scholarly journals 520TiP A multicenter study to evaluate the impact of circulating tumor DNA guided therapy (BESPOKE) in patients with stage II and III colorectal cancer

2020 ◽  
Vol 31 ◽  
pp. S459
Author(s):  
P.M. Kasi ◽  
S. Sawyer ◽  
J. Guilford ◽  
M. Munro ◽  
S. Ellers ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multicenter Study ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
The Impact ◽  
Tumor Dna ◽  
Guided Therapy

INVESTIGATION KRAS MUTATION IN CIRCULATION TUMOR DNA IN DIFFERENT STAGES OF COLORECTAL CANCER

2019 ◽  
Vol 65 (5) ◽  
pp. 701-707
Author(s):  
Vitaliy Shubin ◽  
Yuriy Shelygin ◽  
Sergey Achkasov ◽  
Yevgeniy Rybakov ◽  
Aleksey Ponomarenko ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Volume ◽  
Kras Mutation ◽  
Stage Iv ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Kras Gene ◽  
Kras Mutations ◽  
Droplet Pcr ◽  
Tumor Dna

To determine mutations in the plasma KRAS gene in patients with colorectal cancer was the aim of this study. The material was obtained from 44 patients with colorectal cancer of different stages (T1-4N0-2bM0-1c). Plasma for the presence of KRAS gene mutation in circulating tumor DNA was investigated using digital droplet polymerase chain reaction (PCR). KRAS mutations in circulating tumor DNA isolated from 1 ml of plasma were detected in 13 (30%) patients with cancer of different stages. Of these, with stage II, there were 3 patients, with III - 5 and with IV - 5. Patients who did not have mutations in 1 ml of plasma were analyzed for mutations of KRAS in circulating tumor DNA isolated from 3 ml of plasma. Five more patients with KRAS mutations were found with II and III stages. The highest concentrations of circulating tumor DNA with KRAS mutation were found in patients with stage IV. The increase in plasma volume to 3 ml did not lead to the identification of mutations in I stage. This study showed that digital droplet PCR allows identification of circulating tumor DNA with the KRAS mutations in patients with stage II-IV of colon cancer. The results can be used to determine the degree of aggressiveness of the tumor at different stages of the disease, but not the 1st, and it is recommended to use a plasma volume of at least 3 ml.

An improved method for detection of methylated circulating tumor DNA in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15120-e15120 ◽  
Author(s):  
Nicky Boulter ◽  
Gregor Tevz ◽  
Betty Yu ◽  
Michelle Chan ◽  
David Murray ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stage Iv ◽  
Circulating Tumor Dna ◽  
Qpcr Assay ◽  
Stage I ◽  
Stage Ii ◽  
Detection Methods ◽  
Assay Sensitivity ◽  
Crc Screening ◽  
Tumor Dna

e15120 Background: Assays detecting methylated circulating tumor DNA (ctDNA) hold promise for colorectal cancer (CRC) screening, but there is a need to develop more accurate assays for early stages. In this study, we examined modifications to COLVERA (an IKZF1 and BCAT1 methylation marker qPCR assay) that added a third biomarker (IRF4) as well as introducing double stranded detection. Methods: Bisulfite converted DNA extracted from plasma collected from subjects undergoing diagnosis for CRC was assayed using either a double-stranded (ds) specific multiplexed qPCR for BCAT1 and IKZF1 detection (Assay 1) and/or a single-stranded (ss) specific BCAT1/IRF4, ds-specific IKZF1 multiplexed qPCR (Assay 2). The unmodified COLVERA test (Clinical Genomics) was used for comparison. Detection of any marker was considered positive. Results: Assay 1 performance evaluated against COLVERA on bisulfite converted DNA from 1453 samples showed an improved sensitivity for CRC detection (93/134 (69.4%) vs 79/134 (59.0%) COLVERA, p = 0.02), but specificity was suboptimal (no neoplasia: 861/1023 (84.2%) vs 946/1023 (92.5%) COLVERA, p < 0.0001). The decrease in specificity resulted primarily from modifications in the BCAT1 assay component (1023 no neoplasia: 60 positive with ss- BCAT1 vs 146 positive with ds- BCAT1, p < 0.0001). Thus, a novel configuration, Assay 2 (ss- BCAT1, ss- IRF4 and ds- IKZF1) was compared to Assay 1 using 189 previously untested specimens. Assay 2 showed a notable improvement in specificity (99/104 (95.2%) vs 93/104 (89.4%) Assay 1; p = 0.0351). Both assays exhibited comparable sensitivities for CRC (41/49 (83.7%) vs 39/49 (79.6%), Assay 1, p = 0.3633). Assay 2 was positive in: adenomas, 9/36 (25.0%); Stage I, 3/7 (42.9%); Stage II, 17/19 (89.5%); Stage III, 6/6 (100%); Stage IV, 7/7 (100%) and 8/10 (80%) unstaged CRCs. Prior COLVERA sensitivity estimates were 9% adenoma, 41% Stage I and 76% Stage II. Conclusions: Targeting both of the non-complementary bisulfite converted strands of selective regions of interest markedly improve ctDNA assay sensitivity for cancer including early lesions while achieving good specificity. Prospective evaluation in a true CRC screening population is now underway. Clinical trial information: 12611000318987.

