Circulating tumor DNA: the future of personalized medicine in oncology?

Tissue biopsy has long served as the mainstay of cancer diagnosis, staging, and therapeutic decisions, with its role evolving from simple histologic examination to complex genetic analysis. Despite its utility, biopsy represents only a single time point from a single location, often proving inadequate at fully characterizing a malignancy and its evolution because nearby tissue might contain additional genetic information that would affect staging or treatment. Unfortunately, the invasive nature and inherent selection bias of biopsy limit its usefulness as a real-time monitoring tool. Newer technologies seeking to transcend this shortcoming include analysis of circulating tumor cells and their fragments, such as exosomes and DNA, in peripheral blood. A recent feature in Nature highlights advancements in the detection of circulating tumor DNA (ctDNA) for this purpose (1). This emerging methodology enables sequencing of DNA originating from lysed tumor cells present in a blood sample to follow tumor recurrence and to characterize genetic abnormalities that confer resistance. Free DNA was first discovered in human circulation during the late 1940s, followed by isolation of tumor-specific genetic material in the 1970s. Yet, ctDNA methods for oncology have since lagged behind applications such as prenatal diagnostics. Challenges that have impeded its development and integration into clinical practice include highly variable, often low, ctDNA concentration in blood, especially in early stage tumors. Fortunately, technologic advancements in target selection and amplification methods as well as sequencing methodologies have facilitated the detection of these minute quantities. The authors describe one methodology, known as BEAMing (beads, emulsions, amplification, and magnetics), which boasts an analytical sensitivity of up to 0.01% using enhanced and highly selective target capture. This exquisite detection capability has allowed researchers to explore the clinical applicability of ctDNA to cancer monitoring. A study published by Diehl et al. (2 ) showed early evidence of the strong negative predictive value of ctDNA, demonstrating that undetectable ctDNA levels following tumor resection correlate with the absence of tumor recurrence. Further work has confirmed this finding and demonstrated 1 Department of Pathology, UniversityHospitals CaseMedical Center and 2 Department of Pathology, Case Western Reserve University, Cleveland, OH. * Address correspondence to this author at: 11100 Euclid Avenue Department of Pathology–PTH 5077, Cleveland, OH 44106. Fax 216-844-1840; e-mail [email protected]. Received October 9, 2014; accepted October 14, 2014. DOI: 10.1373/clinchem.2014.234203 © 2014 American Association for Clinical Chemistry What Is Your Guess?