The relationship between the degree of aberrant methylation in colorectal cancer tissue and appearance of tumor-derived DNA in blood.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 579-579
Author(s):  
Erin L Symonds ◽  
Susanne Kartin Pedersen ◽  
Rohan Baker ◽  
Scott Mansfield ◽  
Dawn Bastin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Tumor Staging ◽  
Tumor Resection ◽  
Tumor Stage ◽  
Circulating Tumor Dna ◽  
Early Event ◽  
Cancer Tissue ◽  
Aberrant Methylation ◽  
Secondary Tumors

579 Background: We have developed a blood test for colorectal cancer (CRC) detecting circulating tumor DNA (ctDNA) by measuring the presence of methylated BCAT1 and IKZF1. This study aimed to compare the levels of methylated BCAT1/IKZF1 in tissue from patients with colorectal cancer to those in blood before and after tumor resection. Methods: 80 people with invasive CRC had blood collected prior to resection. Tumor and adjacent non-tumor colorectal tissue was collected at surgery. Five patients had tissue collected from secondary cancers in the liver. Additional blood samples were collected within a year of surgery from 45 of these patients. DNA was extracted from all samples and assayed for methylated BCAT1 and IKZF1 DNA. Results: The median % BCAT1 and IKZF1 methylation in colorectal tissues were 45.7% and 59.9% (tumor), and 4.8% and 0% (non-tumor), p < 0.001. Median methylation levels in secondary tumors of the liver were 4.9% for BCAT1 and 29.5% for IKZF1, compared to 0% for both biomarkers in non-tumor liver tissue (p < 0.01). The methylation levels did not differ across CRC stages (p > 0.05), whereas the detection of ctDNA in the blood was significantly associated with tumor staging (p < 0.01). Of the 21 ctDNA positive CRC patients, 18 (86%) tested negative post resection. Of the 3 that remained blood positive post resection, further cancers were confirmed in two (one with recurrence in the lung, one with thyroid cancer). Conclusions: Aberrant BCAT1 and IKZF1 methylation is an early event in CRC development and is localised to the tumor tissue. Methylated BCAT1 and IKZF1 in blood are dependent on tumor stage and measuring minimal residual disease by detecting ctDNA based on methylated BCAT1 and IKZF1 may inform completeness of tumor resection.

scholarly journals Key biomarkers within the colorectal cancer related inflammatory microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Valentin Calu ◽  
Adriana Ionescu ◽  
Loredana Stanca ◽  
Ovidiu Ionut Geicu ◽  
Florin Iordache ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Staging ◽  
Pearson Correlation ◽  
Tumor Resection ◽  
Correlation Coefficients ◽  
Tumor Stage ◽  
Magnetic Bead ◽  
Tissue Expression ◽  
Tissue Samples ◽  
Inflammatory Microenvironment

AbstractTherapeutic approaches focused on the inflammatory microenvironment are currently gaining more support, as biomolecules involved in the inflammatory colorectal cancer (CRC) tumor microenvironment are being explored. We analyzed tumor and paired normal tissue samples from CRC patients (n = 22) whom underwent tumor resection surgery. We assessed 39 inflammation-involved biomolecules (multiplex magnetic bead-based immunoassay), CEA and CA19-9 (ELISA assay) and the tissue expression levels of occludin and also pErk, STAT1 and STAT3 transcriptional factors (western blot). Tumor staging has been established by histopathological evaluation of HE stained tumor tissue sections. We report 32 biomarkers displaying statistically significant differences in tumor vs. control. Additionally, positive statistical biomarker correlations were found between MMP2–IL8 and BAFF–IL8 (Pearson correlation coefficients > 0.751), while APRIL–MMP2, APRIL–BAFF and APRIL–IL8 were negatively correlated (correlation coefficients < − 0.650). While APRIL, BAFF, IL8 and MMP2 did not modulate with tumor stage, they were inversely related to the immune infiltrate level and CD163 tissue expression. We conclude that the significantly decreased APRIL and increased BAFF, IL8 and MMP2 expression were tumor-specific and deserve consideration in the development of new treatments. Also, the positive correlation between Chitinase 3-like 1 and IL8 (0.57) or MMP2 (0.50) suggest a role in tumor growth and metastasis pathways.

