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

Gong, Jun; Hendifar, Andrew Eugene; Gangi, Alexandra; Zaghiyan, Karen; Atkins, Katelyn M.; Nasseri, Yosef; Murrell, Zuri; Figueiredo, Jane C.; Salvy, Sarah‐Jeanne; Haile, Robert W.; Hitchins, Megan P.

doi:10.3390/cancers13184547

Cited by 17 publications

(9 citation statements)

References 160 publications

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“…In cases where colorectal tumors produced CEA, ctDNA levels aligned with changes in CEA, and furthermore, both were in concordance with radiographic response assessments. Our findings are consistent with the literature showing that plasma ctDNA correlates with conventional measures of tumor response to systemic therapy (by CEA and imaging) in mCRC (12). However, unlike CEA, wherein measurable levels can be found in normal individuals but a proportion of colorectal tumors can be non-secretors of CEA, ctDNA as a measure of minimal residual disease (MRD) is a binary metric whose presence indicates that a large burden of residual metastatic cancer cells remain in one's body (13).…”

Section: Discussionsupporting

confidence: 92%

“…When purposed for detection of tumor mutations through targeted next-generation sequencing (NGS), ctDNA can be used to track dynamic changes in mutations in response to systemic therapy to detect presence of resistance mutations (12). However, in our series we have used a tumor-agnostic, methylated ctDNA marker (mSEPT9) and therefore its assessment of systemic tumor burden is not influenced by tumor mutational profile or prior therapies.…”

Section: Discussionmentioning

confidence: 99%

“…When purposed for MRD detection, the timing of therapy to the collection of blood for ctDNA measurement can influence ctDNA levels. For example, surgery can lead to elevation in ctDNA levels lasting as long as 4 weeks from surgery, which is why many groups have recommended postoperative measures of ctDNA to not occur until 4 weeks after CRC surgery (12,20). Chemotherapy can also cause changes in ctDNA as early as 48 h of chemotherapy infusion, although in another series most changes in ctDNA occurred by cycle 2 of chemotherapy (17,21).…”

Section: Discussionmentioning

confidence: 99%

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Circulating tumor DNA dynamics and response to immunotherapy in colorectal cancer

et al. 2022

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Circulating tumor DNA (ctDNA) is increasingly being investigated as a tool to detect minimal residual disease in resected, stage I-III colorectal cancer. Recent ctDNA studies have indicated that detection of ctDNA following surgery for resectable colorectal cancer confers a significantly higher risk of recurrence than those with negative ctDNA postoperatively. In those with postoperative ctDNA positivity, clearance of minimal residual disease with adjuvant chemotherapy is a positive prognostic indicator. Lastly, ctDNA has demonstrated superior sensitivity to the conventional blood tumor marker carcinoembryonic antigen (CEA) and can offer median lead times of up to 11 months for radiographic detection of recurrence during the surveillance of resected, stage I-III colorectal cancer. In metastatic colorectal cancer (mCRC), there is growing evidence to suggest that plasma ctDNA can be used to monitor tumor response to conventional chemotherapy as well. The present case series demonstrated that plasma ctDNA is a predictor of tumor response to immunotherapy in patients with mCRC that are microsatellite stable or microsatellite instability high. Plasma ctDNA could serve as a dynamic marker of immunotherapy response even in colorectal tumors that were CEA non-producers. Overall, these findings add to ongoing efforts to establish the role of plasma ctDNA in monitoring response to immunotherapy in CRC.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Circulating tumor DNA dynamics and response to immunotherapy in colorectal cancer

et al. 2022

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“…Cell-free DNA plays an increasingly pivotal role in minimal residual disease monitoring for individuals with colon cancer[ 15 ]. Both tumor-informed and tumor-agnostic approaches are being investigated[ 16 ]. The clinical case described in this paper demonstrates the prospect of using cell-free DNA for response assessment, in addition to standard tumor markers such as carcinoembryonic antigen, as illustrated in Figure 1 .…”

Section: Discussionmentioning

confidence: 99%

Response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation: A case report

