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.

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]

Tumor-informed assessment of circulating tumor DNA and its incorporation into practice for patients with hepatobiliary cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4103-4103
Author(s):  
Pashtoon Murtaza Kasi ◽  
Griffin Budde ◽  
Farshid Dayyani ◽  
Gregory P. Botta ◽  
Adam Diehl ◽  
...  
Keyword(s):  
Residual Disease ◽  
Standard Of Care ◽  
Circulating Tumor Dna ◽  
Carbohydrate Antigen ◽  
Response To Treatment ◽  
Additional Tool ◽  
Time Points ◽  
Multiplex Pcr Assay ◽  
Point Analysis ◽  
Tumor Dna

4103 Background: Hepatocellular carcinoma (HCC) and biliary tract cancers [BTC - including cholangiocarcinoma (CCA) and gall bladder cancers (GBC)] represent a heterogeneous group of diseases. Glycoprotein-based tumor markers like alpha-fetoprotein (AFP) or carbohydrate antigen 19-9 (CA-19-9) though part of standard-of-care (SOC), lack sensitivity, and specificity. A fair proportion of these cancers do not produce these glycoproteins. Circulating tumor DNA (ctDNA) testing can fill this void and be used for the assessment of molecular residual disease (MRD), as well as for surveillance purposes in patients with HCC or BTC. Prospective evaluation of this methodology in clinical practice has been limited to date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA. Serial time points were collected on a subset of patients to monitor their ctDNA levels in response to treatment. Results: Here we analyzed 200 plasma samples from a total of 90 patients with HCC (n=27) and BTC (n=63), comprising 46 patients with CCA and 17 patients with GBC. Sample-level ctDNA positivity rates, determined using a tumor-informed assay are presented in table. ctDNA detection was significantly associated with the stage of disease (Wilcoxon rank-sum test, p<0.05). Serial time point analysis was performed on a subset of patients (n=56) that had 2-7 time points available and correlations between ctDNA levels and clinical response were noted and will be presented. Conclusions: Our study is the first to set the benchmark for the utility and feasibility of using a tumor-informed assay in this cohort of hepatobiliary cancers. With adjuvant chemotherapy already a SOC for BTC, and immunotherapy being studied for HCC alongside other novel agents for CCA and GBC, assessment of MRD or ctDNA clearance on therapy would be of value as an additional tool in identifying patients at high risk for recurrence/metastasis. The utility of this study would also lie in incorporation in clinical trials to enrich and study those who are at the highest risk of recurrence i.e. ctDNA positive.[Table: see text]

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.

scholarly journals Histopathologic Differences between Jewish and Arab Population in Israel at First-Time Presentation with Bladder Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-4
Author(s):  
Ofir Avitan ◽  
Zaher Bahouth ◽  
Sarel Halachmi ◽  
Sagi Shprits ◽  
Ismail Masarwa ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Urothelial Cancer ◽  
Categorical Variables ◽  
Arab Women ◽  
Chi Square ◽  
Arab Population ◽  
Different Populations ◽  
Aggressive Tumors ◽  
Arab Men ◽  
First Time

Background. Pathology of urothelial carcinoma may vary in different populations at diagnosis. Our aim was to evaluate the histopathologic differences between Jewish and Arab patients in Israel at first diagnosis of urothelial cancer. Patients and Methods. We retrospectively collected data of all patients with confirmed urothelial cancer, treated at our department between January 2010 and January 2015. We examined the distribution of the histopathologic data among the studied populations. To compare the categorical variables we used the Chi-Square Pearson test. Comparison of independent variables was made by Student’s t-test. P value below 0.05 was considered significant. Results. The study group included 413 patients, 345 Jews and 68 Arabs. The major differences were that Arab patients were younger (62.61 versus 68.55 years, P=0.001), had more aggressive tumors that were detected at a more advanced stage, and had also a higher rate of metastatic disease (7.4% versus 3.2%, P=0.05). Nonurothelial cell tumors were 2.3 times more prevalent in Arab population. Unlike Jewish population, Arab women had higher rate of invasive/metastatic disease compared with Arab men (40% versus 22.4%). Conclusion. At time of diagnosis the tumors were more aggressive in Arab patients, especially in Arab women. The reasons for those differences constitute a target for a separate research. These results should have an impact on prevention medicine and education of physicians treating mixed populations.

