Current and future applications of circulating tumor DNA (ctDNA) to oncology drug development
Alexandra Snyder (1, 2)
(1) Generate Biomedicines (2) Bellevue Hospital, New York University (NYU) Langone Health
Objectives: The objectives of the presentation are
- Describe the assays used to measure ctDNA.
- Discuss the applications of ctDNA in oncology drug development, including for screening, patient selection, and longitudinal modelling.
- Highlight both promise and pitfalls of current applications of ctDNA and how improvements could impact future applications.
Overview/Description of presentation: While all individuals have cell free DNA (cfDNA) circulating in their plasma, in patients with cancer, a small fraction of this cfDNA is shed from tumors as circulating tumor DNA (ctDNA). Since cfDNA was first described in 1948, the ability to measure the ctDNA subset has advanced dramatically, with several assays now used in clinical care, and others in research. Across tumor types, ctDNA burden is prognostic, while its disappearance in the context of a therapeutic intervention appears to be predictive. The three main applications of ctDNA are for screening, patient selection and longitudinal follow up, although there is a continuum between these three states. Because identification of the ctDNA fraction of cfDNA is tantamount to identifying a needle in a haystack, the characteristics of each assay must be fit for purpose. For that reason, screening assays are designed to discern normal from tumor DNA across broad swaths of the genome, yielding as a read-out a likelihood of cancer being present, and requiring a high sensitivity. In contrast, ctDNA tests for patient selection, some of which are already approved for clinical use, tend to be off-the-shelf panels of commonly-altered cancer genes sequenced at great depth that resemble targeted panels applied to tumor tissue. ctDNA assays for longitudinal applications, including understanding response to novel therapies, are still under development. Some resemble broad scope screening assays, while others take the opposite approach, using each patient’s tissue to identify a small number of mutations that are sequenced in the blood at great depth and followed over time. Each application has promises and pitfalls which will be highlighted, including the potential of integrating ctDNA quantification with tumor size change in early oncology. Assay harmonization and consortia efforts are under way and the FDA has issued guidance to try to advance the reliable application of this promising biomarker.
Conclusions/Take home message: ctDNA as a biomarker in oncology is being developed and applied in several contexts (screening, patient selection and longitudinal measurement) to advance oncology drug development. Understanding the strength and weaknesses of assays used will assist investigators in interpreting ctDNA in the context of its clinical application.
References:
[1] Use of Circulating Tumor DNA for Cancer Immunotherapy. Snyder A, Morrissey MP, Hellmann MD.Clin Cancer Res. 2019 Dec 1;25(23):6909-6915. doi: 10.1158/1078-0432.CCR-18-2688. Epub 2019 Jul 8.PMID: 31285372
[2] Translating the evolving molecular landscape of tumors to biomarkers of response for cancer immunotherapy. Anagnostou V, Landon BV, Medina JE, Forde P, Velculescu VE.Sci Transl Med. 2022 Nov 9;14(670):eabo3958. doi: 10.1126/scitranslmed.abo3958. Epub 2022 Nov 9.PMID: 36350985