Clinical Implications and Biomarkers of Clonal Evolution

Recent technological advances in the detection and characterization of cell free circulating tumor DNA (ctDNA) are providing new opportunities for treatment tailoring based on real-time monitoring of clonal evolution. Circulating biomarkers can provide a "liquid biopsy" alternative to tissue biopsies allowing noninvasive tumor genotyping and the serial analysis of genomic changes from a simple blood test. The emerging clinical benefits of ctDNA analysis in the management of solid tumours has led to an expansion of opportunities in the use of ctDNA for disease monitoring in haematological malignancies. Research in this area has rapidly expanded exploring the role of ctDNA for risk stratification, monitoring tumour burden and identifying the early emergence of treatment resistance. In the management of lymphoma, comprehensive analysis of somatic genomic alterations in plasma DNA has emerged as an important clinical tool. The use of ctDNA analysis to follow tumour specific genomic alterations identified on an individual basis can be used to help identify minimal residual disease post treatment and guide therapeutic decisions. Moreover, ctDNA analysis can been utilized to identify distinct biological subtypes of lymphoma and provide insights into patterns of genomic evolution following treatment. The role of ctDNA as a minimally invasive strategy for disease monitoring has also recently been demonstrated in chronic lymphocytic leukemia (CLL) showing additional potential of this technique in haematological malignancies with a circulating disease component. In CLL, ctDNA analysis can reveal changes in the disease across tissue compartments, including the bone marrow and lymph nodes, providing additional information to that which can be assessed by monitoring the circulating disease alone. Serial ctDNA analysis in CLL can allow clonal dynamics to be monitored over time and can identify the emergence of genomic changes associated with Richter's syndrome. Here, I will focus on the use of ctDNA technology to follow disease burden and track genomic changes in patients receiving novel therapies for lymphoid malignancies, as well as the promises and challenges in developing these tools for clinical application.