Análisis de ras en plasma en cáncer colorrectal metastásico: impacto de la fracción mutante alélica en pronóstico

Abstract

Introduction: Despite recent major advances in metastatic colorrectal cancer (mCRC), survival is still poor. There are different prognostic and predictive factors to be taken into account, among them, RAS mutation which is observed in 40% of all tumors. This mutation is determined in solid biopsy but sometimes, as it is not possible to get enough sample for this determination and due to tumor heterogeneity, this mutational status can be analyzed from circulating DNA in blood (liquid biopsy) using BEAMing for instance (a digital PCR-based technology). The main hypothesis of this study is to analyze whether quantitative determination of this mutation (mutant allele fraction-MAF-) could be a prognostic or predictive factor for RAS mutant mCRC._x000D_ Material and Methods: This is a retrospective study comprising a total of 110 patients from two different sites. Main clinical, pathological and survival data have been recorded as well as determination of RAS mutational status in solid biopsy using routine techniques. MAF determination in plasma has been determined using BEAMing and correlation with mutational status in solid tissue using real time PCR has been analyzed. Prognosis impact in overall survival (OS) and progression free survival (PFS) of RAS MAF in a homogenous cohort has been analyzed as well its correlation with different variables. _x000D_ Results: In the whole population, RAS mutation in plasma has been detected with BEAMing in a total of 62 patients (56.4%). Concordance between real time PCR in solid biopsy and BEAMing in plasma is 90% with an estimated Cohen Kappa index of 0.80 (95% CI 0.68-0.91). No statistical significant differences in OS have been detected between RAS mutant and wild type in solid and liquid biopsy. In order to make population homogenous regarding prognosis impact of RAS MAF, a total of 42 patients who have not been operated for metastatic disease have been selected. There are not statistical significant correlations with the most part of the clinical variables except for metastases location. RAS MAF prior to first line therapy shows a significant correlation with OS (HR = 3.514; p = 0.00066), as RAS MAF is lower in patients with longer OS. Moreover, patients with lower MAF show a trend to longer PFS that is not statistically significant. In the multi-variant analysis, RAS MAF is an independent prognosis factor for OS (HR = 2.73; p = 0.006) and PFS (HR = 3.74; p = 0.049). Moreover, patients with higher MAF tend to have progressive disease as best response to treatment (p = 0.007). _x000D_ Conclusions: RAS MAF in plasma could be an independent prognosis factor in patients with RAS mutant mCRC and may help clinicians to make decisions about management of this disease. However, due to the characteristics of this study, prospective studies are needed to validate this technique for the use in the daily practice.

Date of Award	19 Dec 2018
Original language	Spanish
Supervisor	Josep Maria Tabernero Caturla (Director) & Maria Elena Elez Fernandez (Director)