Minimal residual disease by circulating tumor DNA analysis for colorectal cancer patients receiving radical surgery: An initial report from CIRCULATE-Japan.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3608-3608
Author(s):  
Hiroki Yukami ◽  
Yoshiaki Nakamura ◽  
Jun Watanabe ◽  
Masahito Kotaka ◽  
Kentaro Yamazaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Analysis ◽  
Residual Disease ◽  
Clinical Stage ◽  
Circulating Tumor Dna ◽  
Patient Specific ◽  
Detection Rates ◽  
Initial Report ◽  
Post Surgery ◽  
Tumor Dna

3608 Background: Circulating tumor DNA (ctDNA) analysis can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). We are conducting a prospective observational study to monitor MRD status in patients with clinical stage II–IV or relapsed CRC amenable to radical surgical resection (GALAXY study), as part of the CIRCULATE-Japan, a nationwide ctDNA-guided precision adjuvant therapy project. Methods: Analysis of ctDNA is being performed at pre- and post-surgery timepoints and will continue periodically for up to 2 years using Signatera, a personalized, tumor-informed ctDNA assay that is designed to track 16 patient-specific somatic variants based on whole-exome sequencing of tumor tissue. The association of peri-operative ctDNA status with clinicopathological characteristics was investigated. Results: As of January 13, 2021, 941 patients have been enrolled in the GALAXY study, of which 400 patients had their pre-operative ctDNA status evaluated. Of the 400 patients, baseline ctDNA was detected in 92% (367/400) of the patients: consisting of 35 patients with pathological stage (pStage) I, 135 with pStage II, 152 with pStage III, and 78 with pStage IV or relapsed disease (pStage IV/R). Patient-specific Signatera assays targeting 16 variants were designed for 100% of the patients. Out of the 6400 designed variants 99.3% passed quality control in the plasma analysis and produced the final results. Among 4425 genes selected for 400 patients, 3330 genes were selected for only one patient, while TP53 was the most commonly selected in 113 patients (28%). Median ctDNA levels, measured in mean tumor molecules per mL of plasma and ctDNA detection rate, stratified by stage are presented in table. Positive ctDNA status post-surgery was significantly associated with advanced pStage, pT and pN, and lymphovascular invasion. Of the 13 patients with recurrence, 10 were detected with a positive ctDNA at 4-weeks post-surgery, before confirmation of recurrence by the radiological imaging. Conclusions: Preoperative ctDNA detection rates were observed to be in >90% in patients with pStage II–III by personalized ctDNA assay based on unique somatic variants, specific to each patient. ctDNA- based MRD detected post-surgery (4W) was significantly associated with certain known clinicopathological factors for recurrence with ctDNA positivity associated with a very short-term of recurrence. Clinical trial information: 000039205. [Table: see text]

Tumor-informed assessment of molecular residual disease and its incorporation into practice for patients with early and advanced-stage colorectal cancer (CRC-MRD Consortia).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4108-4108 ◽  
Author(s):  
Pashtoon Murtaza Kasi ◽  
Farshid Dayyani ◽  
Van K. Morris ◽  
Scott Kopetz ◽  
Aparna Raj Parikh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Disease ◽  
Residual Disease ◽  
Early Stage ◽  
Circulating Tumor Dna ◽  
Response To Treatment ◽  
Chi Square ◽  
Multiplex Pcr Assay ◽  
Crc Management ◽  
First Time

4108 Background: Circulating tumor DNA (ctDNA) testing can be used for the assessment of molecular residual disease (MRD) in patients with early-stage or advanced colorectal cancer (CRC). Prospective evaluation of this methodology in clinical practice has been limited to-date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera 16-plex bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA for MRD assessment. We analyze and present results from an ongoing early adopter program of ctDNA testing across the spectrum of CRC management. Results: Here we present a total of 250 patients with colon (n=200), rectal (n=40), and other lower gastrointestinal cancers (n =10; anal, appendiceal, small bowel). MRD positivity rates and ctDNA quantification (mean tumor molecules/mL) are shown in Table. ctDNA detection was significantly associated with stage of disease (p<0.0001 Chi-square: 70.33). Additionally, in patients with radiologically measurable active metastatic disease, ctDNA detection rate was 100%. On the contrary, patients with advanced/metastatic disease who had partial response to treatment or no evidence of disease (NED) showed 28.5% and 19.2% of ctDNA-positivity, respectively. Conclusions: This is the first large, real-world study reporting on the results from a clinically validated MRD assay. For the first time we delineate MRD rates and quantify ctDNA concentration in patients with early-stage and advanced CRC. Furthermore, we provide an initial readout that effective ongoing treatment in patients with CRC may be correlated with ctDNA clearance. Ongoing analysis expanded to a cohort of 1200 clinical cases including correlation with genomic and serial testing will be presented. [Table: see text]

scholarly journals Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases

2021 ◽  
pp. 1166-1177
Author(s):  
Fotios Loupakis ◽  
Shruti Sharma ◽  
Madiha Derouazi ◽  
Sabina Murgioni ◽  
Paola Biason ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Overall Survival ◽  
Systemic Therapy ◽  
Residual Disease ◽  
Prognostic Biomarker ◽  
Circulating Tumor Dna ◽  
Significant Prognostic Factor ◽  
Resection Of Metastases ◽  
Tumor Dna

