17 results on '"Kåre Andersson Gotschalck"'
Search Results
2. Comparing single‐target and multitarget approaches for postoperative circulating tumour DNA detection in stage II–III colorectal cancer patients
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Tenna Vesterman Henriksen, Thomas Reinert, Mads Heilskov Rasmussen, Christina Demuth, Uffe Schou Løve, Anders Husted Madsen, Kåre Andersson Gotschalck, Lene Hjerrild Iversen, and Claus Lindbjerg Andersen
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circulating tumour DNA ,colorectal cancer ,liquid biopsy ,residual disease ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Circulating tumour DNA (ctDNA) detection for postoperative risk stratification in cancer patients has great clinical potential. However, low ctDNA abundances complicates detection. Multitarget (MT) detection strategies have been developed to increase sensitivity. Yet, empirical evidence supporting performance gains of MT vs. single‐target (ST) strategies in a postoperative setting is limited. We compared ctDNA detection in 379 paired plasma samples from 112 stage II–III colorectal cancer patients by ST digital PCR and MT sequencing of 16 patient‐specific variants. The strategies exhibited good concordance (90%, Cohen's Kappa 0.79), with highly correlated ctDNA quantifications (Pearson r = 0.985). A difference was observed in ctDNA detection preoperatively (ST 72/92, MT 88/92). However, no difference was observed immediately after surgery in recurrence (ST 11/22, MT 10/22) or nonrecurrence (both 2/34) patients. In serial samples, detection was similar within recurrence (ST 13/16, MT 14/16) and nonrecurrence (ST 3/49, MT 1/49) patients. Both approaches yielded similar lead times to standard‐of‐care radiology (ST 4.0 months, MT 4.1 months). Our findings do not support significant performance gains of the MT strategy over the ST strategy for postoperative ctDNA detection.
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- 2022
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3. Identifying Recurrences Among Non-Metastatic Colorectal Cancer Patients Using National Health Data Registries: Validation and Optimization of a Registry-Based Algorithm in a Modern Danish Cohort
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Jesper Nors, Trine Block Mattesen, Deirdre Cronin-Fenton, Aurélie Mailhac, Jesper Bertram Bramsen, Kåre Andersson Gotschalck, Rune Erichsen, and Claus Lindbjerg Andersen
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Epidemiology ,oncology ,surveillance ,time to recurrence ,Clinical Epidemiology ,chemotherapy - Abstract
Jesper Nors,1,2,* Trine Block Mattesen,1,* Deirdre Cronin-Fenton,3 Aurélie Mailhac,3 Jesper Bertram Bramsen,1,2 KÃ¥re Andersson Gotschalck,2,4 Rune Erichsen,2,3,5 Claus Lindbjerg Andersen1,2 1Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Surgery, Horsens Regional Hospital, Horsens, Denmark; 5Department of Surgery, Randers Regional Hospital, Horsens, Denmark*These authors contributed equally to this workCorrespondence: Claus Lindbjerg Andersen, Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, DK-8200, Denmark, Tel +45 78455319, Email cla@clin.au.dkPurpose: Colorectal cancer (CRC) recurrence is not routinely recorded in Danish health data registries. Here, we aimed to revalidate a registry-based algorithm to identify recurrences in a contemporary cohort and to investigate the accuracy of estimating the time to recurrence (TTR).Patients and Methods: We ascertained data on 1129 patients operated for UICC TNM stage IâIII CRC during 2012â 2017 registered in the CRC biobank at the Department of Molecular Medicine, Aarhus University Hospital, Denmark. Individual-level data were linked with data from the Danish Colorectal Cancer Group database, Danish Cancer Registry, Danish National Registry of Patients, and Danish Pathology Registry. The algorithm identified recurrence based on diagnosis codes of local recurrence or metastases, the receipt of chemotherapy, or a pathological tissue assessment code of recurrence more than 180 days after CRC surgery. A subgroup was selected for validation of the algorithm using medical record reviews as a reference standard.Results: We found a 3-year cumulative recurrence rate of 20% (95% CI: 17â 22%). Manual medical record review identified 80 recurrences in the validation cohort of 522 patients. The algorithm detected recurrence with 94% sensitivity (75/80; 95% CI: 86â 98%) and 98% specificity (431/442; 95% CI: 96â 99%). The positive and negative predictive values of the algorithm were 87% (95% CI: 78â 93%) and 99% (95% CI: 97â 100%), respectively. The median difference in TTR (TTRMedical_chart-TTRalgorithm) was â 8 days (IQR: â 21 to +3 days). Restricting the algorithm to chemotherapy codes from oncology departments increased the positive predictive value from 87% to 94% without changing the negative predictive value (99%).Conclusion: The algorithm detected recurrence and TTR with high precision in this contemporary cohort. Restriction to chemotherapy codes from oncology departments using department classifications improves the algorithm. The algorithm is suitable for use in future observational studies.Keywords: time to recurrence, surveillance, chemotherapy, oncology