Buzard,

Douglass,

Gustafson

et al. 2023

World J Gastrointest Oncol

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Minimally invasive surgery is increasingly indicated in the management of malignant disease. Although oesophagectomy is a difficult operation, with a long learning curve, there is actually a shift towards the laparoscopic/thoracoscopic/ robotic approach, due to the advantages of visualization, surgeon comfort (robotic surgery) and the possibility of the whole team to see the operation as well as and the operating surgeon. Although currently there are still many controversial topics, about the surgical treatment of patients with gastro-oesophageal junction (GOJ) adenocarcinoma, such as the type of open or minimally invasive surgical approach, the type of oesophago-gastric resection, the type of lymph node dissection and others, the minimally invasive approach has proven to be a way to reduce postoperative complications of resection, especially by decreasing pulmonary complications. The implementation of new technologies allowed the widening of the range of indications for this type of surgical approach. The short-term and long-term results, as well as the benefits for the patient - reduced surgical trauma, quick and easy recovery - offer this type of surgical treatment the premises for future development. This article reviews the updates and perspectives on the minimally invasive approach for GOJ adenocarcinoma.

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“…A tumor-informed assay relies on initial genomic profiling of the tumor tissues to identify tumor-derived alterations that could be evaluated and monitored using ctDNA. This approach has shown high analytical sensitivity with an improved risk of recurrence prediction ( 28 ). However, recent studies have shown that tumor-agnostic assays, that are independent on prior tumor genomic knowledge of the patient, may also achieve comparable sensitivity to tumor-informed assay in identifying patients with a higher risk of recurrence ( 19 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

Tumor-informed or tumor-agnostic circulating tumor DNA as a biomarker for risk of recurrence in resected colorectal cancer patients

et al. 2023

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IntroductionCirculating tumor DNA (ctDNA) has been increasingly recognized as a promising minimally-invasive biomarker that could identify patients with minimal residual disease and a high risk of recurrence after definitive treatment. In this study, we’ve compared the clinical utility and sensitivity of 2 different approaches to ctDNA analyses: tumor-informed and tumor-agnostic in the management of colorectal (CRC) patients. The clinical benefits of a single timepoint ctDNA analysis compared to serial ctDNA monitoring after definitive treatment were also evaluated to uncover the ideal surveillance protocol.MethodsPatient-paired resected tumor tissues, peripheral blood cells, and a total of 127 pre-operative and serial plasma cell-free DNA (cfDNA) samples after definitive treatment from 38 CRC patients that had undergone curative intent surgery were analyzed using a commercial NGS cfDNA panel.ResultsUp to 84% (32/38) of the recruited patients were detected with at least 1 genomic alteration from the tumor tissues that could be monitored using the tumor-informed ctDNA approach and none of the detected alterations were clonal hematopoiesis (CH) related. In contrast, 37% (14/38) of patients were detected with at least 1 monitoring alteration after exclusion of CH mutations using the tumor-agnostic approach. Serial plasma samples after definitive therapy were available for 31 patients. In the landmark ctDNA analysis, 24% (7/29) of patients had detectable ctDNA and were more likely to relapse than ctDNA-negative patients (p < 0.05). The landmark analysis sensitivity and specificity for recurrence were 67% and 87%, respectively. The incorporation of longitudinal ctDNA analysis at 6-months intervals improved the sensitivity to 100%. The median variant allele frequency (VAF) of the ctDNA mutations detected during surveillance was 0.028% (range: 0.018-0.783), where up to 80% (8/10) of the mutations were detected at VAF lower than the tumor-agnostic detection limit of 0.1%. Utilizing the tumor-agnostic approach reduced the recurrence detection sensitivity to 67% (4/6). Serial ctDNA analyses predicted disease recurrence at a median of 5 months ahead of radiological imaging.ConclusionLongitudinal monitoring using tumor-informed ctDNA testing shows high analytical sensitivity, low probability of false-positive results due to CH mutations, and improved sensitivity in detecting recurrence which may modify the clinical management of CRC.

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

Cited by 17 publications

References 160 publications

Circulating tumor DNA dynamics and response to immunotherapy in colorectal cancer

Circulating tumor DNA dynamics and response to immunotherapy in colorectal cancer

Response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation: A case report

Tumor-informed or tumor-agnostic circulating tumor DNA as a biomarker for risk of recurrence in resected colorectal cancer patients

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