Metastatic Colorectal Cancer Clinical and Genetic Prognostic and Predictive Factors. Summary of the Doctoral Thesis

Abstract

Colorectal cancer is one of the most common cancer types in the world. Although the results of early colorectal cancer treatment have improved significantly in recent decades, no effective therapy is currently available for advanced or metastatic disease. From a genetic standpoint, colorectal cancer is not a single disease, but a heterogeneous group of malignancies arising within the colon. Prognosis of mCRC is determined by oncogenetic pathway, localization of the primary tumour, molecular genetics of cancer, microenvironment and tumour stroma, and host microbiome. The progress in clinical and molecular studies have determined mechanisms of development and progression of colorectal cancer, and also helped to define most effective treatment strategy for each patent to prolong survival. Aim of the study was to demonstrate that both the clinical factors and chromosomal aberrations can be used as a prognostic and predictive factors in patients with metastatic colorectal cancer. Methods. The promotion work consists of three separate studies. In the first study, clinical factors (age, year of diagnosis, type of chemotherapy and number of treatment lines, localization of metastases) and their impact on progression free survival (PFS) and overall survival (OS) were analysed. 220 mCRC patients who received chemotherapy between 2004 and 2016 in P.Stradins CUH Clinic of Oncology (PSCUH) were included in retrospective study. In the second, prospective study, the impact of clinical factors – such as neutropenia and duration of previous treatment – on progression free survival in 14 patients with refractory mCRC receiving trifluridine/tipiracil (FTD/TPI) from April 2016 to January 2017 in PSCUH and RECUH/LOC were analysed. In the third, prospective study, impact of massive chromosomal fragmentation chromothripsis on progression free survival in 19 mCRC patients receiving first line FOLFOX chemotherapy in 2011–2012 were analysed. Results. The results of our study revealed that treatment strategy and survival of patients with unresectable mCRC is equal to data from published clinical studies. There was no significant difference in survival between synchronous and metachronous mCRC. Improved overall survival (OS) was observed in patients receiving more than one line of chemotherapy (HR 0.49; p = 0.0002), and in patient < 50 years (HR 0.49; p = 0.0002), but decreased OS was observed in patients with multiple metastases (p = 0.059). In patients with refractory mCRC receiving FTD/TPI treatment, two positive clinical predictive markers were identified – neutropenia and duration of previous treatment > 18 months. Increased mPFS (HR 0.24; p = 0.033) and mOS (HR 0.25; p = 0.075) was observed in patients with Grade 3 and 4 neutropenia. Similarly, increased mPFS (HR 0.15; p = 0.029) and mOS (HR 0.23; p = 0.069) was observed in patients with duration of previous treatment > 18 months. High breakpoint instability index (BPI) and chromothripsis are positive predictive markers in mCRC patients receiving first line FOLFOX chemotherapy. In patients without chromothripsis, mPFS was decreased (HR 3.43; p = 0.03), but the impact on OS was not detected. Conclusion. Different clinical and genetic factors may be used as a predictive and prognostic markers in treatment of mCRC.