Use of circulating tumor DNA in colorectal cancer patients to assess tumor burden and response to therapy: An observational study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3528-3528
Author(s):  
Erin L. Symonds ◽  
Susanne Kartin Pedersen ◽  
Bernita Hui Li Yeo ◽  
Hiba Al Naji ◽  
Susan E. Byrne ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Size ◽  
Residual Disease ◽  
Early Stage ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Post Treatment ◽  
Response To Therapy ◽  
Maximum Diameter ◽  
Curative Intent

3528 Background: Residual disease after treatment for colorectal cancer (CRC) poses a risk for recurrence but imaging and CEA are limited in their capacity to detect residual disease. A simple test is needed for assessing treatment response. This study determined whether levels of methylated BCAT1/IKZF1 DNA in blood correlate with tumor burden and whether post-treatment levels inform efficacy of different treatments for CRC. Methods: Patients with primary CRC had blood collected prior to treatment (n = 282, 59.9% males, median age 68.5y). Cell free DNA (cfDNA) was extracted from plasma and assayed for methylation in BCAT1 and IKZF1. Detection of methylation in either gene deemed a sample positive; levels were expressed as %methylation (average methylation/average cfDNA). Positive patients had additional samples collected post-treatment for early stage CRC (surgery, n = 31), advanced/metastatic CRC (surgery + adjuvant chemotherapy, n = 15), and rectal cancer (neoadjuvant therapy, surgery +/- chemotherapy, n = 6), or following mid-therapy suspension of treatment in advanced CRC (n = 24). Tumor size was expressed as the maximum diameter of the primary (assessed surgically or by MRI). Results: Pretreatment results increased with CRC stage. Positivity by stage was: I, 23.7% (14/59); II, 62.1% (54/87); III, 68.6% (70/102); IV, 85.3% (29/34). Level by stage: I, 0.0%; II, 0.06%; III, 0.07%; IV, 4.07%, p < 0.001). Pretreatment levels correlated significantly with tumor size (r = 0.372, p < 0.001). Post-treatment blood was collected a median 2.4mo (IQR 1.7-3.9) after therapy completion. Positivity decreased after completing treatment (Table), with 88.4% of cases (46/52) becoming ctDNA negative. All cases with complete treatment had a reduction in biomarker levels, whereas in those with incomplete therapy, 54.5% (12/22) remained positive and the pre- and post-treatment levels were not significantly different. Of those positive after treatment, 13 had a further blood sample: 8 had become ctDNA negative and all but one remained disease free. Five remained positive and all had further suspected or confirmed disease. Conclusions: Levels of methylated BCAT1 and IKZF1 DNA in blood correlated with tumor burden; levels became undetectable in the majority of patients following completion of planned curative intent treatment. The methylated ctDNA blood test aids monitoring of responses to therapy and identification of those cases with residual cancer who might benefit from ongoing therapy.[Table: see text]

Circulating Tumor DNA Minimal Residual Disease Detection of Non–Small-Cell Lung Cancer Treated With Curative Intent

2022 ◽  
Author(s):  
Bruna Pellini ◽  
Aadel A. Chaudhuri
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Post Treatment ◽  
Small Cell Lung ◽  
Curative Intent ◽  
Tumor Dna ◽  
Minimal Residual

Circulating tumor DNA (ctDNA) minimal residual disease (MRD) is a powerful biomarker with the potential to improve survival outcomes for non–small-cell lung cancer (NSCLC). Multiple groups have shown the ability to detect MRD following curative-intent NSCLC treatment using next-generation sequencing–based assays of plasma cell-free DNA. These studies have been modest in size, largely retrospective, and without thorough prospective clinical validation. Still, when restricting measurement to the first post-treatment timepoint to assess the clinical performance of ctDNA MRD detection, they have demonstrated sensitivity for predicting disease relapse ranging between 36% and 100%, and specificity ranging between 71% and 100%. When considering all post-treatment follow-up timepoints (surveillance), including those beyond the initial post-treatment measurement, these assays' performances improve with sensitivity and specificity for identifying relapse ranging from 82% to 100% and 70% to 100%, respectively. In this manuscript, we review the evidence available to date regarding ctDNA MRD detection in patients with NSCLC undergoing curative-intent treatment and the ongoing prospective studies involving ctDNA MRD detection in this patient population.

