Methodological, biological and clinical aspects of circulating free DNA in metastatic colorectal cancer

Abstract

Background: Circulating DNA can be used to measure the total cell-free DNA (cfDNA) and for detection and quantification of tumor-specific genetic alterations in the peripheral blood, and the broad clinical potential of circulating DNA has attracted increasing focus over the past decade. Concentrations of circulating DNA are high in metastatic colorectal cancer (CRC), and the total levels of cfDNA have been reported to hold strong prognostic value. Colorectal tumors are characterized by a high frequency of well known, clinically relevant genetic alteration, which is readily detected in the cfDNA and holds potential for tailoring of palliative therapy and for monitoring during treatment. This review aims to present the current literature which has specifically reported data on the potential utility of cfDNA and on tumor-specific mutations in metastatic colorectal cancer (mCRC). Method: Methodological, biological and clinical aspects are discussed based on the most recent development in this specific setting, and eligible studies were identified by systematic literature searched from Pubmed and EMBASE in addition to conference papers and communications. Results: The literature regarding cfDNA in CRC is broad and heterogeneous concerning aims, nomenclature, methods, cohorts and clinical endpoints and consequently difficult to include in a single systematic search. However, the available data underline a strong clinical value of measuring both total cfDNA levels and tumor-specific mutations in the plasma of patients with mCRC, pre-and during systemic therapy. Conclusion: This paper had gathered the most recent literature on several aspects of cfDNA in mCRC, including methodological, biological and clinical aspects, and discussed the large clinical potential in this specific setting, which needs to be validated in carefully designed prospective studies in statistically relevant cohorts.

Clinical utility of circulating tumor DNA for colorectal cancer

“…Another study showed a strong association between ctDNA positivity and recurrence‐free survival (RFS), and overall survival (OS) in patients with CRC irrespective of tumor stage, study size, tumor markers, detection methods, and sample type . A meta‐analysis of 1076 patients with mCRC treated with chemotherapy confirmed that baseline total cfDNA levels correlate with OS . The utility of ctDNA and cfDNA as a prognostic parameter and alternative modality for mutation detection before treatment in metastatic CRC (mCRC) was demonstrated in the randomized CORRECT phase III trial .…”

“…For example, liquid biopsies have been successfully applied to identify mechanisms of resistance for epidermal growth factor (EGFR) inhibitor in mCRC patients . Significant proportions of CRC harbor mutations in KRAS , BRAF , or NRAS that could cause resistance to an EGFR inhibitor, and these hotspot mutations are candidates for mutations detectable in plasma . Previous reports showed that patients with RAS wild‐type CRC in tissue, and plasma that is positive for KRAS and BRAF mutations can be resistant to the EGFR inhibitor .…”

“…54 A meta-analysis of 1076 patients with mCRC treated with chemotherapy confirmed that baseline total cfDNA levels correlate with OS. 55 The utility of ctDNA and cfDNA as a prognostic parameter and alternative modality for mutation detection before treatment in metastatic CRC (mCRC) was demonstrated in the randomized CORRECT phase III trial. 56 In this trial, 166 mCRC patients received a placebo and 337…”

“…63 Significant proportions of CRC harbor mutations in KRAS, BRAF, or NRAS that could cause resistance to an EGFR inhibitor, and these hotspot mutations are candidates for mutations detectable in plasma. 55,58 Previous reports showed that patients with RAS wild-type CRC in tissue, and plasma that is positive for KRAS and BRAF mutations can be resistant to the EGFR inhibitor. 46,[64][65][66] Importantly, CRC presumably contain resistant mutant clones before treatment and the proportion of these resistant clones increase under therapeutic pressure.…”

“…Prognostic biomarker • Patients with detectable ctDNA in their plasma showed not only worse survival but also shorter progression-free survival than those without it [52][53][54][55]58,59 • Baseline total cfDNA levels correlate with overall survival in patients with mCRC treated with chemotherapy 56,57 Minimal residual disease and recurrence monitoring…”