MACC1 expression predicts development of metastases, outperforming microsatellite stability status, as well as KRAS/BRAF mutation status.

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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4940-2) contains supplementary material, which is available to authorized users.

Pancreatic ductal adenocarcinoma is a highly aggressive disease, and medical as well as surgical therapeutic options are limited. This article reviews stage dependent treatment options, with a special focus on the current controversy of perioperative treatment regimens in initially borderline resectable or locally advanced patients. Neoadjuvant treatment can potentially increase the rate of complete tumor resection and may be more effective than adjuvant systemic therapy. Further, in the case of disease progression during or after neoadjuvant therapy, patients can be spared extensive surgery. Today, common therapeutic regimens include gemcitabine/nab-paclitaxel and FOLFIRINOX, as well as chemoradiation. However, because of the paucity of evidence from randomized trials, most guidelines do not recommend neoadjuvant therapy in resectable tumors, and for borderline or locally advanced tumors only within clinical trials. Importantly, every patient should be discussed in multidisciplinary tumor boards.