Over the past decades the TNM staging system has remained the best indicator for the clinical outcome of CRC patients, and it is used to stratify patients for adjuvant chemotherapy after surgical resection of the tumor. Currently, adjuvant chemotherapy is not recommended for stage II patients. Previously, we developed a systems model of the BCL2 family of proteins (DR_MOMP) to assess cancer cells’ resistance to induce mitochondrial outer membrane permeabilization (MOMP), based on absolute protein levels and the interaction of pro- and anti-apoptotic BCL2 family proteins.
Reverse Phase Protein Arrays (RPPA) were used to determine BAK, BAX, BCL2, BCL(X)L and MCL1 protein levels in primary tumours collected from two distinct cohorts: 1) 138 stage II CRC patients from a completed clinical trial, randomised to adjuvant 5-FU-based chemotherapy or observation only, 2) 128 stage III CRC patients treated with adjuvant 5-FU-based chemotherapy. DR_MOMP was employed to calculate the amount of cellular stress required to induce MOMP based on tumour protein levels. Protein level (RPPA) and mRNA expression (SeqV2 RSEM) data from the TCGA COAD cohort was used to validate the findings.
1) Stage II patients randomised to observation only and classified as high-risk by DR_MOMP had an approximately 2-fold increased risk of death compared to patients receiving chemotherapy or classified as low-risk (HR 2.4; 95% CI 1.2-4.8; p-value = 0.02). 2) Stage III patients treated with chemotherapy and classified as high-risk had a more than 10-fold increased risk of death compared to low-risk patients (HR 10.6; 95% CI 2.4-46.3; p-value < 0.0001). The hazard ratio (HR) was similar in 261 stage II-IV patients of the TCGA COAD cohort (HR 10.6; 95% CI 1.2-12.5; p-value = 0.01).
Our system holds promise as a novel predictive biomarker to stratify stage II CRC patients for adjuvant chemotherapy and as a prognostic biomarker for stage III patients. It could be combined with traditional staging to assess risk and in subsequent clinical management of patients.