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]

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.

scholarly journals ctDNA to Guide Adjuvant Therapy in Localized Colorectal Cancer (CRC)

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2869
Author(s):  
Laura Masfarré ◽  
Joana Vidal ◽  
Concepción Fernández-Rodríguez ◽  
Clara Montagut
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Adjuvant Chemotherapy ◽  
Residual Disease ◽  
Early Stage ◽  
Recurrence Risk ◽  
Circulating Tumor Dna ◽  
Key Points ◽  
The Impact ◽  
Critical Overview

Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC.

Detection of residual disease and recurrence in early-stage non-small cell lung cancer (NSCLC) patients using sensitive personalized ctDNA sequencing assays.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15560-e15560
Author(s):  
Katrin Heider ◽  
Davina Gillian Gale ◽  
Giovanni Marsico ◽  
Andrea Ruiz-Valdepeñas ◽  
Garima Sharma ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Residual Disease ◽  
Early Stage ◽  
Small Cell ◽  
Post Treatment ◽  
Stage I ◽  
Small Cell Lung ◽  
Curative Intent ◽  
Early Stage Nsclc ◽  
Generation Sequencing

e15560 Background: Detection of residual circulating tumour DNA (ctDNA) in patient plasma following curative intervention for localized non-small cell lung cancer (NSCLC) could identify patients who are at higher risk of relapse. These patients may benefit from adjuvant treatment, even if they have no macroscopic disease identified by radiographic imaging, which is the current standard of care. Here we evaluate the performance of the Inivata personalized sequencing assays to detect ctDNA in a cohort of 90 patients with early-stage NSCLC undergoing treatment with curative intent. Methods: The Inivata assay uses a highly sensitive next-generation sequencing platform, to identify tumor-specific variants from exome sequencing of tumor tissue and to track up to 48 patient-specific mutations in plasma specimens by multiplex PCR and ultra-high-depth next-generation sequencing. Samples from 90 patients with Stage I-III NSCLC who underwent radical treatment with curative intent, either surgery or radiotherapy ± chemotherapy, were collected as part of the LUng cancer - CIrculating tumor DNA (LUCID) study. Results: 350 plasma samples from 90 patients were analyzed using the Inivata assay, including samples collected before and after treatment and at subsequent follow-up visits. ctDNA was detected in pre-treatment samples in 38% of 32 patients (12/32) with Stage I NSCLC and in 90% of 21 patients (19/21) with Stage II/III disease, at allele fractions ranging from 6 parts per million (ppm, equivalent to 0.0006%) to over 20,000 ppm (equivalent to 2%). In plasma samples collected post-treatment, ctDNA was detected in close to 50% of cases. Conclusions: These findings highlight the Inivata assay is a sensitive method for detection of residual ctDNA and recurrence in early stage NSCLC. Initial detection rates ranged from 38% in Stage I disease to 90% for patients with Stage II/III disease prior to treatment, including detection of ctDNA to levels as low as a few parts per million. ctDNA was detected in at least one post-treatment timepoint in close to 50% patients. Together with additional data to be presented from the full 90 patient cohort, this suggests a possible route to improving treatment and designs of adjuvant trials for early stage NSCLC by detection of residual disease post-treatment and monitoring for early detection of relapse.

scholarly journals Future perspectives of circulating tumor DNA in colorectal cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770574 ◽  
Author(s):  
C Nadal ◽  
T Winder ◽  
A Gerger ◽  
David Tougeron
Keyword(s):  
Colorectal Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Genetic Material ◽  
Treatment Resistance ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Response Monitoring ◽  
Cancer Management ◽  
Tumor Dna

Tumor biopsy is currently the gold standard for diagnosis and in determining cell signaling pathways involved in the development of treatment resistance. However, there are major challenges with this technique, including the need for serial sampling to monitor treatment resistance, which is invasive and also has the potential for selection bias due to intra-tumoral and inter-tumoral heterogeneity. These challenges highlight the need for more effective methods for obtaining Tumor samples. Liquid biopsy analyzes genetic material or tumor cells shed into the blood from the primary tumor and metastatic sites and consequently provides a comprehensive, real-time picture of the tumor burden in an individual patient. Indeed, liquid biopsy has the potential to revolutionize cancer management. Here, we review recent studies on the potential clinical applications of liquid biopsy using circulating tumor DNA in colorectal cancer, including screening, diagnosis, detection of minimal residual disease after surgery, detection of recurrence, prognosis, predicting treatment response, monitoring tumor burden or response during treatment, and tracking resistance. We also discuss recent data demonstrating the utility of detecting KRAS-mutated circulating tumor DNA, both at diagnosis to determine an appropriate treatment strategy and during anti-epidermal growth factor receptor therapy to predict treatment resistance. The future integration of liquid biopsy into clinical practice is discussed, together with alternative approaches and key questions that need to be answered in future clinical studies before this technology can be implemented and used routinely.

