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.

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 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

scholarly journals Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3522
Author(s):  
Andreas Koulouris ◽  
Christos Tsagkaris ◽  
Ippokratis Messaritakis ◽  
Nikolaos Gouvas ◽  
Maria Sfakianaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Recurrence Risk ◽  
Disease Recurrence ◽  
Circulating Tumor Dna ◽  
Genetic Mutations ◽  
Liquid Biopsies ◽  
Molecular Alterations ◽  
Life Saving ◽  
Novel Biomarkers ◽  
Genetic Signatures

Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy, although considerable progress has resulted from molecular alterations in guiding optimal use of available treatments. CRC recurrence remains a great barrier in the disease management. Hence, the spotlight turns to newly mapped fields concerning recurrence risk factors in patients with resectable CRC with a focus on genetic mutations, microbiota remodeling and liquid biopsies. There is an urgent need for novel biomarkers to address disease recurrence since specific genetic signatures can identify a higher or lower recurrence risk (RR) and, thus, be used both as biomarkers and treatment targets. To a large extent, CRC is mediated by the immune and inflammatory interplay of microbiota, through intestinal dysbiosis. Clarification of these mechanisms will yield new opportunities, leading not only to the appropriate stratification policies, but also to more precise, personalized monitoring and treatment navigation. Under this perspective, early detection of post-operative CRC recurrence is of utmost importance. Ongoing trials, focusing on circulating tumor cells (CTCs) and, even more, circulating tumor DNA (ctDNA), seem to pave the way to a promising, minimally invasive but accurate and life-saving monitoring, not only supporting personalized treatment but favoring patients’ quality of life, as well.

Serial circulating tumor DNA analysis to assess recurrence risk, benefit of adjuvant therapy, growth rate and early relapse detection in stage III colorectal cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3540-3540
Author(s):  
Tenna V Vesterman Henriksen ◽  
Noelia Tarazona ◽  
Amanda Frydendahl ◽  
Thomas Reinert ◽  
Juan Antonio Carbonell-Asins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Rate ◽  
High Risk ◽  
Growth Rates ◽  
Recurrence Risk ◽  
Circulating Tumor Dna ◽  
Stage Iii ◽  
Ct Scans ◽  
Risk Patients ◽  
Tumor Dna

3540 Background: Challenges in the postoperative management of stage III colorectal cancer include: 1) selection of high-risk patients for adjuvant chemotherapy (ACT), 2) lack of markers to assess ACT efficacy, 3) assessment of recurrence risk after ACT, and 4) lack of markers to guide treatment decisions for high-risk patients e.g. additional therapy or intensified surveillance. Circulating tumor DNA (ctDNA) is a promising marker with potential to mitigate the challenges. Here we used serial ctDNA measurements to assess the correlation between recurrence and ctDNA detection: postoperative, during and after ACT, and during surveillance; and to assess growth rates of metachronous metastases. Uniquely, we also used concurrent CT scans and ctDNA measurements to compare the sensitivity for detecting recurrence. Methods: Stage III CRC patients treated with curative intent at Danish and Spanish hospitals in 2014-2019 were recruited (n = 166). Blood samples (n = 1227) were collected prior to and immediately after surgery, and every third month for up to 36 months. Per patient 16 personal mutations were used to quantify plasma ctDNA (Signatera, bespoke mPCR NGS assay). Results: Detection of ctDNA was a strong recurrence predictor, both postoperatively (HR 7.2, 95% CI 3.8-13.8, P< 0.001), directly after ACT (HR = 18.2, 95% CI 7.1-46, P < 0.001), and when measured serially after end of treatment (HR = 41, 95% CI 16-100, P < 0.001). The recurrence rate of postoperative ctDNA positive patients treated with ACT was 80% (16/20). Patients who stayed ctDNA positive during ACT all recurred. Serial post-treatment ctDNA measurements revealed exponential growth for all recurrence patients following either a SLOW (26%-increase/month) or a FAST (126%-increase/month) pattern (P < 0.001). From ctDNA detection to radiologic recurrence, ctDNA levels of FAST patients increased by a median 117-fold, and up to 554-fold. The 3-year overall survival was 43% for FAST patients and 100% for SLOW and non-recurrence patients (HR = 41.3, 95% CI 7.5-228, P < 0.001). Coinciding CT scans and ctDNA measurements (n = 113 patients, 235 coinciding events, median 2 per patient) showed a high agreement (92%) and ctDNA either detected residual disease before the CT scan (n = 7 patients) or at the same time (n = 14 patients). The median lead-time was 7.5 months. Conclusions: The study confirmed the prognostic power of serial postoperative ctDNA analysis. Moreover, it provided novel analyses demonstrating that ctDNA is more sensitive for recurrence detection than CT scans and can be used for tumor growth rate assessments. The difference between FAST and SLOW growing tumors suggest that growth rates could guide whom to start on systemic therapy rapidly and whom to send for diagnostic imaging. Altogether, the study highlights many potential utilities of ctDNA in guiding clinical decision-making.

Circulating tumor DNA (ctDNA) as a marker of recurrence risk in stage II colon cancer (CC).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 11015-11015 ◽  
Author(s):  
Jeanne Tie ◽  
Isaac Kinde ◽  
Yuxuan Wang ◽  
Hui-li Wong ◽  
Iain Skinner ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Recurrence Risk ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Stage Ii Colon Cancer ◽  
Tumor Dna
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