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- 2023
4. The effect of antithrombotic treatment on the fecal immunochemical test for colorectal cancer screening:a nationwide cross-sectional study
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Simon Ladefoged Rasmussen, Christian Torp-Pedersen, Kåre Andersson Gotschalck, and Ole Thorlacius-Ussing
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Feces ,Cross-Sectional Studies ,Anticoagulants/therapeutic use ,Mass Screening/methods ,Fibrinolytic Agents/therapeutic use ,Occult Blood ,Gastroenterology ,Administration, Oral ,Humans ,Colonoscopy ,Colorectal Neoplasms/diagnosis ,Early Detection of Cancer/methods - Abstract
Background Screening for colorectal cancer (CRC) using the fecal immunochemical test (FIT) has been widely adopted. The use of antithrombotic treatment is increasing in the Western world. This study aimed to assess the effects of antithrombotic treatment on the FIT-based Danish national screening program for CRC. Methods This was a cross-sectional study of all individuals returning a FIT from 2014 until 2016. The effect of antithrombotic treatment on FIT positivity and the positive predictive value (PPV) were assessed using proportions and multivariable Poisson regression. Results Of 884 036 invited individuals, we identified 551 570 participants. A positive FIT was observed in 9052 of 77 007 individuals (11.8 %) receiving antithrombotic treatment compared with 28 387 of 474 587 individuals (6.0 %) receiving no treatment. The adjusted relative risk (RR) for a positive FIT was 1.59 (95 %CI 1.56–1.63) for any treatment. Nonvitamin K oral anticoagulants (NOACs) were associated with the largest increase in FIT positivity (adjusted RR 2.40, 95 %CI 2.48–2.54). The proportion of CRC detected at colonoscopy was slightly lower among patients on antithrombotic treatment (6.0 %, 95 %CI 5.5 %–6.6 %) than among treatment-naïve patients (6.4 %, 95 %CI 6.1 %–6.7 %). The PPV for CRC or high risk adenomas was decreased nearly twofold in patients treated with NOAC (adjusted RR 0.58, 95 %CI 0.51–0.66]). Conclusion Antithrombotic treatment was associated with a decreased PPV in FIT-based CRC screening.
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- 2023
5. Supplementary Data from Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences
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Claus Lindbjerg Andersen, Andres Cervantes, Alexey Aleshin, Himanshu Sethi, Kåre Andersson Gotschalck, Lene Hjerrild Iversen, Ole Thorlacius-Ussing, Per Vadgaard Andersen, Uffe S. Løve, Anders Husted Madsen, Susana Roselló, Marisol Huerta, Desamparados Roda, Dina Hafez, Derrick Renner, Shruti Sharma, Juan Antonio Carbonell-Asins, Francisco Gimeno-Valiente, Thomas Reinert, Amanda Frydendahl, Noelia Tarazona, and Tenna Vesterman Henriksen
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Supplementary Data from Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences
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- 2023
6. Data from Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences
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Claus Lindbjerg Andersen, Andres Cervantes, Alexey Aleshin, Himanshu Sethi, Kåre Andersson Gotschalck, Lene Hjerrild Iversen, Ole Thorlacius-Ussing, Per Vadgaard Andersen, Uffe S. Løve, Anders Husted Madsen, Susana Roselló, Marisol Huerta, Desamparados Roda, Dina Hafez, Derrick Renner, Shruti Sharma, Juan Antonio Carbonell-Asins, Francisco Gimeno-Valiente, Thomas Reinert, Amanda Frydendahl, Noelia Tarazona, and Tenna Vesterman Henriksen
- Abstract
Purpose:Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates.Experimental Design:We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing.Results:Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7–13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4–167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9–172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1–6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography.Conclusions:Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.See related commentary by Morris and George, p. 438