PURPOSE More than 50% of patients with stage IV colorectal cancer (metastatic colorectal cancer [mCRC]) relapse postresection. The efficacy of postoperative systemic treatment is limited in this setting. Thus, these patients would greatly benefit from the use of a reliable prognostic biomarker, such as circulating tumor DNA (ctDNA) to identify minimal or molecular residual disease (MRD). PATIENTS AND METHODS We analyzed a cohort of 112 patients with mCRC who had undergone metastatic resection with curative intent as part of the PREDATOR clinical trial. The study evaluated the prognostic value of ctDNA, correlating MRD status postsurgery with clinical outcomes by using a personalized and tumor-informed ctDNA assay (bespoke multiple PCR, next-generation sequencing assay). Postresection, systemic therapy was given to 39.2% of the patients at the discretion of the treating physician. RESULTS Postsurgical, MRD positivity was observed in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (hazard ratio [HR]: 5.8; 95% CI, 3.5 to 9.7; P < .001). MRD-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; P < .001. At the time of analyses, 96% (49 of 51) of patients were alive in the MRD-negative arm compared with 52.4% (32 of 61) in the MRD-positive arm. Patients who did not receive systemic therapy and were MRD-negative in the combined ctDNA analysis at two time points had an overall survival of 100%. In the multivariate analysis, ctDNA-based MRD status was the most significant prognostic factor associated with disease-free survival (HR: 5.78; 95% CI, 3.34 to 10.0; P < .001). CONCLUSION This study confirms that in mCRC undergoing resection of metastases, postoperative MRD analysis is a strong prognostic biomarker. It holds promises for being implemented in clinical decision making, informing clinical trial design, and further translational research.

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

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4547
Author(s):  
Jun Gong ◽  
Andrew Hendifar ◽  
Alexandra Gangi ◽  
Karen Zaghiyan ◽  
Katelyn Atkins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Neoadjuvant Therapy ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Stage I ◽  
Phase Iii ◽  
Resected Stage ◽  
Tumor Dna ◽  
Minimal Residual

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.

Circulating tumor DNA as a marker of minimal residual disease following local treatment of metastases from colorectal cancer

2020 ◽  
Vol 59 (12) ◽  
pp. 1424-1429
Author(s):  
Anders K. Boysen ◽  
Niels Pallisgaard ◽  
Christina S. A. Andersen ◽  
Karen-Lise G. Spindler
Keyword(s):  
Colorectal Cancer ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Local Treatment ◽  
Circulating Tumor Dna ◽  
Tumor Dna ◽  
Minimal Residual

Circulating Tumor DNA as a Biomarker for Outcomes Prediction in Colorectal Cancer Patients

2020 ◽  
Vol 21 ◽  
Author(s):  
Angelica Petrillo ◽  
Massimiliano Salati ◽  
Dario Trapani ◽  
Michele Ghidini
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Early Stage ◽  
Recurrence Risk ◽  
Early Response ◽  
Circulating Tumor Dna ◽  
Response To Treatment ◽  
Molecular Profile ◽  
Liquid Biopsies ◽  
Tissue Biopsy

Abstract:: Circulating tumour DNA (ctDNA) is a novel tool that has being investigated in several types of tumours, includ-ing colorectal cancer (CRC). In fact, the techniques based on liquid biopsies are proposed as appealing non-invasive alter-natives to tissue biopsy, adding more insights into tumour molecular profile, heterogeneity and for cancer detection and monitoring. Additionally, some analysis showed that in CRC patients ctDNA seems to act as biomarker able to predict the outcome (prognostic role) and the response to treatments (predictive role). In particular, in the early stage CRC (stage I-III) it could represent a time marker of adjuvant therapy benefit as well as a marker of minimal residual disease and recurrence risk in addition to the already recognized risk factors. In metastatic CRC, the analysis of molecular tumour profile by ctDNA has shown to have high concordance with the tissue biopsy at diagnosis. Additionally, some studies demonstrated that ctDNA level during the treatment was linked with early response to treatment and prognosis. Finally, the quantitative anal-ysis of ctDNA and copy number alterations may be useful in order to detect resistance to therapy at the time of progression of disease and to help in finding new therapeutic targets.

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