Circulating tumor DNA is a sensitive marker for routine monitoring of treatment response in advanced colorectal cancer

2020 ◽  
Vol 41 (11) ◽  
pp. 1507-1517
Author(s):  
Donghui Zou ◽  
Robert Day ◽  
Judy A Cocadiz ◽  
Sarah Parackal ◽  
Wilson Mitchell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
P Value ◽  
Chemotherapy Response ◽  
Clinical Relapse ◽  
Curative Surgery ◽  
Droplet Pcr ◽  
Tumor Dna

Abstract Accurate assessment of chemotherapy response provides the means to terminate ineffective treatment, trial alternative drug regimens or schedules and reduce dose to minimize toxicity. Here, we have compared circulating tumor DNA (ctDNA) with carcinoembryonic antigen (CEA) for the cycle by cycle assessment of chemotherapy response in 30 patients with metastatic colorectal cancer. CtDNA (quantified using individualized digital droplet PCR (ddPCR) assays) and CEA levels were determined immediately prior to each chemotherapy cycle over time periods ranging from 42–548 days (average of 10 time points/patient). Twenty-nine/thirty (97%) patients had detectable ctDNA compared with 83% whose tumors were CEA-positive (&gt;5 ng/ml) during the monitoring course. Over the course of treatment, 20 disease progression events were detected by computed tomography; ctDNA predicted significantly more of these events than CEA (16 (80%) versus 6 (30%), respectively; P-value = 0.004). When progression was detected by both ctDNA and CEA, the rise in ctDNA occurred significantly earlier than CEA (P-value = 0.046). Partial responses to chemotherapy were also detected more frequently by ctDNA, although this was not significant (P-value = 0.07). In addition, another 28 colorectal cancer patients who underwent potentially curative surgery and showed no evidence of residual disease were monitored with ctDNA for up to 2 years. Clinical relapse was observed in 6/28 (21%) patients. Four out of 6 of these patients showed a significant increase in ctDNA at or prior to relapse. Overall, ctDNA analyses were able to be performed in a clinically relevant timeline and were a more sensitive and responsive measure of tumor burden than CEA.

scholarly journals Detection of Tumor Recurrence via Circulating Tumor DNA Profiling in Patients with Localized Lung Cancer: Clinical Considerations and Challenges

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3759
Author(s):  
Bryan Ulrich ◽  
Anne Pradines ◽  
Julien Mazières ◽  
Nicolas Guibert
Keyword(s):  
Lung Cancer ◽  
Residual Disease ◽  
Lung Cancer Screening ◽  
Circulating Tumor Dna ◽  
Definitive Treatment ◽  
Curative Intent ◽  
Screening Programs ◽  
Adjuvant Therapies ◽  
Sequencing Platforms ◽  
Tumor Dna

Approximately 30% of patients with non-small-cell lung cancer (NSCLC) present with localized/non-metastatic disease and are eligible for surgical resection or other “treatment with curative intent”. Due to the high prevalence of recurrence after treatment, adjuvant therapy is standard care for most patients. The effect of adjuvant chemotherapy is, however, modest, and new tools are needed to identify candidates for adjuvant treatments (chemotherapy, immunotherapy, or targeted therapies), especially since expanded lung cancer screening programs will increase the rate of patients detected with localized NSCLC. Circulating tumor DNA (ctDNA) has shown strong potential to detect minimal residual disease (MRD) and to guide adjuvant therapies. In this manuscript, we review the technical aspects and performances of the main ctDNA sequencing platforms (TRACERx, CAPP-seq) investigated in this purpose, and discuss the potential of this approach to guide or spare adjuvant therapies after definitive treatment of NSCLC.

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]

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