FasL by using the K sample log-rank exact test demonstrating that significantly shorter DFS and OS were observed in Fas-negative and FasLpositive patients in both stage I-IIa and IIb.Conclusions: Data presented herein demonstrated that, according to a number of in vitro studies, the prognosis for BC patients receiving adjuvant anthracycline-based chemotherapy strongly depends on the Fas/FasL status. Therefore, a concomitant altered pattern of Fas/FasL expression seems to configure an aggressive tumor phenotype linked to disease progression.

The search for optimal cutoff points for apoptosis and proliferation rate in prognostification of early stage breast cancer patients treated with anthracyclines in adjuvant settings

“…Another explanation of this observation is brought by in vitro studies, in which it was shown that apoptosis in response to different cytotoxic drugs is also triggered through an autocrine/paracrine mechanism, by an intact Fas system activation pathway [23]. This result is in accordance with suggestion of some preclinical studies showing that surface death receptors (Fas) play key role in drug-induced apoptosis of solid tumor and leukemia [24].…”

FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target

“…In breast cancer patients, Botti et al . noted significantly shorter disease-free and overall survival periods in 167 FAS-negative and FASL-positive stage I/II breast cancer patients (40). In contrast, higher expression levels of FAS are associated with smaller tumor size, negative lymph nodes and prolonged disease-free survival (41).…”

A Role for the Fas/FasL System in Modulating Genetic Susceptibility to T-Cell Lymphoblastic Lymphomas

“…However, such parallel behavior contradicts to a certain degree what has been published for other tumors. Several authors have reported that solid tumors usually express elevated levels of FasL but reduced levels of Fas receptor (31,32). Up-regulation of FasL has been linked to some advantage for tumor cells through the triggering of apoptosis-independent pathways, resulting in up-regulation of antiapoptotic and tumorigenic genes and/or an increase in motility and invasiveness, particularly for apoptosis-resistant tumor cells (33).…”