Circulating tumor DNA as a promising biomarker of relapse risk for stage II-III colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4079-4079
Author(s):  
Gong Chen ◽  
Feng Wang ◽  
Jun-Jie Peng ◽  
San-Jun Cai ◽  
Ke-Feng Ding ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Curative Resection ◽  
Disease Free Survival ◽  
Early Recurrence ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Free Survival ◽  
Colorectal Cancer Patients ◽  
Disease Free ◽  
Tumor Dna

4079 Background: About 30-50% colorectal cancer patients undergoing a curative resection will experience disease recurrence ultimately. Early detection of recurrence is of great significance for improving the prognosis of colorectal cancer patients. Circulating tumor DNA (ctDNA) has been suggested to be a promising biomarker for postoperative surveillance and prognosis prediction in various cancers including colorectal cancer. However, its performance in predicting early recurrence of colorectal cancer as well as appropriate testing procedures still needs large-scale prospective studies to evaluate. Methods: A total of 246 patients with stage II-III colorectal cancer and underwent curative resection from three clinical centers of China were enrolled in this multicenter prospective cohort study. Tissue samples as well as serial plasma samples before surgery, 7 days and 6 months after surgery and 3 months interval afterwards until recurrence were collected, and subjected to deep targeted-panel sequencing containing 425 cancer-related genes. ctDNA baseline genomic alterations and dynamic changes were analyzed. Its performance in predicting early recurrence was evaluated and compared with other clinical routine investigations, including serum biomarkers CEA and CA199, and CT examination. Results: The ctDNA positive rates at baseline (before surgery) and 7 days after surgery were 72.9% and 18.1% respectively. Among 199 patients with complete survival data, 18 patients were recurrent during follow up period with a median disease-free survival of 280.5 days (114-461 days). At baseline, high clinical stage (p = 0.035), and PTEN mutation (p = 0.009) were significantly associated with increased recurrent risk; while APC mutation (p = 0.04) predicted a decreased recurrent risk. Detection of ctDNA 7 days after surgery [HR: 5.9 (1.94-17.97); p = 0.0004] or any time point before clinical recurrence [HR: 6.14 (2.3-16.38); p < 0.0001] was associated with a significantly higher recurrent risk, and the HR increased accordingly with ctDNA mutation level. In multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathological risk factors. CEA status was not significantly (p > 0.4) associated with disease-free survival. A risk scoring model comprising of clinical variables and ctDNA detection after surgery was constructed and can predict 18-month recurrence with an AUC of 0.77. Conclusions: ctDNA is a promising marker of risk stratification, and early relapse detection in resected stage II/III CRC patients. Clinical trial information: NCT03312374 .

scholarly journals Postoperative circulating tumor DNA as markers of recurrence risk in stages II to III colorectal cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Gong Chen ◽  
Junjie Peng ◽  
Qian Xiao ◽  
Hao-Xiang Wu ◽  
Xiaojun Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Standard Of Care ◽  
Recurrence Risk ◽  
Disease Recurrence ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Sampling Point ◽  
Radiological Imaging ◽  
Definitive Therapy ◽  
Tumor Dna

