Circulating tumor DNA analysis in the era of precision oncology

Abstract

The spatial and temporal genomic heterogeneity of various tumor types and advances in technology have stimulated the development of circulating tumor DNA (ctDNA) genotyping. ctDNA was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment. The role of ctDNA is now well established in the clinical decision in certain alterations and tumors, such as the epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer and the v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer. The role of ctDNA analysis in other tumor types remains to be validated. Evolving data indicate the association of ctDNA level with tumor burden, and the usefulness of ctDNA analysis in assessing minimal residual disease, in understanding mechanisms of resistance to treatment, and in dynamically guiding therapy. ctDNA analysis is increasingly used to select therapy. Carefully designed clinical trials that use ctDNA analysis will increase the rate of patients who receive targeted therapy, will elucidate our understanding of evolution of tumor biology and will accelerate drug development and implementation of precision medicine. In this article we provide a critical overview of clinical trials and evolving data of ctDNA analysis in specific tumors and across tumor types.

Keywords: circulating tumor DNA analysis; clinical trials; genomic profiling; targeted therapy.

Figure 1. Potential use of plasma genotyping in cancer.

Early stage disease: Screening will require the use of large NGS panels, with both high sensitivity and perfect specificity. Before surgery, determination of tumor burden in plasma has the potential to help guide neo-adjuvant or adjuvant therapy and monitor response, using large panels or patient-specific assays based on the molecular profile of the tissue biopsy when available. After surgery, NGS (large gene panels or patient-specific assays) can detect MRD and guide adjuvant therapy (early detection) or detect relapse. Low tumor shed in plasma will be the main limitation to the integration of plasma genotyping in early stage disease. Advanced stage disease: At diagnosis, ctDNA can guide genotype-directed therapy (using targeted assays focusing on a predefined gene of interest (i. e. EGFR in NSCLC) or targeted NGS covering genes of interest). The variations in allelic fractions allow for monitoring of treatment response, which may be helpful for pharmacodynamics analyses in phase I studies. When acquired resistance to targeted therapies occurs, ctDNA can detect specific mechanisms of resistance (targeted assay like for EGFR T790M or targeted NGS), taking into consideration the different clones present within the primary tumor (P) and all metastatic sites (M1, M2), and guide treatment adjustments.