Liquid biopsy circulating tumor DNA testing in metastatic colorectal cancer

The aim of the project is to translate liquid biopsy ctDNA analyses from a research laboratory setting into clinical application to predict and monitor treatment response to anti-EGFR therapeutic antibodies. Merck supports the clinical study ‘PLCRC-ORCA’, which is performed as a substudy of the prospective Dutch CRC cohort study (PLCRC), coordinated by the UMCU. Molecular ctDNA analysis is performed at the NKI.

The Dutch guideline for treatment of mCRC patients includes the use of therapeutic monoclonal antibodies (mAbs) directed against EGFR. However, these drugs are expensive (average cost of €17,000 to €30,000 per patient). Therefore, it is important to select the right treatment for each individual patient (personalised medicine). Anti-EGFR therapy is not effective when the RAS oncogene is mutated. Analysis of RAS mutation status in tumor tissue has been implemented in the clinical setting to predict which patients will not benefit from anti-EGFR therapy, leaving approximately half of the new mCRC patients per year eligible for anti-EGFR treatment (1600 new patients/year). This procedure is a great example how companion diagnostics are beneficial to both patient care and health budgets.

Tumor tissue is not always readily available for DNA mutation testing. The use of liquid biopsies for ctDNA mutation analysis is an attractive complementary or alternative approach. The objectives of the present study are: 1) Comparison of multiple technological platforms for detection of RAS mutations in ctDNA; and 2) Detection of mutations in ctDNA for longitudinal monitoring of treatment response. To achieve this goal, this project will compare sensitivity, cost, and clinical applicability of various ctDNA detection platforms; and collect blood samples longitudinally for ctDNA analyses.

This project will deliver a comparison of technology platforms for liquid biopsy ctDNA analysis of RAS mutations; and define a strategy and demonstrate clinical applicability to effectively use liquid biopsy ctDNA testing in molecular diagnostics to improve patient care. Increasing the readiness of implementation of liquid biopsy ctDNA testing for treatment response in metastatic CRC is another step forward toward innovation.