Mihir Gupta, MD, a neurosurgery resident at the University of California San Diego and postdoctoral fellow at Massachusetts General Hospital Department of Neurosurgery, and Ganesh M. Shankar, MD, PhD, Assistant Professor of Neuro­surgery, Massachusetts General Hospital and Harvard Medical School, commented for The ASCO Post on the use of circulating tumor DNA (ctDNA) to detect central nervous system (CNS) lymphoma and the study by Mutter et al. “Securing an accurate and timely diagnosis of CNS neoplasms remains uniquely challenging. Acqui­sition of tissue by neurosurgical biopsy is associated with risks, including intra­cranial hemorrhage or injury to eloquent structures. Meanwhile, current liquid-based diagnostics such as cytology and flow cytometry from cerebrospinal fluid or peripheral blood carry low positive and negative predictive values. Further complicating the diagnostic workup is the low pretest probability of CNS lymphoma, even when suspected on clinical and radiographic grounds, as the ultimate diagnosis is frequently a different neoplastic or even non-neoplastic entity.¹

Mihir Gupta, MD

Ganesh M. Shankar, MD, PhD

Highly Sensitive Multigene Assay

“We recently demonstrated that a [polymerase chain reaction]-based assay for ctDNA in cerebrospinal fluid and plasma can accurately and sensitively detect point mutations characteristic of malignancies such as CNS lymphoma and glioma within 80 minutes of sample acquisition. This approach is predicated on detection of hotspot mutations in genes frequently altered in CNS neoplasms, including MYD88, H3F3A, IDH1/2, and TERT.¹ In a plenary presentation at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition selected among the ‘Best of ASH,’ teams from Stanford University and Germany extend this approach with a robust next-generation sequencing panel to detect mutations characteristic of CNS lymphoma from cerebrospinal and plasma ctDNA.² This highly sensitive multigene assay is particularly promising for diagnosing CNS lymphoma, especially when the highly recurrent MYD88 L265P alteration is absent.

“There is also an unmet clinical need for liquid biomarkers to guide prognostication, therapy selection, and treatment response assessment for CNS neoplasms. This is in part because an integrated histomolecular classification of these rare entities has only recently been established³ and continues to evolve.⁴ In this context, the authors demonstrate that the presence of ctDNA in plasma using their method is a significant predictor of progression-free and overall survival in a large cohort of patients with CNS lymphoma. The presence of ctDNA may thus be considered for risk-stratification and defining patient populations prior to clinical trial enrollment.

“The authors’ machine learning method also presents an exciting platform for future incorporation of additional ctDNA-derived biomarkers such as methylation and epigenetic signatures gaining adoption in other cancers.⁵ The potential ability to detect minimal residual or relapsed disease through such reliable biomarkers also poses an intriguing possible role for Ommaya reservoir placement to enable frequent sampling of cerebrospinal fluid and track treatment response in the CNS. Importantly, the authors demonstrate that the Karnofsky performance score is the strongest prognostic factor in their cohort, emphasizing the irreplaceable role of rigorous clinical evaluation.

Important Frontiers

“Collectively, this work is a critical step toward clinical translation of ­ctDNA-based assays for CNS neoplasms, mirroring the tremendous progress that has been made in the setting of solid-organ and hematologic cancers. In recent trials, obtaining ctDNA results typically requires a median of 10 to 11 days^6,7 and requires substantial infrastructure. Improving the speed, cost, and accessibility of these promising assays thus represents important frontiers for future efforts. n

DISCLOSURE: Dr. Gupta and Dr. Shankar reported no conflicts of interest.

REFERENCES

1. Gupta M, et al: A rapid genotyping panel for detection of primary central nervous system lymphoma. Blood 138:382-386, 2021.

2. Mutter JA, et al: Profiling of circulating tumor DNA for noninvasive disease detection, risk stratification, and MRD monitoring in patients with CNS lymphoma. 2021 ASH Annual Meeting & Exhibition. Abstract 6. Presented December 12, 2021.

3. Louis DN, et al: The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol 131:803-820, 2016.

4. Louis DN, et al: The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol 23:1231-1251, 2021.

5. Parikh AR, et al: Minimal residual disease detection using a plasma-only circulating tumor DNA assay in patients with colorectal cancer. Clin Cancer Res 27:5586-5594, 2021.

6. Nakamura Y, et al: Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med 26:1859-1864, 2020.

7. Turner NC, et al: Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH). Lancet Oncol 21:1296-1308, 2020.