TY - JOUR
T1 - Genomic approaches to cancer and minimal residual disease detection using circulating tumor DNA
AU - Semenkovich, Nicholas P.
AU - Szymanski, Jeffrey
AU - Earland, Noah
AU - Chauhan, Pradeep S.
AU - Pellini, Bruna
AU - Chaudhuri, Aadel
N1 - Funding Information:
This work was supported by the National Institute for General Medical Sciences (AAC), under award number R35 GM142710, the National Cancer Institute under award number U2C CA252981 (AAC), and the National Institute of Diabetes and Digestive and Kidney Diseases under award number T32 DK007120 (NPS). This work was additionally supported by the V Foundation V Scholar Award (AAC), the Washington University Alvin J. Siteman Cancer Research Fund (AAC), and the Children’s Discovery Institute (AAC). Figures were created with BioRender.com.
Funding Information:
NPS, JJS, and AAC have patent filings related to lung cancer detection. NPS has served as a consultant/advisor to Acuta Capital Partners. BP receives research support to the institution from Bristol Myers Squibb, has received speaker honoraria from BioAscend, Merck, MJH Life Science, Play to Know AG, Grupo Pardini, GBOT, Foundation Medicine, and has done consulting/advisory board work with Guidepoint, Guardant Health, Foundation Medicine, Illumina, Regeneron and AstraZeneca. BP reports funding from the Bristol Myers Squibb Foundation/the Robert A. Winn Diversity in Clinical Trials Awards Program, outside of the submitted work. AAC has patent filings related to cancer biomarkers, and has licensed technology to Droplet Biosciences, Tempus Labs and to Biocognitive Labs. AAC has served as a consultant/advisor to Roche, Tempus, Geneoscopy, NuProbe, Illumina, Daiichi Sankyo, AstraZeneca, AlphaSights, DeciBio, and Guidepoint. AAC has received honoraria from Roche, Foundation Medicine, and Dava Oncology. AAC has stock options in Geneoscopy, research support from Roche and Tempus Labs, and ownership interests in Droplet Biosciences and LiquidCell Dx.
Publisher Copyright:
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2023/6/22
Y1 - 2023/6/22
N2 - Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable mutations to personalize systemic therapy, detect post-treatment minimal residual disease (MRD), and predict responses to immunotherapy. ctDNA can also be isolated from a range of different biofluids, with the possibility of detecting locoregional MRD with increased sensitivity if sampling more proximally than blood plasma. However, ctDNA detection remains challenging in early-stage and post-treatment MRD settings where ctDNA levels are minuscule giving a high risk for false negative results, which is balanced with the risk of false positive results from clonal hematopoiesis. To address these challenges, researchers have developed ever-more elegant approaches to lower the limit of detection (LOD) of ctDNA assays toward the part-per-million range and boost assay sensitivity and specificity by reducing sources of low-level technical and biological noise, and by harnessing specific genomic and epigenomic features of ctDNA. In this review, we highlight a range of modern assays for ctDNA analysis, including advancements made to improve the signal-to-noise ratio. We further highlight the challenge of detecting ultra-rare tumor-associated variants, overcoming which will improve the sensitivity of post-treatment MRD detection and open a new frontier of personalized adjuvant treatment decision-making.
AB - Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable mutations to personalize systemic therapy, detect post-treatment minimal residual disease (MRD), and predict responses to immunotherapy. ctDNA can also be isolated from a range of different biofluids, with the possibility of detecting locoregional MRD with increased sensitivity if sampling more proximally than blood plasma. However, ctDNA detection remains challenging in early-stage and post-treatment MRD settings where ctDNA levels are minuscule giving a high risk for false negative results, which is balanced with the risk of false positive results from clonal hematopoiesis. To address these challenges, researchers have developed ever-more elegant approaches to lower the limit of detection (LOD) of ctDNA assays toward the part-per-million range and boost assay sensitivity and specificity by reducing sources of low-level technical and biological noise, and by harnessing specific genomic and epigenomic features of ctDNA. In this review, we highlight a range of modern assays for ctDNA analysis, including advancements made to improve the signal-to-noise ratio. We further highlight the challenge of detecting ultra-rare tumor-associated variants, overcoming which will improve the sensitivity of post-treatment MRD detection and open a new frontier of personalized adjuvant treatment decision-making.
UR - http://www.scopus.com/inward/record.url?scp=85162842966&partnerID=8YFLogxK
U2 - 10.1136/jitc-2022-006284
DO - 10.1136/jitc-2022-006284
M3 - Review article
C2 - 37349125
AN - SCOPUS:85162842966
SN - 2051-1426
VL - 11
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 6
M1 - e006284
ER -