Abstract
BackgroundEven though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk.MethodsEighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox’s proportional hazard models and integrative two-step cluster analysis.ResultsDistant metastasis risk was significantly correlated with oncogenic KRAS mutations (p = 0.015), expression of SASH1 (p = 0.016), and the density of CD8-positive T-cells (p = 0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation (p = 0.008) and density of CD8-positive TILs (p = 0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) (p = 0.032). Increased expression of osteopontin (p = 0.019) and low density of CD8-positive T-cells (p = 0.043) were significantly associated with unfavourable response to 5-FU.ConclusionsIntegrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients.
Highlights
Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient
Patient collective Overall, 84 patients with complete resection (R0) of UICC stage III colon cancer were included from two independent clinical centres
No significant period effects were observed for clinical or molecular parameters over the accrual period (Additional file 1: Figure S1). As this can be considered as distinct entity and prognosis would have been further influenced by neoadjuvant therapy [5]
Summary
Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. 30% of patients with colorectal cancer present with local lymph node spread but no distant metastasis at the time of diagnosis (UICC/AJCC stage III). Therapy management is complex for patients with stage III disease, even though oncological tumor resection including lymph node dissection is still the condition precedent for cure. Since the early 1980s, 5-FU based adjuvant chemotherapy with or without Oxaliplatin was established for patients with stage III colorectal cancer [3,4,5]. Adjuvant chemotherapy in stage III colorectal cancer leads to a reduction of tumor recurrence to approximately 30%, from 50% without chemotherapy [6], yet simultaneously exposing all patients to considerably harmful side effects. Neither the TNM classification system [2] nor currently available histopathological or biomarkers [8] warrant stratification for the prediction of recurrence risk in this stage
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