Abstract 4924: Retrospective evaluation of a system model of the BCL2 family of proteins as a predictive and prognostic biomarker for the clinical outcome of stage II-IV colorectal cancer patients
Authors: Lindner Andreas U. , Salvucci Manuela , Cremona Mattia , Monsefi Naser , Curry Sarah , Morgan Clare , Resler Alexa , O’Byrne Robert , Bacon Orna , Stuehler Michael , Flanagan Lorna , Wilson Richard , Johnston Patrick G. , Salto-Tellez Manuel , Camilleri-Broët Sophie , McNamara Deborah A. , Hennessy Bryan T. , Kay Elaine W. , Laurent-Puig Pierre , Van Schaeybroeck Sandra , Prehn Jochen H.M. 
Published: July 2016

Abstract
With 1.4 million new cases every year, colorectal cancer (CRC) is the fourth most common cancer worldwide [Globocan 2012, WHO]. Despite therapeutic advances and improvements in overall care, TNM staging remains the best prognostic indicator for CRC patients’ clinical outcomes and is pivotal for deciding on use of adjuvant chemotherapy after resection of the tumour. Adjuvant chemotherapy is not recommended for many stage II patients and mostly high-risk patients receive chemotherapy. However, there is a lack of robust biomarkers for identifying patient response to chemotherapy, recurrence and mortality risk.
We developed a system model of the BCL2 family of proteins (DR_MOMP) to assess the sensitivity of cells to genotoxic stress and to induce apoptosis triggered by chemotherapy. It calculates the stress dose required to induce mitochondrial outer membrane permeabilization (MOMP) based on absolute protein levels and the interaction of pro- and anti-apoptotic BCL2 family proteins. Cells predicted to require a high stress dose showed decreased cell death rates after being exposed to 5FU and Oxaliplatin. Profiles of BAK, BAX, BCL2, BCL(X)L and MCL1 were determined by Reverse Phase Protein Array (RPPA) technology in FFPE primary tumours collected from two distinct cohorts: stage III CRC patients who underwent adjuvant 5FU-based chemotherapy (n = 128), and stage II CRC patients from a completed clinical trial with patients randomised to adjuvant 5FU-based chemotherapy or observation only (n = 138). Protein profiles were inputted into DR_MOMP to determine chemotherapy sensitivity and to classify patients into high- or low risk categories. Findings were validated on the TCGA COAD cohort using both protein (RPPA) and mRNA (SeqV2 RSEM) expression data.
Stage II patients classified as high-risk by DR_MOMP and randomised to observation only had approximately 2-fold increased risk of death from CRC compared to those classified as low-risk or received chemotherapy (HR 2.4; 95% CI 1.2-4.8; p-value = 0.0199). Among stage III patients treated with FOLFOX, those classified as high- versus low-risk had a more than 10-fold increased risk of death from CRC (HR 10.6; 95% CI 2.4-46.3; p-value &lt; 0.0001). We validated this finding in 261 stage II-IV patients of the TCGA COAD cohort (HR 10.6; 95% CI 1.2-12.5; p-value = 0.0125). DR_MOMP predicted mortality risk independent of TNM staging and KRAS mutation status.
Our system delivers a novel predictive and prognostic biomarker that could be combined with TNM staging when assessing initial risk and subsequent clinical management of CRC patients.
Citation Format: Andreas U. Lindner, Manuela Salvucci, Mattia Cremona, Naser Monsefi, Sarah Curry, Clare Morgan, Alexa Resler, Robert O’Byrne, Orna Bacon, Michael Stuehler, Lorna Flanagan, Richard Wilson, Patrick G. Johnston, Manuel Salto-Tellez, Sophie Camilleri-Broët, Deborah A. McNamara, Bryan T. Hennessy, Elaine W. Kay, Pierre Laurent-Puig, Sandra Van Schaeybroeck, Jochen H.M. Prehn. Retrospective evaluation of a system model of the BCL2 family of proteins as a predictive and prognostic biomarker for the clinical outcome of stage II-IV colorectal cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4924.