Microsatellite instability (MSI-H) is associated with a high immunoscore but not with PD-L1 expression or increased survival in patients (pts.) with metastatic colorectal cancer (mCRC) treated with oxaliplatin (ox) and fluoropyrimidine (FP) with and without bevacizumab (bev): a pooled analysis of the AIO KRK 0207 and RO91 trials.

INTRODUCTION: In a retrospective analysis of two randomized phase III trials in mCRC patients treated first line with oxaliplatin, fluoropyrimidine with and without Bevacizumab (the AIO KRK 0207 and R091 trials) we evaluated the association of high microsatellite instability (MSI-H), immunoscore (IS) and PD-L1 expression in relation to overall survival (OS). METHODS: In total, 550 samples were analysed. Immunohistochemical analysis of the MMR proteins and additionally fragment length analysis was performed, molecular examinations via allele-discriminating PCR in combination with DNA sequencing. Furthermore PD-L1 and IS were assessed. RESULTS: MSI-H tumors were more frequent in right sided tumors (13.66% vs. 4.14%) and were correlated with mutant BRAF (p = 0.0032), but not with KRAS nor NRAS mutations (MT). 3.1% samples were found to be PD-L1 positive, there was no correlation of PDL1 expression with MSI-H status, but in a subgroup analysis of MSI-H tumors the percentage of PD-L1 positive tumors was higher than in MSS tumors (9.75% vs. 2.55%). 8.5% of samples showed a positive IS, MSI-H was associated with a high IS. The mean IS of the pooled population was 0.57 (SD 0.97), while the IS of MSI-H tumors was significantly higher (mean of 2.4; SD 1.4; p =< 0.0001). DISCUSSION: Regarding OS in correlation with MSI-H, PD-L1 and IS status we did not find a significant difference. However, PD-L1 positive mCRC tended to exhibit a longer OS compared to PD-L1 negative cancers (28.9 vs. 22.1 months).

High microsatellite instability (MSI-H) is associated with distinct clinical and molecular characteristics and an improved survival in early Colon cancer (CC); real world data from the AIO molecular registry Colopredict Plus.

Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.

Impact of the Localization of the Primary Tumor and RAS/BRAF Mutational Status on Maintenance Strategies After First-line Oxaliplatin, Fluoropyrimidine, and Bevacizumab in Metastatic Colorectal Cancer: Results From the AIO 0207 Trial.

INTRODUCTION: Numerous trials have examined the prognostic and predictive value of localization of the primary tumor (LPT) in metastastic colorectal cancer, there is limited information about the predictive value of LPT on different maintenance strategies. MATERIALS AND METHODS: We analyzed progression-free survival (PFS)/overall survival (OS) on maintenance therapy according to LPT and mutational subgroups (BRAF/RAS) in patients from the AIO (Arbeitsgemeinschaft Internistische Onkologie) 0207 trial. Following induction, 471 patients were randomized to fluoropyrimidine (FU)/bevacizumab (Bev), Bev, or no treatment. Data on LPT were available in 414 (91%) patients. RESULTS: A total of 291 patients were left-sided (LPTl, 70%), and 123 were right-sided (LPTr, 30%). The median PFS was 3.9 months for LPTr and 5.3 months for LPTl (P = .11; hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.96-1.48). There was no predictive impact of LPT on the maintenance strategies. The pairwise comparison of treatment arms showed a better PFS for FU/Bev versus no treatment independent from LPT (left, P < .0001; HR, 2.39; 95% CI, 1.73-3.31; right, P = .011; HR, 1.78; 95% CI, 1.14-2.80). Analysis for OS (429 patients) confirmed the strong prognostic impact of LPT (left vs. right: 24.0 vs. 16.7 months; P < .0001; HR, 1.65; 95% CI, 1.32-2.06), but also without major interaction between the LPT and maintenance arms. The strong negative prognostic impact of BRAF mutation was confirmed in right-/left-sided metastastic colorectal cancer, reaching significance in LPTl. In patients with RAS mutational status, the negative prognostic impact of the mutation remains, but its effect is stronger in LPTl (P < .0001). CONCLUSION: The strong prognostic factor of LPT is confirmed undergoing oxaliplatin/FU/Bev induction therapy, whereas there seems to be no major predictive impact of LPT on different maintenance strategies.