Colorectal cancer and brain metastases: An aggressive disease with a different response to treatment

2018 ◽  
Vol 105 (5) ◽  
pp. 427-433 ◽  
Author(s):  
Georges Chahine ◽  
Tony Ibrahim ◽  
Tony Felefly ◽  
Abir El-Ahmadie ◽  
Pamela Freiha ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Brain Metastases ◽  
Median Survival ◽  
Metastatic Disease ◽  
Antiangiogenic Therapy ◽  
Response To Treatment ◽  
Aggressive Disease ◽  
Dismal Prognosis ◽  
Poor Outcomes ◽  
Different Response

Introduction: Brain metastases (BM) are rare in colorectal cancer (CRC) and are associated with a dismal prognosis. This work aims to report the rate of BM in CRC patients treated in a single institution, along with survival and prognostic factors. Methods: Medical charts for patients with histologically proven CRC were retrospectively reviewed. Results: A total of 538 patients were identified, of whom 33% developed any metastatic disease and 4.4% presented BM. Lung was the most frequently associated metastatic site (in 68% of the cases). The only factor independently associated with BM development was the presence of metastatic disease at the time of initial presentation. The median duration from initial diagnosis to BM development was 38.6 months (SD 29.1 months). Median survival after BM development was 62 days (95% confidence interval [CI] 56–68). Patients diagnosed with BM within 1 year of cancer diagnosis responded significantly better to treatment than those who acquired BM later, with a median survival after BM diagnosis of 261 days versus 61 days, respectively ( p = .002). Patients with BM who received antiangiogenic therapy had an improved median survival compared to those who did not (151 days vs 59 days, p = 0.02; hazard ratio for death 0.29 [95% CI 0.09–0.94]). Conclusion: CRC with BM is an aggressive disease resistant to standard treatment and is associated with poor outcomes. Adding antiangiogenic therapy might be of value for those patients. Patients with BM developing early in the disease course might respond better to treatment.

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]

Cost implications of reactive versus prospective testing for dihydropyrimidine dehydrogenase (DPD) deficiency in patients with colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3627-3627
Author(s):  
Gul Ahmed ◽  
Jo O' Keeffe ◽  
Denise O Mullane ◽  
Alison Bransfield ◽  
Andrew Kenny ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Disease ◽  
Standard Dose ◽  
Dihydropyrimidine Dehydrogenase ◽  
Severe Toxicity ◽  
First Line ◽  
Time Period ◽  
Cost Implications ◽  
The Cost ◽  
First Time

3627 Background: DPD is an enzyme encoded by the DPYD gene involved in the metabolism of the chemotherapy drug 5-fluorouracil (5FU) and the oral 5FU prodrug capecitabine. Patients (pts) with DPYD mutations are at risk of severe toxicities from standard dose 5FU, although they may safely receive lower dose therapy with careful monitoring and dose escalation. Methods: In this retrospective study we identified all pts starting 5FU-based chemotherapy for colorectal cancer (CRC) at our institution between Jan 1 2010 and Dec 31 2012. During this time DPD testing was usually performed in a reactive manner, typically for pts experiencing severe toxicities. We reviewed the charts of pts who tested positive for DPYD mutations and assessed the financial implications of their hospitalizations with toxicity. These costs were compared to the costs which would have incurred if all pts starting such therapy had been proactively tested. Results: A total of 134 pts started first-line 5FU-based chemotherapy for CRC over the study period, 66 in the adjuvant setting and 68 for metastatic disease. 31 pts had DPYD mutation testing performed. 6 tests (19% of those tested, 4.5% of the total population) revealed heterozygote DPYD mutations. 5 pts had already experienced severe treatment-related toxicity resulting in cessation of therapy, while one was tested prospectively and received chemotherapy with dose reduction ab initio. The total cost related to hospitalization with toxicity for these 5 pts was €155,083. At €177 per test, the cost to prospectively test all pts starting first-line 5FU-based therapy over the time period would have been €23,718 representing a saving of €131,365 through avoiding these admissions alone. 4 pts who tested positive for DPYD mutations were receiving adjuvant therapy and none restarted therapy following severe toxicity early in their therapy. 2 pts subsequently relapsed with metastatic disease. Conclusions: Prospective testing for DPYD mutations in pts with CRC starting 5FU-based therapy for the first time represents a considerable cost-saving opportunity, in addition to potentially avoiding prolonged hospitalization and morbidity for a sizeable minority of pts.

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