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Brain Tissue Is the Issue

December 13, 2021

The Utility of Circulating Tumor DNA in Patients With Central Nervous System Lymphoma 

Ah-Reum (Autumn) Jeong, MD, and Aaron M. Goodman, MD

Dr. Aaron Goodman (@AaronGoodman33) is an associate professor in the Division of Blood and Marrow Transplantation at the University of California San Diego (UCSD) Moores Cancer Center, San Diego. His specialties include bone marrow transplantation and cellular therapies, and his clinical/research interests are rare diseases, Castleman disease, and T-cell lymphomas. Dr. Goodman hails from Chicago and attended University of Illinois for undergrad, Emory for medical school, Washington University for residency, and UCSD for hematology-oncology fellowship. Dr. Goodman also offered insight into his life outside hematology. “I play in a rock band and have played guitar since age six,” he said. 

Joining Dr. Goodman this year is Junior Author Dr. Ah-Reum (Autumn) Jeong (@AutumnJeong). Dr. Jeong is a hematology/oncology fellow at Moores Cancer Center, University of California San Diego, in La Jolla, with a clinical/research interest is in lymphoma. She studied at Cornell University for undergraduate, and received her MD at University of Southern California, where she also did her internal medicine residency. She hails from Los Angeles and played lacrosse in high school. 

A fundamental rule in practicing oncology is that “tissue is the issue” when trying to secure a cancer diagnosis. Tissue biopsy is almost always necessary prior to starting treatment with rare exception (acute promyelocytic leukemia). Central nervous system lymphoma (CNSL), including both primary and secondary disease, refers to lymphoma involving the brain, spinal cord, or both. A biopsy is often challenging in these patients due to the location of the lymphoma and invasiveness of the procedure with its associated risk. Imaging modalities are often nondiagnostic — brain magnetic resonance imaging (MRI) can be confounded by infections and other primary brain tumors. Furthermore, residual enhancement is often seen on brain MRI after treatment, and it is extremely difficult to ascertain whether patients are truly in remission or not. Repeat brain biopsies are often not done, unlike in systemic lymphoma where biopsies are repeated when concerned for disease progression or relapse. This greatly limits the ability to obtain genomic studies that may guide trial design or treatment decisions. 

Florian SchererCirculating tumor DNA (ctDNA) is an attractive, noninvasive method that can be used to monitor minimal residual disease (MRD) and disease recurrence. Next-generation sequencing is applied to the plasma samples to detect any circulating DNA from the tumor tissue that has seeped into the blood. This technique is now frequently used in practice for noninvasive molecular profiling and monitoring for MRD and early recurrence in variety of solid malignancies such as gastrointestinal and lung cancers. Recently, this technology has been studied in lymphomas. However, the application of ctDNA in CNSL has been challenging due to low ctDNA concentrations in the plasma and low detection rates.

At the 2021 ASH Annual Meeting Plenary Scientific Session, Dr. Florian Scherer (pictured) presented the utility of ctDNA of the plasma and cerebrospinal fluid (CSF) for disease detection, prognosis, and response to treatment of patients with primary and/or secondary CNSL. In this study, a deep sequencing technique was applied to the biopsy tissue, plasma, and CSF specimens from 92 patients with CNSL to detect ctDNA. The authors’ goal was to correlate the ctDNA concentration with both the tumor burden measured by MRI and clinical outcomes. The detection of ctDNA in the CSF correlated with periventricular involvement of the lymphoma.

Remarkably, the authors were able to detect genetic aberrations in 100 percent of CNSL tumor biopsies and 100 percent of CSF samples! Additionally, ctDNA was detected in 78 percent of pre-treatment plasma samples. The concentrations of ctDNA were variable with median allele frequency of 0.04 percent (range, 0.0004% to 5.94%) in the plasma and 0.62 percent (range, 0.0049% to 50.47%) in the CSF. The authors found that the ctDNA concentration of the plasma correlated with total tumor volume measured by MRI. 

The detection of pre-treatment ctDNA in the plasma conferred a worse prognosis. Those with detectable pre-treatment plasma ctDNA had higher tumor volume, 4.6 times higher risk of disease progression, and 6.1 times higher risk of mortality compared to patients with an undetectable plasma ctDNA. The plasma ctDNA could also be monitored during curative-intent treatment to gauge response. Those who had detectable plasma ctDNA during treatment had a 6.2 times higher risk of progressive disease and 7.9 times higher risk of mortality compared to patients with an undetectable plasma ctDNA. 

Finally, the authors generated a machine learning algorithm from publicly available tumor whole-genome sequencing data and the current study’s 30 CNSL cohort, 44 patients with other neoplastic or inflammatory CNS disorders, and healthy controls to distinguish between CNSL and other conditions. The novel machine learning technique was applied to 183 specimens from an independent cohort composed of CNS lymphoma and other CNS conditions. The algorithm was found to have a 100 percent specificity and 100 percent positive predictive value (no false-positives) for the diagnosis of CNSL, with a sensitivity of 57 percent in the CSF and 21 percent in the plasma. The authors proposed an algorithm that incorporates ctDNA profiling for noninvasive diagnosis of CNSL. 

For those interested in learning more about ctDNA, we recommend watching the Scientific Workshop “Circulating Tumor DNA in Diagnostics – Hope or Hype?” available via the virtual platform through December 17, and the oral abstracts by Mohammad Shahrokh Esfahani, PhD, and colleagues (abstract 37) and Hua-Jay J. Cherng, MD, and colleagues (abstract 38). 

Hopefully in the near future, brain biopsy may be deferred in patients with imaging findings concerning for CNSL and CSF/plasma mutation detection by ctDNA. This may result in patients getting a diagnosis and receiving treatment more quickly, which is of critical importance in CNS lymphoma to prevent further neurologic deterioration. Furthermore, this technique may allow stratifying CNSL patients into risk groups to help guide therapy, and we eagerly await this technology to be incorporated into trial designs. The authors’ findings are an encouraging first step to a noninvasive diagnostic and prognostic use of ctDNA in CNSL. 

Dr. Jeong and Dr. Goodman indicated no relevant conflicts of interest.  

Florian Scherer
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