Towards improved treatment of metastatic colorectal cancer: novel insights in tumor sidedness and liquid biopsies
19 February 2018
UAntwerp, Campus Drie Eiken, Building O, Auditorium O1 - Universiteitsplein 1 - 2610 Wilrijk (route: UAntwerpen, Campus Drie Eiken
Prof M. Peeters, Prof G. Van Camp
PhD defence Nele Boeckx - Faculty of Medicine and Health Sciences
Metastatic colorectal cancer (mCRC) is a major health problem with a high morbidity and mortality. Although the advent of targeted therapies has led to improved survival outcomes, the five-year survival rate for mCRC patients is only 10%.
Targeted therapies are associated with high costs, side effects and primary and acquired resistance. Although anti-epidermal growth factor receptor (anti-EGFR) therapy has been restricted to RAS wild-type (WT) tumors, many patients do not respond to targeted therapies and almost all patients develop resistance during treatment. Therefore, accurate follow-up is extremely important. Currently, mCRC patients are monitored using radiographic evaluation and the analysis of tumor marker carcinoembryonic antigen which have both their limitations.
The main objectives of this thesis are improving patient selection for targeted therapies by identifying patients who will not respond to therapy and improving disease monitoring. This could lead to early changes in therapy and consequently to improved survival outcomes and/or quality of life in mCRC patients.
In the first part of this thesis, we investigated the impact of primary tumor sidedness (left- or right-sided CRC) on panitumumab efficacy in order to improve patient selection for anti-EGFR therapy. Therefore, survival data of four randomized clinical trials investigating the effect of panitumumab, were re-analyzed according to primary tumor location. We discovered that the addition of panitumumab to chemotherapy or best supportive care (BSC) was beneficial in RAS WT patients with left-sided disease compared to chemotherapy with or without bevacizumab or BSC alone.
In the second part, the potential of liquid biopsies as a follow-up marker during treatment was evaluated, aiming to improve current disease monitoring. Therefore, plasma samples were collected at different time points during treatment in 24 mCRC patients. Circulating cell-free DNA was analyzed using NPY methylation and tumor-specific mutation assays for droplet-based digital PCR. In this way, the fraction of circulating tumor DNA (ctDNA) was calculated. The changes in ctDNA fraction corresponded to the results of radiographic evaluation. In general, a steep decrease in ctDNA fraction was observed two weeks after treatment start, possibly indicating response to treatment. In addition, ctDNA fraction remained low in patients undergoing curative surgery, while it was increased again in patients showing disease progression. Our results indicate that liquid biopsies have the potential to be used as a follow-up marker to complement radiographic evaluation. Importantly, unlike tumor-specific mutations, analyzing NPY methylation has the major advantage that it can be detected in almost every mCRC patient.
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