Abstract Background Precise methods for postoperative risk stratification to guide the administration of adjuvant chemotherapy (ACT) in localized colorectal cancer (CRC) are still lacking. Here, we conducted a prospective, observational, and multicenter study to investigate the utility of circulating tumor DNA (ctDNA) in predicting the recurrence risk. Methods From September 2017 to March 2020, 276 patients with stage II/III CRC were prospectively recruited in this study and 240 evaluable patients were retained for analysis, of which 1290 serial plasma samples were collected. Somatic variants in both the primary tumor and plasma were detected via a targeted sequencing panel of 425 cancer-related genes. Patients were treated and followed up per standard of care. Results Preoperatively, ctDNA was detectable in 154 of 240 patients (64.2%). At day 3–7 postoperation, ctDNA positivity was associated with remarkably high recurrence risk (hazard ratio [HR], 10.98; 95%CI, 5.31–22.72; P < 0.001). ctDNA clearance and recurrence-free status was achieved in 5 out of 17 ctDNA-positive patients who were subjected to ACT. Likewise, at the first sampling point after ACT, ctDNA-positive patients were 12 times more likely to experience recurrence (HR, 12.76; 95%CI, 5.39–30.19; P < 0.001). During surveillance after definitive therapy, ctDNA positivity was also associated with extremely high recurrence risk (HR, 32.02; 95%CI, 10.79–95.08; P < 0.001). In all multivariate analyses, ctDNA positivity remained the most significant and independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors. Serial ctDNA analyses identified recurrence with an overall accuracy of 92.0% and could detect disease recurrence ahead of radiological imaging with a mean lead time of 5.01 months. Conclusions Postoperative serial ctDNA detection predicted high relapse risk and identified disease recurrence ahead of radiological imaging in patients with stage II/III CRC. ctDNA may be used to guide the decision-making in postsurgical management.

scholarly journals Evaluation of Circulating Tumor DNA for Methylated BCAT1 and IKZF1 to Detect Recurrence of Stage II/Stage III Colorectal Cancer (CRC)

2020 ◽  
Vol 29 (12) ◽  
pp. 2702-2709
Author(s):  
Benjamin L. Musher ◽  
Joshua E. Melson ◽  
Gianni Amato ◽  
David Chan ◽  
Marisa Hill ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Stage Iii ◽  
Tumor Dna

Circulating tumor DNA analysis before and after resection for colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3597-3597
Author(s):  
Erin L. Symonds ◽  
Susanne Kartin Pedersen ◽  
David Murray ◽  
Graeme P Young
Keyword(s):  
Colorectal Cancer ◽  
Dna Analysis ◽  
Tumor Resection ◽  
Circulating Tumor Dna ◽  
High Rate ◽  
Ct Scans ◽  
Post Surgery ◽  
Response To Chemotherapy ◽  
The Impact ◽  
Tumor Dna

3597 Background: Detection of circulating tumor DNA (ctDNA) has broad clinical utility including disease monitoring, prognostication and response to chemotherapy. ctDNA is commonly detected by targeting tumor-specific features including mutations, insertions, deletions or hypermethylation. The two genes, BCAT1 and IKZF1, are methylated with high frequency in colorectal cancer (CRC). This study aimed to analyze the impact of tumor resection on ctDNA levels by assaying pre- and postoperative blood samples for methylated BCAT1 and IKZF1. Methods: 91 people (age 32-86 years, 53% male) with invasive CRC, but without neoadjuvant therapy, had blood collected prior to surgery and within 12 months (1-12 months) after resection. Cancers were clinicopathologically staged. DNA extracted from plasma was assayed for methylated BCAT1/ IKZF1 and detection of either marker was deemed positive for ctDNA. Results: 47 (52%) of the 91 CRC patients were ctDNA positive before resection, including 5/30 (17%) stage I, 17/28 (61%) stage II, 23/31 (74%) stage III and 2/2 (100%) stage IV. After resection 75% (35/47) became ctDNA negative (median 2 months after resection), and all had apparent tumour clearance. Of the 35 postoperative ctDNA negative cases 22 had further surveillance CT scans within study timeframe. 86% (20/22) showed no recurrent CRC but 2 of these developed a new cancer (metachronous CRC, prostate). The remaining 2 tested ctDNA positive 14 and 25 months later and recurrence was confirmed. Of the 12 postoperative ctDNA positive cases, two were found to not have complete tumour clearance at surgery (residual disease). Follow-up CT scans were available for a further 8 patients which revealed that 4 later presented with cancer (3 recurrence, 1 thyroid) at a median 15 months after resection. The remaining 4 postoperative positive cases were negative at subsequent blood testing (median 8 months later). Conclusions: Methylated BCAT1/IKZF1 DNA in preoperative blood is dependent on tumor stage, but informs the completeness of resection given the high rate (74.5%) of ctDNA disappearance post-surgery. If cases persistently test ctDNA positive after surgery or become ctDNA positive later, residual or recurrent disease should be suspected, respectively.

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