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

• Published in: Clinical cancer research 2004-02, Vol.10 (4), p.1360-1365
• Main Authors: BOTTI, Claudio, BUGLIONI, Simonetta, NATALI, Pier Giorgio, MOTTOLESE, Marcella, BENEVOLO, Maria, GIANNARELLI, Diana, PAPALDO, Paola, COGNETTI, Francesco, VICI, Patrizia, DI FILIPPO, Franco, DEL NONNO, Franca, VENANZI, Franco Maria
• Format: Article
• Language: English
• Subjects: Aged; Anthracyclines - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Breast Neoplasms - metabolism; Chemotherapy, Adjuvant; Cohort Studies; Cyclophosphamide - pharmacology; Disease-Free Survival; Epirubicin - pharmacology; Fas Ligand Protein; fas Receptor - biosynthesis; fas Receptor - metabolism; Female; Humans; Immunohistochemistry; Medical sciences; Membrane Glycoproteins - metabolism; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Pharmacology. Drug treatments; Phenotype; Prognosis; Proportional Hazards Models; Prospective Studies; Time Factors; Treatment Outcome; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-1092-03

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-node-metastasis (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 FasL-positive 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.