Jurik A. Mutter, BSc
In a collaborative study from the University of Freiburg and Stanford University reported in the Journal of Clinical Oncology, Jurik A. Mutter, BSc, of the Faculty of Medicine, University of Freiburg, and colleagues found that circulating tumor DNA (ctDNA) identified prior to and during treatment was associated with poorer outcomes in patients with primary central nervous system (CNS) lymphoma.1
The study included 92 patients with CNS lymphoma continuously enrolled between January 2016 and April 2021 at the University Medical Center Freiburg. Plasma and cerebrospinal fluid samples were assessed by ultrasensitive targeted next-generation sequencing platforms, consisting of Cancer Personalized Profiling by deep Sequencing (CAPP-seq) and Phased Variant Enrichment and Detection Sequencing (PhasED-seq).
Prior to treatment, ctDNA was detectable in 61 of 78 (78%) plasma and 24 of 24 (100%) CSF samples. Among ctDNA-positive patients, 82% had disease progression at 1 year, and 78% died within 2 years, whereas 68% with undetectable ctDNA were progression-free at 1 year, and 90% were alive at 2 years. Hazard ratios were 4.6 (P < .0001) for progression-free survival and 9.6 (P = .0001) for overall survival. On multivariate analysis including established clinical and radiographic risk factors, higher continuous pretreatment ctDNA levels were associated with poorer progression-free survival (hazard ratio [HR] = 1.4, P = .03) and overall survival (HR = 1.6, P = .006).
Among 28 patients undergoing ctDNA profiling in plasma samples collected during curative-intent induction immunochemotherapy, those who were ctDNA-positive at any time during treatment had significantly poorer progression-free survival (HR = 6.2, P = .0002) and overall survival (HR = 7.9, P = .004) vs those who were ctDNA-negative during treatment.
As noted by the investigators, CNS lymphoma diagnosis often remains unconfirmed because of contraindications to invasive biopsies. A proof-of-principle machine-learning approach for biopsy-free CNS lymphoma diagnosis based on ctDNA levels and ctDNA mutation profiles yielded a classifier that showed sensitivities for identifying CNS lymphoma of 59% in CSF samples and 25% in plasma samples. The classifier showed 100% specificity and positive predictive value in samples from patients with non-CNS lymphoma brain cancers.
The investigators concluded: “We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNS [lymphoma]. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNS [lymphoma].”
In an accompanying editorial, Christian Grommes, MD, of the Department of Neurology, Memorial Sloan Kettering Cancer Center, identified steps needed to incorporate ctDNA profiling into clinical practice for diagnosing and monitoring patients with primary CNS lymphoma.2 The author points out the need for a marker such as ctDNA in this setting. Previous studies have indicated that identification of MYD88 L265P mutations in CSF might assist in the diagnosis of primary CNS lymphoma; however, genomic markers have not yet been incorporated into routine diagnostic workups for primary CNS lymphoma. Further, currently only clinical parameters such as patient age and performance status are used in predictive models and risk stratification in clinical trials in primary CNS lymphoma.
Christian Grommes, MD
Florian Scherer, MD
The author identified several steps required to promote ctDNA profiling into clinical practice in primary CNS lymphoma (summarized here):
The findings reported by Mutter et al need to be confirmed in a larger patient population. Ideally, this can be achieved within prospective studies in a less heterogeneous patient cohort and linked to efforts toward benchmarking the methodology by Mutter et al against other platforms evaluating ctDNA profiling in primary CNS lymphoma (eg, ClinicalTrials.gov identifier NCT04401774).
It will be important to establish the relative sensitivity and specificity of ctDNA profiling in plasma vs CSF using contemporaneously collected plasma and CSF samples. The availability of a blood-based diagnostic assay would be particularly useful in a clinical setting when CSF collection may not be clinically safe (for example, in patients with posterior fossa primary CNS lymphoma or large deep white matter tumors exerting mass effect).
It will be important to consider (and shorten) the turnaround time of genomic assays. Treatment of primary CNS lymphoma is often initiated within hours of obtaining the results of a diagnostic tumor biopsy and completion of staging imaging, and a delay in treatment initiation might result in poorer clinical outcome.
The author concluded: “Mutter et al … should be complimented for opening the door toward broader genomic profiling of [primary CNS lymphoma], which may not only improve the diagnosis and monitoring of this aggressive primary brain malignancy but also accelerate the development of emerging precision medicine approaches for [primary CNS lymphoma].”
Florian Scherer, MD, of the Department of Hematology and Oncology, University Medical Center Freiburg, Germany, is the corresponding author of the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by Else Kröner-Fresenius-Stiftung, Deutsche Forschungsgemeinschaft, and others. Dr. Mutter reported no conflicts of interest. Dr. Grommes has received honoraria from Scribbs; has served as a consultant or advisor to BTG, Kite/Gilead, Ono Pharmaceutical, and Roche; has reported other financial relationships with Bayer, Bristol Myers Squibb, Pharmacyclics, and Celgene. Dr. Scherer has received research funding from Roche Sequencing Solutions and Gilead Sciences.
1. Mutter JA, Alig SK, Esfahani MS, et al: Circulating tumor DNA profiling for detection, risk stratification, and classification of brain lymphomas. J Clin Oncol 41:1684-1694, 2023.
2. Grommes C: Circulating tumor DNA in the blood: A new frontier in primary CNS lymphoma? J Clin Oncol 41:1649-1651, 2023.