Clinical utility of circulating tumor DNA for colorectal cancer

Abstract

Colorectal cancer (CRC) is currently the most common type of cancer in Japan, and its prognosis has improved because of development of diagnosis and advancement in treatments including surgery and chemotherapy. However, because of intratumor heterogeneity and clonal evolution, tumors often develop resistance to treatment. Genotyping tumor tissue in search of somatic genetic alterations for actionable information has become routine examination in clinical practice. However, the inherent molecular heterogeneity of metastatic tumors and the ability of cancer genomes to dynamically evolve are not properly captured by tissue specimens only. Circulating tumor DNA (ctDNA) carrying tumor-specific genetic or epigenetic alterations is released into the circulation from tumor cells undergoing apoptosis or necrosis. Analysis of ctDNA has the potential to change clinical practice by exploiting blood rather than tissue, as a source of information. Here, we provide an overview of the characteristics of ctDNA and focus on detection methods for ctDNA, and the feasibility of use of ctDNA to monitor tumor dynamics for patients with colorectal cancer.

Keywords: circulating tumor DNA; colorectal cancer; liquid biopsy; next-generation sequencing; tumor mutation burden.

Figure 1

Clinical relevance of circulating tumor DNA (ctDNA) for advanced colorectal cancer. This figure shows key applications of liquid biopsies in the clinical setting. These include tumor genotyping in the diagnosis of cancer, assessing drug response, tracking minimal residual disease, and monitoring clonal evolution

Figure 2

Liquid biopsies to monitor cancer evolution during target therapy. Time‐course analysis of tumor‐specific mutations in the blood of patients is useful to monitor a response and resistance to molecular targeted drugs. For example, we describe a patient with metastatic colorectal cancer treated with EGFR inhibitor. Circulating tumor DNA allows us to identify, track, and quantify clones bearing distinct alleles. Monitoring truncal mutations (TP53, APC) allow us to track tumor burden whereas lesion‐specific mutations (KRAS, BRAF) reflect clonal evolution during chemotherapy. Data of this figure are derived from a combination of our original data with other studies.32, 64, 65, 66 EGFR, epidermal growth factor receptor; PD, progressive disease; VEGF, vascular endothelial growth factor