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- 2023
7. Impact of Whole Genome Doubling on Detection of Circulating Tumor DNA in Colorectal Cancer
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Jonas Kabel, Tenna Vesterman Henriksen, Christina Demuth, Amanda Frydendahl, Mads Heilskov Rasmussen, Jesper Nors, Nicolai J. Birkbak, Anders Husted Madsen, Uffe S. Løve, Per Vadgaard Andersen, Thomas Kolbro, Alessio Monti, Ole Thorlacius-Ussing, Mikail Gögenur, Jeppe Kildsig, Nis Hallundbæk Schlesinger, Peter Bondeven, Lene Hjerrild Iversen, Kåre Andersson Gotschalck, and Claus Lindbjerg Andersen
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circulating tumor DNA ,Cancer Research ,Oncology ,whole genome doubling ,cancer diagnostics ,colorectal cancer - Abstract
Objective: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients.Methods: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients.Results: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12-2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22-5.03) and Stage II (OR = 1.76, 95%CI: 1.11-2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44-1.53) patients.Conclusion: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell. Objective: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients. Methods: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients. Results: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12–2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22–5.03) and Stage II (OR = 1.76, 95%CI: 1.11–2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44–1.53) patients. Conclusion: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell.
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- 2023
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8. Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences
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Lene Hjerrild Iversen, Claus L. Andersen, Derrick Renner, Thomas Reinert, Ole Thorlacius-Ussing, Desamparados Roda, Tenna V Henriksen, Alexey Aleshin, Andrés Cervantes, Noelia Tarazona, Per Vadgaard Andersen, Shruti Sharma, Susana Roselló, J.A. Carbonell-Asins, Dina Hafez, Anders Husted Madsen, Uffe S. Løve, Kåre Andersson Gotschalck, Amanda Frydendahl, Marisol Huerta, F. Gimeno-Valiente, and Himanshu Sethi
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Adjuvant chemotherapy ,Clinical Decision-Making ,Circulating Tumor DNA ,Text mining ,Predictive Value of Tests ,Internal medicine ,Biomarkers, Tumor ,Stage III colorectal cancer ,medicine ,Adjuvant therapy ,Humans ,Tumor growth ,Aged ,Neoplasm Staging ,business.industry ,Prognosis ,Minimal residual disease ,Confidence interval ,Circulating tumor DNA ,Female ,Drug Monitoring ,Neoplasm Recurrence, Local ,Colorectal Neoplasms ,business - Abstract
Purpose: Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates. Experimental Design: We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing. Results: Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7–13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4–167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9–172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1–6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography. Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making. See related commentary by Morris and George, p. 438
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- 2021
9. Preoperative findings on non-specific CT in patients with primary acute intestinal ischemia: a case–control study
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David Straarup, Rasa Mikalone, Kåre Andersson Gotschalck, and Ole Thorlacius-Ussing
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medicine.medical_specialty ,Control study ,Acute intestinal ischaemia ,Subgroup analysis ,Mesenteric ischaemia ,Critical Care and Intensive Care Medicine ,Gastroenterology ,Inferior mesenteric artery ,Ischemia ,Internal medicine ,medicine.artery ,medicine ,Humans ,Orthopedics and Sports Medicine ,Pneumatosis intestinalis ,Computed tomography ,Retrospective Studies ,business.industry ,Case-control study ,Case ,Odds ratio ,Arteriosclerosis ,medicine.disease ,Acute Intestinal Ischemia ,Case-Control Studies ,Mesenteric Ischemia ,Radiological weapon ,Emergency Medicine ,Diagnostic imaging ,Surgery ,medicine.symptom ,Tomography, X-Ray Computed ,business ,Intestinal Obstruction - Abstract
