Liquid biopsy in lymphoma: Is it primed for clinical translation?

Abstract

The simultaneous growth in our understanding of lymphoma biology and the burgeoning therapeutic options has come with a renewed drive for precision‐based approaches and how best to incorporate them into contemporary and future patient care. In the hunt for accurate and sensitive biomarkers, liquid biopsies, particularly circulating tumour DNA, have come to the forefront as a promising tool in multiple cancer types including lymphomas, with considerable implications for clinical practice. Liquid biopsy analyses could supplement existing tissue biopsies with distinct advantages including the minimally invasive nature and the ease with which it can be repeated during a patient's clinical journey. Circulating tumour DNA (ctDNA) analyses has been and continues to be evaluated across lymphoma subtypes with potential applications as a diagnostic, disease monitoring and treatment selection tool. To make the leap into the clinic, these assays must demonstrate accuracy, reliability and a quick turnaround to be employed in the real‐time clinical management of lymphoma patients. Here, we review the available ctDNA assays and discuss key practical and technical issues around improving sensitivity. We then focus on their potential roles in several lymphoma subtypes exemplified by recent studies and provide a glimpse of different features that can be analysed beyond ctDNA.

Rare central nervous system lymphomas

“…Looking ahead, emerging technologies such as ctDNA in plasma and CSF offer great promise as a paradigm‐shift in biological classification, as well as offering an opportunity for individualised, dynamic assessment of treatment response 11 . Moreover, ctDNA should provide much greater sensitivity for the detection of concomitant subclinical disease in both systemic and CNS compartments.…”

“…Indeed, one small study detected this mutation in the CSF ctDNA of 20/26 patients with CNS lymphoma 12 . Importantly, ctDNA analysis does not distinguish between DLBCL and lymphoplasmacytic histological subtypes 11 . Nevertheless, ctDNA (from blood and/or CSF) holds much promise for the diagnosis of CNS lymphoma and is likely to provide additional contributions to the differential diagnoses of less common CNS lymphoma entities.…”

“…9 More recently, there has been increased interest in the use of circulating tumour DNA (ctDNA) to aid diagnosis across lymphoma subtypes and improve the sensitivity of detecting disease recurrence. 10,11 A specific example is the diagnostic utility of the myeloid differentiation primary response 88 (MYD88) L265P mutation given its presence in >80% of PCNSL cases. Indeed, one small study detected this mutation in the CSF ctDNA of 20/26 patients with CNS lymphoma.…”

“…Looking ahead, emerging technologies such as ctDNA in plasma and CSF offer great promise as a paradigm-shift in biological classification, as well as offering an opportunity for individualised, dynamic assessment of treatment response. 11 Moreover, ctDNA should provide much greater sensitivity for the detection of concomitant subclinical disease in both systemic and CNS compartments. Importantly, ctDNA and sequencing technology, together with enhanced potential for discovery science on small and/or fixed tissue specimens, promises further opportunities to develop biologically-rational therapies informed by a more precise understanding of subtype specific pathobiology.…”

“…The combined sensitivity of CSF cytology, flow cytometry, CSF lactate dehydrogenase (LDH) isozyme 5, β2‐microglobulin, and immunoglobulin heavy (IGH) chain rearrangement studies (for B‐cell lymphomas) is superior to CSF cytology alone but even this integrated approach provides only moderate specificity 9 . More recently, there has been increased interest in the use of circulating tumour DNA (ctDNA) to aid diagnosis across lymphoma subtypes and improve the sensitivity of detecting disease recurrence 10,11 . A specific example is the diagnostic utility of the myeloid differentiation primary response 88 ( MYD88 ) L265P mutation given its presence in >80% of PCNSL cases.…”