Instability Of Non Standard Microsatellites In Metastatic Colorectal Cancer Patients Treated With A Bevacizumab Based Chemotherapy

Bevacizumab (B) is a biological agent frequently included in the treatment of metastatic colon cancer (mCRC), although at present there is no effective biomarker that can predict its efficacy. Few studies report a positive association of microsatellite instability (MSI) with the response to anti-angiogenic therapy, but the role of MSI in relation to B efficacy needs to be better understood. Elevated microsatellite alterations at selected tetranucleotides repeats (EMAST) can be observed at higher rate in mCRC patients compared to MSI. The predictive and prognostic role of EMAST has not been completely investigated so far. Moreover, it is known that angiogenesis in mCRC goes through the activation of VEGF-A, but VEGF-B can be involved in some compensatory effect during anti-VEGF-A treatments. By exploring the UCSC Genome Browser database, we found that the VEGF-B gene possesses a poly-dinucleotide microsatellite (normally 19xAG) which somatic instability has never been reported. In this study, we analyzed the status of MSI, five EMAST markers (D20S82, D20S85, D8S321, D9S242, MYCL1) and the VEGF-B microsatellite in relation to prognosis in 145 mCRC patients treated with chemotherapy alone (n=51) or chemotherapy plus B (n=94). MSI high (MSI-H) was detected in four patients (3%) out of 141 participants. Using a multivariable model and adjusting for patient characteristics, microsatellite status remains significantly associated with progression free survival (PFS) and overall survival (OS). The PFS hazard ratio (HR) for MSI-H patients was 3.18 (95% CI 1.09-9.25; p=0.034) and the OS HR was 6.45 (95% CI 2.08-19.99; p=0.001). Eleven (7.8%) patients out of 140 were positive to at least two EMAST markers. EMAST instability was associated with a general worse prognosis, trend that become significant in the group of patients treated with CT plus B in term of PFS (median survival 5 months vs 11. months, p=0.0006) and OS (median survival 6.1 months vs 29.1 months, p The 24.2% of patients (29 out of 120) showed a VEGF-B-poly-AG instability. Amplification of the poly-AG is associated with worse outcome in PSF (7.0 month of median survival vs 28.0 months for patients with shortened poly-AG; p=0.005) in patients treated with CT alone, suggesting that an extended microsatellite in VEGF-B might have a role in the resistance to chemotherapy. In conclusion, MSI, EMAST and VEGF-B poly-AG instability are associated with prognosis in mCRC patients treated with CT or CT plus B. MSI and EMAST instability are associated with worse prognosis in CT+B patients, while VEGF-B microsatellite instability is linked to worse prognosis in CT patients. Further investigations are needed but we can hypothesize that MSI, EMAST and VEGF-B poly-AG instability can have some relevance for the clinical outcome of the disease. Citation Format: Francesca Pirini, Luigi Pasini, Sara Ravaioli, Gianluca Tedaldi, Emanuela Scarpi, Giorgia Marisi, Chiara Molinari, Daniele Calistri, Alessandro Passardi, Paola Ulivi. Instability of non standard microsatellites in metastatic colorectal cancer patients treated with a bevacizumab based chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5296.