Purpose: Primary acute intestinal ischaemia (AII) is an abdominal catastrophe caused by intravascular obstruction of blood supply. It is difficult to diagnose. Computerized tomography (CT) scan is the modality of choice for diagnostic evaluation. Majority of previous studies have evaluated CT findings in patients where AII was suspected. However, unveiling the unique radiological findings also in not initially suspected AII patients, might lead to the timely management of AII patients, and is the aim of this study. Methods: In a single-center, retrospective case–control study, preoperative radiological findings from abdominal CT scans in 48 patients with primary AII were compared with 80 non-ischemic controls. Radiological findings were analyzed using multivariable logistical regression with adjustment for age and gender and reported as odds ratios (OR) with 95% confidence intervals (CI) and p values. Results: Thirty-nine (81%) cases with AII were referred to an abdominal CT scan without a specific clinical suspicion of AII. Three main radiological categories (intestinal wall pathology [OR 7.4, CI 2.3–24.0, p value < 0.001], gastrointestinal vessel pathology [OR 19.3, CI 4.6–80.5, p value < 0.001) and intestinal diameter [OR 4.7, CI 1.6–13.4, p value 0.004]) were significantly different in AII patients. Subgroup analysis implied that pneumatosis intestinalis, increased contrast enhancement in the bowel wall, inferior mesenteric artery arteriosclerosis and colonic contraction were predictors of AII. Conclusion: Radiological changes within the intestinal wall, luminal diameter and gastrointestinal vessels are independent predictors of AII. Awareness of these radiological findings, therefore, plays a central role in patients with an indistinct clinical picture in early recognition and treatment of a life-threatening AII. Trial registration number: NCT04361110 (April 24, 2020), retrospectively registered.
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- 2021
10. Author response for 'Comparing single‐target and multi‐target approaches for postoperative circulating tumor DNA detection in stage II‐III colorectal cancer patients'
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null Tenna Vesterman Henriksen, null Thomas Reinert, null Mads Heilskov Rasmussen, null Christina Demuth, null Uffe Schou Løve, null Anders Husted Madsen, null Kåre Andersson Gotschalck, null Lene Hjerrild Iversen, and null Claus Lindbjerg Andersen
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- 2022
11. Novel blood-based biomarker candidates in screening for colorectal cancer
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Jason Lee Liggett, Mathias M Petersen, Jakob Kleif, Morten Rasmussen, Lars Nannestad Jørgensen, Jakob Benedict Seidelin, Mogens R. Madsen, Jesper Vilandt, Kåre Andersson Gotschalck, Lars M. Andersen, Ali Khalid, Berit Andersen, Ib Jarle Christensen, Herbert A. Fritsche, Eric S. Mayer, and Christina Therkildsen
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Cancer Research ,Oncology - Abstract
244 Background: Colorectal cancer (CRC) is the third most common cancer worldwide motivating national screening strategies utilizing fecal immunochemical tests (FIT). Blood-based biomarkers could be an alternative method to increase compliance in population-based screening programs for early detection of CRC. We aimed to identify new blood-based biomarkers that could be potential candidates for use in colorectal cancer screening. Methods: In a nested cohort study of 1967 FIT positive participants of the Danish CRC screening program serum levels of GDF-15, hepsin, IL-8, keratin1-10, L1CAM, MIA, monocyte MCP-1, NSE and OPG were measured using the Luminex xMAP immunoassay platform. Main outcomes were CRC vs non-CRC and CRC, high-risk adenomas (HRA) or medium-risk adenomas (MRA) vs low-risk adenomas (LRA) or clean colorectum. Odds ratios for associations between biomarker expressions and outcomes were calculated using logistic regression models and visualized by area under the receiver operating characteristic (ROC) curve (AUC). Analyses were made on the Luminex biomarkers alone and with addition of clinical and demographic information. Results: FIT-induced colonoscopies detected 240 CRCs and 625 HRA or MRA. Multivariate analyses using all biomarkers and age found hepsin, IL-8 and OPG significantly (p
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- 2023
12. Fear of cancer recurrence and quality of life in a ctDNA based surveillance program following curative intended treatment of colorectal cancer – a substudy of IMPROVE-IT2
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Jesper Berg Nors, Therese Juul, Kåre Andersson Gotschalck, Claus Lindbjerg Andersen, and Lene Hjerrild Iversen
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- 2021
