Circulating tumor DNA in B-cell lymphoma: technical advances, clinical applications, and perspectives for translational research

Abstract

Noninvasive disease monitoring and risk stratification by circulating tumor DNA (ctDNA) profiling has become a potential novel strategy for patient management in B-cell lymphoma. Emerging innovative therapeutic options and an unprecedented growth in our understanding of biological and molecular factors underlying lymphoma heterogeneity have fundamentally increased the need for precision-based tools facilitating personalized and accurate disease profiling and quantification. By capturing the entire mutational landscape of tumors, ctDNA assessment has some decisive advantages over conventional tissue biopsies, which usually target only one single tumor site. Due to its non- or minimal-invasive nature, serial and repeated ctDNA profiling provides a real-time picture of the genetic composition and facilitates quantification of tumor burden any time during the course of the disease. In this review, we present a comprehensive overview of technologies used for ctDNA detection and genotyping in B-cell lymphoma, focusing on pre-analytical and technical requirements, the advantages and limitations of various approaches, and highlight recent advances around improving sensitivity and suppressing technical errors. We broadly review potential applications of ctDNA in clinical practice and for translational research by describing how ctDNA might enhance lymphoma subtype classification, treatment response assessment, outcome prediction, and monitoring of measurable residual disease. We finally discuss how ctDNA could be implemented in prospective clinical trials as a novel surrogate endpoint and be utilized as a decision-making tool to guide lymphoma treatment in the future.

Long‐term outcomes of frontline intensification in primary CNS lymphoma: A real‐world single‐center experience

“…In contrast, detecting circulating tumor DNA in CSF or serum by PhasED sequencing could be a novel strategy for outcome prediction and monitoring of measurable residual disease in PCNSL patients. 22 Our study has several limitations. It's a retrospective study trying to elucidate the survival benefits of frontline intensification in real-world PCNSL patients, and we have tried our best to adjust for measurable confounding factors for reducing biases; in fact, there has not been any randomized control trial capable of determining the survival benefit provided by frontline intensification.…”

“…In contrast, detecting circulating tumor DNA in CSF or serum by PhasED sequencing could be a novel strategy for outcome prediction and monitoring of measurable residual disease in PCNSL patients. 22 …”

Clinical implications of circulating tumor DNA in predicting the outcome of diffuse large B cell lymphoma patients receiving first-line therapy

“…Plasma circulating tumor DNA (ctDNA) has shown great potential as a noninvasive biomarker alternative to tumor tissue biopsy for molecular profiling and has been investigated for prognosis prediction, tracking response to treatment, and predicting disease recurrence in a variety of solid and hematologic tumors [12][13][14][15][16]. Notably, some studies have employed next-generation sequencing to reveal the clinical value of pretreatment ctDNA and ctDNA dynamics during treatment in DLBCL patients [17].…”

Primary refractory plasmablastic lymphoma: A precision oncology approach

“…Additionally, genomic profiling of tumor sites provides a more decisive overview on its molecular constitution leading to the most reliable identification of therapeutic vulnerabilities (62,63). However, recent major technical advances have broadened the spectrum of molecular techniques leading to a more and more comprehensive convergence between the molecular studies from primary tumor tissues on the one hand and from the peripheral blood (liquid biopsy) on the other (64). We believe that there will be an essential role for liquid biopsy approaches in the upcoming era of precision oncology.…”