Abstract 2829: Identification of the role of SRBC methylation-associated gene silencing as predictive factor of oxaliplatin secondary resistance in metastasic colorectal cancer patients

Abstract

Abstract Background: Resistance acquisition to chemotherapeutic agents is one of the main problems that come up during cancer treatment. The mechanisms of developing resistance are poorly understood, and the causes underlying the loss of sensitivity to common chemotherapy drugs, like oxaliplatin, are largely unknown. The importance of epigenetic alterations has long been demonstrated in cancer. Several studies have shown that promoter methylation-associated silencing inactivates tumor suppressor genes (TSGs) as effectively as mutations and is one of the cancer-predisposing hits described in Knudson's two hit hypothesis. SRBC gene is a TSG the inactivation of which has been associated with malignant tumor progression, being involved in membrane traffic, cell cycle, proliferation, apoptosis and DNA damage mechanisms. In a previous work, we demonstrated the involvement of SRBC methylation-associated expression silencing in oxaliplatin resistance acquisition by using in vitro models and functional analysis. Thus, in the present work, we propose to investigate the role of SRBC promoter methylation alterations as potential predictive biomarker of oxaliplatin chemoresistance in metastasic CRC (mCRC) patients. Material and methods: By Methylation-Specific PCR and pyrosequencing, we analysed SRBC promoter methylation in two independent cohorts of 131 and 58 primary tumors from mCRC patients treated with 5FU-oxaliplatin combination. Chi-square and Fisher test were used to assess the categorical variables associations. Kaplan-Meier plots and Log-Rank test were used to estimate progression-free survival (PFS). The association between gene methylation and clinical parameters with PFS was assessed through univariate and multivariate Cox proportional hazards regression models. We considered statistically significant a two-sided p-value (P) lower than 0.05. Results: SRBC epigenetic inactivation occurred in primary tumors from a discovery cohort of colorectal cancer patients (29.8%, 39 of 131), where it predicted shorter PFS (HR = 1.83; 95% CI = 1.15-2.92; Log-Rank P= 0.01), particularly in oxaliplatin-treated cases for which metastasis surgery was not indicated (HR = 1.96; 95% CI = 1.13-3.40; Log-Rank P= 0.01). In a validation cohort of unresectable metastases colorectal tumors treated with oxaliplatin (n=58), SRBC hypermethylation was also associated with shorter PFS (HR = 1.90; CI= 1.01-3.60; Log-Rank P= 0.045). Conclusions: Remarkably, SRBC promoter hypermethylation was related to worse PFS rate in mCRC patients with unresectable liver metastasis who received 5FU-oxaliplatin based treatment. These results provide a basis for future clinical studies to validate SRBC hypermethylation as a predictive marker for oxaliplatin resistance in mCRC patients. Citation Format: Anna Martinez-Cardus, Catia Moutinho, Cristina Santos, Valentin Navarro-Perez, Eva Martinez-Balibrea, Eva Musulen, Francisco Javier Carmona, Andrea Sartore-Bianchi, Andrea Cassingena, Salvatore Siena, Elena Elez, Josep Tabernero, Ramon Salazar, Albert Abad, Manel Esteller. Identification of the role of SRBC methylation-associated gene silencing as predictive factor of oxaliplatin secondary resistance in metastasic colorectal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2829. doi:10.1158/1538-7445.AM2014-2829