13. Abstract 1959: Sensitive detection of circulating tumor DNA by whole genome sequencing: Validation of MRDetect using serial blood samples from stage III colorectal cancer patients
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Amanda Frydendahl, Thomas Reinert, Jesper Nors, Sunil Deochand, Dillon Maloney, Noah Friedman, Tomer Lauterman, Danielle Afterman, Imane Bourzgui, Nidhi Ramaraj, Zohar Donenhirsh, Ronel Veksler, Ravi Kandasamy, Iman Tavassoly, Jonathan Rosenfeld, Anders Husted Andersen, Uffe S. Løve, Per V. Andersen, Ole Thorlacius-Ussing, Lene Hjerrild Iversen, Kåre Andersson Gotschalck, Boris Oklander, Asaf Zviran, and Claus Lindbjerg Andersen
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Cancer Research ,Oncology - Abstract
Background: While detection of circulating tumor DNA (ctDNA) is associated with poor cancer prognosis, the clinical utility for guiding treatment decisions is unresolved. Patients with minimal residual disease (MRD) often have less than one genome equivalent of ctDNA per 10 mL blood. Consequently, it is stochastic whether a 10 mL sample contains ctDNA from a particular genomic locus. Consequently, the sensitivity of ctDNA detection methods targeting a limited number of tumor loci is heavily affected by sampling bias. To overcome this challenge, we developed MRDetect; a whole genome sequencing (WGS) approach, which detects ctDNA using the patient-specific cumulative signal from tens of thousands of mutations throughout the genome. Recently, we showed how MRDetect found ctDNA fractions down to 10-4. Here, we performed a validation study to confirm the prognostic impact of MRDetect. Aim: Validation of MRDetect for sensitive ctDNA detection to monitor residual disease in stage III colorectal cancer (CRC) patients treated with curative intent. Methods: From a large, uniform cohort of stage III CRC patients n = 146), we had plasma samples collected every third month (n = 938, median = 9 per patient) and a median follow-up of 34 months. For each patient, a genome-wide mutational signature was established by WGS of tumor and matched normal DNA. Enhanced by an AI-based error suppression model, this signature was used to detect ctDNA in 1-2 mL plasma samples using WGS (20x coverage). We used de-novo point mutation and copy number variation analysis to investigate cancer evolution after treatment. To evaluate the reproducibility of MRDetect, aliquot samples (n = 2x190 samples) from 5 recurrence and 10 non-recurrence patients were processed and sequenced at two independent laboratories. Outcome measures: ctDNA status, tumor fraction, false positive rate, Time To ctDNA Recurrence (TTcR), and Time To radiological Recurrence (TTrR). Results: Analysis of paired samples showed great reproducibility with high agreement between both ctDNA status calls (Cohens Kappa = 0.81) and the estimated tumor fractions (r2 = 0.99). MRDetect revealed post-operative ctDNA in all recurrence patients (5/5) with detected tumor fractions down to 2 x 10-4. Median TTcR was 0.9 month (range 0.5 - 7.3 months) while median TTrR was 12.8 months (range 11.3 - 31.1 months). The false positive rate was 1% (1/100), assessed in longitudinal samples from the 10 non-relapsing patients. Tumor evolution dynamics in plasma samples revealed novel amplification and deletions, which were absent in the primary tissue but confirmed in metachronous metastases. We will present results from the full cohort at AACR 2022. Conclusion: MRDetect detects ctDNA with high sensitivity and specificity and enables effective postoperative assessment of MRD, cancer evolution dynamics and early relapse detection. Citation Format: Amanda Frydendahl, Thomas Reinert, Jesper Nors, Sunil Deochand, Dillon Maloney, Noah Friedman, Tomer Lauterman, Danielle Afterman, Imane Bourzgui, Nidhi Ramaraj, Zohar Donenhirsh, Ronel Veksler, Ravi Kandasamy, Iman Tavassoly, Jonathan Rosenfeld, Anders Husted Andersen, Uffe S. Løve, Per V. Andersen, Ole Thorlacius-Ussing, Lene Hjerrild Iversen, Kåre Andersson Gotschalck, Boris Oklander, Asaf Zviran, Claus Lindbjerg Andersen. Sensitive detection of circulating tumor DNA by whole genome sequencing: Validation of MRDetect using serial blood samples from stage III colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1959.
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- 2022
14. 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
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J.A. Carbonell-Asins, Marisol Huerta, Susana Roselló, Lene Hjerrild Iversen, Claus L. Andersen, Ole Thorlacius-Ussing, Tenna V Henriksen, Alexey Aleshin, Andrés Cervantes, Uffe S. Løve, