Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer

Tie, Jeanne; Cohen, Joshua D.; Lahouel, Kamel; Lo, Serigne; Wang, Yuxuan; Kosmider, Suzanne; Wong, Rachel; Shapiro, Jeremy; Lee, Margaret; Harris, Sam; Khattak, Adnan; Burge, Matthew; Harris, Marion; Lynam, James; Nott, Louise M.; Day, Fiona; Hayes, Theresa; McLachlan, Sue‐Anne; Lee, Belinda; Ptak, Janine; Silliman, Natalie; Dobbyn, Lisa; Popoli, Maria; Hruban, Ralph H.; Lennon, Anne Marie; Papadopoulos, Nicholas E.; Kinzler, Kenneth W.; Vogelstein, Bert; Tomasetti, Cristian; Gibbs, Peter

doi:10.1056/nejmoa2200075

Cited by 397 publications

(311 citation statements)

References 40 publications

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“…Frattini et al reported colon cancer patients having higher ctDNA concentrations than patients with rectal cancer (colon: 500 ng/mL, rectal: 250 ng/mL in plasma) [ 63 ], while Cassinotti et al observed the opposite [ 64 ]. However, there is consensus on the usefulness of ctDNA biomarkers in CRC, as they show promise in the initial diagnosis, monitoring minimal residual disease, evaluation of treatment response in metastasis, identifying drivers of treatment sensitivity and resistance, and guiding therapeutic strategies to overcome resistance ( Table 2 ) [ 53 , 65 ].…”

Section: Cell-free Nucleic Acids As Crc Biomarkersmentioning

confidence: 99%

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Styk

Buglyó

Pös

et al. 2022

Cancers

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Colorectal cancer (CRC) is the 3rd most common malignant neoplasm worldwide, with more than two million new cases diagnosed yearly. Despite increasing efforts in screening, many cases are still diagnosed at a late stage, when mortality is high. This paper briefly reviews known genetic causes of CRC (distinguishing between sporadic and familial forms) and discusses potential and confirmed nucleic acid biomarkers obtainable from liquid biopsies, classified by their molecular features, focusing on clinical relevance. We comment on advantageous aspects such as better patient compliance due to blood sampling being minimally invasive, the possibility to monitor mutation characteristics of sporadic and hereditary CRC in a disease showing genetic heterogeneity, and using up- or down-regulated circulating RNA markers to reveal metastasis or disease recurrence. Current difficulties and thoughts on some possible future directions are also discussed. We explore current evidence in the field pointing towards the introduction of personalized CRC management.

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Section: Cell-free Nucleic Acids As Crc Biomarkersmentioning

confidence: 99%

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Styk

Buglyó

Pös

et al. 2022

Cancers

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“…[27] However, in three independent clinical trials including the DYNAMIC trial of 291 stage II CRC patients and a recent multi-center study of 240 stage II&III CRC patients at our cancer center, only 35-41% of recurrences of CRC patients are detected by postoperative ctDNA-based prognostic markers(sensitivity for stage II CRC=35%, Supplementary Table S5 ). [28–30] In all studies, ctDNA positive groups had a significantly higher recurrence risk than ctDNA negative groups. Yet, in all studies, ctDNA failed to detect ∼60% of the stage II CRC patients who developed a recurrence.…”

Section: Discussionmentioning

confidence: 92%

Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment

Wang

Zhou

et al. 2022

Preprint

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BackgroundStage II colorectal cancer(CRC) patients after surgery alone have a five-year survival rate of ∼60-80%; the incremental benefit of adjuvant chemotherapy is <5%. Predicting risk of recurrence and selecting effective personalized adjuvant drugs for stage II CRC using formalin-fixed, paraffin-embedded(FFPE) samples is a major challenge.Methods1319 stage II CRC patients who enrolled in 2011-2019 at Sun Yat-sen University Cancer Center were screened. RNAseq data of FFPE tumor samples of 222 stage II MSS CRC patients(n.recurrence=47, n.norecurrence=175, median follow-up=41 months) were used to develop a method TFunctionalProg for dissecting heterogeneous subgroups of recurrence, predicting risk of recurrence and proposing adjuvant drugs.ResultsTFunctionalProg showed significant predictive values in 222 stage II MSS CRCs. The TFunctionalProg low-risk group had significantly better RFS (validation set (HR=4.78, p-value=1e-4, low-risk group three-year RFS=92.6%, high-risk group three-year RFS=59.7%). TFunctionalProg dissected two subgroups of transition states of stage II MSS CRCs at a high risk of recurrence; each state displays distinct levels of hybrid epithelial-mesenchymal traits, cytotoxic cell inhibition and FOLFOX resistance. Based on mechanisms in two subgroups, TFunctionalProg proposed personalized rational adjuvant drug combinations of immunotherapy, chemotherapy and repurposed CNS drugs. The complementary utility of TFunctionalProg and ctDNA-based prognostic biomarkers were presented.ConclusionTFunctionalProg was validated using FFPE samples to predict the risk of recurrence and propose rational adjuvant drug combinations for stage II CRCs.

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“…Recently published DYNAMIC trial results utilizing the SafeSeqS assay further support the ctDNA-guided adjuvant therapy paradigm [63]. DYNAMIC was a prospective randomized phase II study to assess whether ctDNA-guided adjuvant therapy in resected stage II colon cancer patients could reduce ACT use without increasing recurrence risk.…”

Section: Ctdna-guided Mrd Assessment: Studies In Colorectal Cancermentioning

confidence: 95%

Finding Waldo: The Evolving Paradigm of Circulating Tumor DNA (ctDNA)—Guided Minimal Residual Disease (MRD) Assessment in Colorectal Cancer (CRC)

Chakrabarti

Kasi

Parikh

et al. 2022

Cancers

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Circulating tumor DNA (ctDNA), the tumor-derived cell-free DNA fragments in the bloodstream carrying tumor-specific genetic and epigenetic alterations, represents an emerging novel tool for minimal residual disease (MRD) assessment in patients with resected colorectal cancer (CRC). For many decades, precise risk-stratification following curative-intent colorectal surgery has remained an enduring challenge. The current risk stratification strategy relies on clinicopathologic characteristics of the tumors, meaning that it lacks precision and results in over-and undertreatment in a significant proportion of patients. Consequently, a biomarker that can reliably identify patients harboring MRD would be of critical importance in refining patient selection for adjuvant therapy. Several prospective cohort studies have provided compelling data suggesting that ctDNA could be a robust biomarker for MRD that outperforms all existing clinicopathologic criteria. Numerous clinical trials are currently underway to validate the ctDNA-guided MRD assessment and adjuvant treatment strategies. Once validated, the ctDNA technology will likely transform the adjuvant therapy paradigm of colorectal cancer, supporting ctDNA-guided treatment escalation and de-escalation. The current article presents a comprehensive overview of the published studies supporting the utility of ctDNA for MRD assessment in patients with CRC. We also discuss ongoing ctDNA-guided adjuvant clinical trials that will likely shape future adjuvant therapy strategies for patients with CRC.

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Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer

Cited by 397 publications

References 40 publications

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment

Finding Waldo: The Evolving Paradigm of Circulating Tumor DNA (ctDNA)—Guided Minimal Residual Disease (MRD) Assessment in Colorectal Cancer (CRC)

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