Abstract 2610: Consequences of a high incidence of microsatellite instability (non-Lynch) and BRAF mutated tumors in a population based cohort of metastatic colorectal cancer

Abstract

Abstract Background: Clinical trials in metastatic colorectal cancer (mCRC) have shown few patients with microsatellite instable high (MSI-H) tumors and BRAF mutations (mutBRAF). Recent data show that patients with MSI-H tumors benefit from immunotherapy and there are promising data of adding BRAF inhibitors to standard treatment in patients with mutBRAF. It is therefore important to know the frequency of these molecular changes and their importance for outcome in unselected populations of mCRC. Methods: A prospectively collected population-based cohort of 798 mCRC patients from three geographic areas in Scandinavia was studied. Gene analysis was available for 446 cases for BRAF and KRAS analysis, MSI analysis was done for mutBRAF only. Immunohistochemistry was performed for BRAF and MMR in 611 patients. Kaplan-Meier method, logistic regression and Cox proportional hazards models were used for statistical analyses. Results: Totally 8 % (46/589 patients) were MSI-H and 20 % (119/586 patients) were mutBRAF. MSI-H tumours harboured mutBRAF in 76 % of cases and 29 % of mutBRAF was MSI-H. MSI-H correlated to female sex, age >75 years, right-sided tumor, mutBRAF, lymph node metastasis and less often lung and liver metastasis. Patients with MSI-H received less often chemotherapy compared to MSS patients; 46 % vs. 64 % received 1st line, 13 % vs. 38 % received 2nd line and 2 % vs. 17 % received 3rd line chemotherapy, respectively. Patients with MSI-H had poorer prognosis, however only significant in BRAF wildtype (wtBRAF) patients, and the negative prognostic potential of mutBRAF was only valid in MSS tumors. Median overall survival (OS) was 4 months in MSI-H vs. 11 months in MSS tumors (p < 0.001). After multivariate analysis of OS in patients given 1st line chemotherapy MSI-H and mutBRAF was independent poor prognostic factors with HR 2.2 (95 % CI: 1.09, 4.60, p = 0.028) and HR 1.9 (95 % CI: 1.24, 2.97, P = 0.004) respectively. Median progression-free survival (PFS) during 1st line chemotherapy was 4 months for MSI-H vs. 8 months for MSS tumors (p = 0.087), and multivariate analysis of PFS showed HR 2.21 (95 % CI: 1.10, 4.44, p = 0.027). MSI-H and wtBRAF patients (n=10) had the worst prognosis with median OS of 1 month (p <0.001) and median PFS after 1st line chemotherapy of 2 months (p = 0.015). Conclusion: In unselected patients with mCRC, MSI-H and mutBRAF are more common than previously reported, and consequently more patients could benefit from immunotherapy and BRAF inhibitor treatments. Most MSI-H patients harbored mutBRAF (non-Lynch) in contrast to patients in recent mCRC immunotherapy trials, and further studies are needed to evaluate the effect of immunotherapy in this subgroup. Chemotherapy had minimal effect in MSI-H patients and fewer received 2-line palliative chemotherapy indicating that these patients could be considered for immunotherapy as 1st line treatment. Citation Format: Kristine Aasebø, Anca Dragomir, Magnus Sundström, Per Pfeiffer, Per-Henrik Edqvist, Geir Eide, Fredrik Ponten, Camilla Qvortrup, Bengt Glimelius, Halfdan Sørbye. Consequences of a high incidence of microsatellite instability (non-Lynch) and BRAF mutated tumors in a population based cohort of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2610.