Prognostic significance of postsurgery circulating tumor <scp>DNA</scp> in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies

Tie, Jeanne; Cohen, Joshua D.; Lo, Serigne; Wang, Yuxuan; Li, Lu; Christie, Michael; Lee, Margaret; Wong, Rachel; Kosmider, Suzanne; Skinner, Iain; Wong, Hui Li; Lee, Belinda; Burge, Matthew; Yip, Desmond; Karapetis, Christos S.; Price, Timothy; Tebbutt, Niall C.; Haydon, Andrew; Ptak, Janine; Schaeffer, Mary J.; Silliman, Natalie; Dobbyn, Lisa; Popoli, Maria; Tomasetti, Cristian; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Gibbs, Peter

doi:10.1002/ijc.33312

Cited by 86 publications

(87 citation statements)

References 34 publications

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“…Invariably, with increasing clinical usage of plasma ctDNA assays the debate on whether tumor-informed or tumor-uninformed ctDNA assays represent the optimal ctDNA testing approach will likely continue. Several tumor-informed ctDNA assays have been developed with limits of detection that are below 0.1% MAF [ 150 ]. Accordingly, the longitudinal sensitivity and specificity for recurrence approach 88% and 98%, respectively, for tumor-informed ctDNA assays.…”

Section: Future Considerationsmentioning

confidence: 99%

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

Gong

Hendifar

Gangi

et al. 2021

Cancers

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Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I–III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I–III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic.

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Section: Future Considerationsmentioning

confidence: 99%

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

Gong

Hendifar

Gangi

et al. 2021

Cancers

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“…In addition, ctDNA has the potential to provide information about the genomic changes of the tumour [16] . In patients with stage I-III CRC, postoperative ctDNA is a strong independent prognostic biomarker for MRD and recurrence-free survival (RFS) [17] , [18] , [19] . These data suggest that ctDNA may be a potential marker for selecting early-stage CRC patients for adjuvant systemic therapy [ 15 , [20] , [21] , [22] , [23] , [24] ].…”

Section: Introductionmentioning

confidence: 99%

Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases

et al. 2021

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Background Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS). Methods Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS -mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system. Findings With a median follow-up of 19.6 months, the median RFS for patients with detectable ( N = 6, [26%]) and undetectable ( N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively ( p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1–9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4–15, p = 0.01) were associated with poorer RFS and were strongly correlated ( r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS. Interpretation The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response.

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“…The ICP v2 covers 2800 COSMIC mutations in 50 cancer-related genes, which are presented in Table S1 . The mutational status of tumor tissues was determined as previously described [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Clinical Implication of Liquid Biopsy in Colorectal Cancer Patients Treated with Metastasectomy

Lee

Park

Chang

et al. 2021

Cancers

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Background & Aims: The application of circulating tumor DNA (ctDNA) has been studied for predicting recurrent disease after surgery and treatment response during systemic treatment. Metastasectomy can be curative for well-selected patients with metastatic colorectal cancer (mCRC). This prospective study investigated the ctDNA level before and after metastasectomy in patients with mCRC to explore its potential as a predictive biomarker. Methods: We collected data on 98 metastasectomies for mCRC performed from March 2017 to February 2020. Somatic mutations in the primary and metastatic tumors were identified and tumor-informed ctDNAs were selected by ultra-deep targeted sequencing. Plasma samples were mandatorily collected before and 3–4 weeks after metastasectomy and serially, if patients agreed. Results: Data on 67 of 98 metastasectomies (58 patients) meeting the criteria were collected. ctDNA was detected in 9 (29%) of 31 cases treated with upfront metastasectomy and in 7 (19.4%) of 36 cases treated with metastasectomy after upfront chemotherapy. The detection rate of ctDNA was higher in liver metastasis (p = 0.0045) and tumors measuring ≥1 cm (p = 0.0183). ctDNA was less likely to be detected if the response to chemotherapy was good. After metastasectomy, ctDNA was found in 4 (6%) cases with rapid progressive disease. Conclusion: The biological factors affecting the ctDNA shedding from the tumor should be considered when applying ctDNA assays in a clinical setting. After metastasectomy for oligometastatic lesions in good responders of chemotherapy, most ctDNA was cleared or existed below the detection level. To assist clinical decision making after metastasectomy for mCRC using ctDNA, further studies for improving specific outcomes are needed.

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Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies

Abstract: Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across

Cited by 86 publications

References 34 publications

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases

Clinical Implication of Liquid Biopsy in Colorectal Cancer Patients Treated with Metastasectomy

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