Circulating Tumor DNA Could Be a New Noninvasive Tool for CNS Lymphoma Prediction

Take-aways:

• In an analysis of tumor biopsies, plasma samples, and cerebrospinal fluid specimens from patients with CNSL, all CNSL tumor biopsies featured genetic aberrations
• Assessing pretreatment ctDNA concentrations was predictive of survival and allowed for risk-stratification into favorable or poor prognostic groups.
• The ctDNA-based system showed both high specificity and positive predictive value, suggesting patients with CNSL might be able to forego invasive surgical biopsies for the purposes of diagnosis.

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According to new research presented as a plenary abstract during the 2021 ASH Annual Meeting, circulating tumor DNA (ctDNA) accurately reflects tumor burden and may serve as a useful clinical biomarker for risk and outcome in patients with central nervous system lymphoma (CNSL). Presenter Florian Scherer, MD, of the University Medical Center Freiburg in Germany, also noted that ctDNA could allow for surgery-free classification of lymphoma.

This method could also address one of the major challenges of clinical management of CNS lymphomas, Dr. Scherer noted. “Outcomes following methotrexate-based therapies are highly heterogenous and patients experiencing disease progression or relapse have a very poor prognosis,” he said. “However, tools for accurate risk stratification and prediction of clinical outcomes are largely missing.”

In this study, Dr. Scherer and researchers analyzed tumor biopsies, plasma samples, and cerebrospinal fluid (CSF) specimens from a total of 92 patients with CNSL and 44 patients with other brain cancers or inflammatory cerebral diseases using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) and Phased Variant Enrichment and Detection Sequencing (PhasED-Seq). The researchers targeted 794 distinct genetic regions.

Next, the investigators correlated concentrations of ctDNA with radiologic tumor burden measures and evaluated associations with clinical outcomes at specified clinical timepoints. They then used a supervised machine learning approach from tumor whole-genome sequencing data and genotyping analyses to develop a novel classifier to noninvasively distinguish CNSL from other CNS tumors. The classifier was also based on mutational landscapes in both plasma and CSF. Subsequently, the researchers performed an independent validation on the dataset.

They found that all CNSL tumor biopsies featured genetic aberrations. The investigators reported a median of 262 mutations per patient. All CSF specimens and 78% of plasma samples had detectable pretreatment plasma ctDNA. Concentrations of ctDNA ranged from 0.0049% to 50.47% allele frequency in CSF and 0.0004% to 5.94% allele frequency in plasma.

The researchers also compared the observed ctDNA concentrations with those recorded in a previously published cohort of patients with systemic diffuse large B-cell lymphoma. Overall, levels of plasma ctDNA in this cohort were more than 200-fold lower in patients with CNSL. There was also a significant association between concentrations of ctDNA and total radiographic tumor volumes (TRTV), determined by magnetic resonance imaging. However, there was no association between ctDNA concentrations and clinical risk scores or concurrent steroid therapy.

Looking at clinical outcomes and ctDNA concentrations, the investigators found that assessing pretreatment ctDNA concentrations was predictive of progression-free survival (PFS) and overall survival (OS). The investigators were also able to risk-stratify patients into favorable or poor prognostic groups based on ctDNA and TRTV as pretreatment biomarkers. When patients were receiving curative-intent induction therapy, ctDNA positivity was significantly associated with both PFS and OS.

Finally, in the independent validation cohort, the investigators applied the novel machine learning classifier to 207 specimens from patients with and without CNSL. The ctDNA-based system showed both high specificity (100%) and positive predictive value (100%). The researchers noted that these findings suggest that a significant proportion of patients with CNSL “might be able to forego invasive surgical biopsies” for the purposes of diagnosis.

Reference

Andreas J, Alig S, Lauer EM, et al. Profiling of Circulating Tumor DNA for Noninvasive Disease Detection, Risk Stratification, and MRD Monitoring in Patients with CNS Lymphoma. Abstract #6. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021.