c-FLIP L expression defines two ovarian cancer patient subsets and is a prognostic factor of adverse outcome Marina Bagnoli, Federico Ambrogi 1 , Silvana Pilotti 2 , Paola Alberti, Antonino Ditto 3 , Mattia Barbareschi 4 , Enzo Galligioni 5 , Elia Biganzoli 1,6 , Silvana Canevari* and Delia Mezzanzanica* Unit of Molecular Therapies, Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 20133 Milan, Italy 1 Institute of Medical Statistics and Biometry, Universita ` degli Studi di Milano, Via Vanzetti 5, 20133 Milan, Italy Departments of 2 Anatomy Pathology and 3 Surgical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 20133 Milan, Italy Departments of 4 Pathology and 5 Gynecological Surgery, S. Chiara Hospital, L.go Medaglie d’Oro, 9 38100 Trento, Italy 6 Unit of Medical Statistics and Biometry, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 20133 Milan, Italy (Correspondence should be addressed to S Canevari; Email: silvana.canevari@istitutotumori.mi.it) *(S Canevari and D Mezzanzanica contributed equally to this work) Abstract The impairment of apoptotic pathways represents an efficient mechanism to promote chemoresistance in cancer cells. We previously showed that in epithelial ovarian cancer (EOC) cells, long isoform of cellular FLICE-inhibitory protein (c-FLIP L ) accounts for apoptosis resistance in a context of functional p53 and resistance could be overcome by c-FLIP L downmodulation. Here, we studied the association between c-FLIP L and p53 expressions and their prognostic impact in EOC patients. Tumor tissue from 207 patients diagnosed with primary EOC was analyzed by immunohistochemistry (IHC) for c-FLIP L and p53 expressions, and multiple correspondence analysis (MCA) was used to evaluate the multivariable pattern of association among patients’ clinical–pathological characteristics and biological determinants. IHC revealed c-FLIP L expression and p53 nuclear accumulation inversely related (PZ0.0001; odds ratioZ0.29, confidence interval (CI)Z0.15–0.055). MCA indicated that p53 accumulation was associated to clinical–pathological variables, while c-FLIP L expression contributed to the overall association pattern independently from other’s clinical characteristics and complementary to p53. Kaplan–Meier curves showed a reduced survival time according to c-FLIP L expression in concert with p53 accumulation (median overall survival (OS): 35 months) compared with lack of expression of both markers (median OS: 110 months; log-rank test, P valueZ0.024). The multivariable Cox regression model, adjusted for known prognostic factors, identified c-FLIP L expression, but not p53 nuclear accumulation, as an independent prognostic factor for adverse outcome (hazard ratioZ1.82, 95% CIZ1.17–2.82; PZ0.008). Altogether these data support the independent contribution of c-FLIP L in refining the prognostic information obtained from standard clinical–pathological indicators, confirming its pivotal role in promoting cell survival. Endocrine-Related Cancer (2009) 16 443–453 Introduction Epithelial ovarian carcinoma (EOC) remains the leading cause of death for gynecologic cancer in women in western countries. Because more than two- third of patients are diagnosed with advanced disease, surgical debulking is not sufficient to eradicate the tumor, which often spreads into the peritoneal cavity. In the attempt to eradicate residual disease, patients receive a platinum-based therapy. After an initial response to front-line chemotherapy, the patients Endocrine-Related Cancer (2009) 16 443–453 Endocrine-Related Cancer (2009) 16 443–453 1351–0088/09/016–443 q 2009 Society for Endocrinology Printed in Great Britain DOI: 10.1677/ERC-08-0218 Online version via http://www.endocrinology-journals.org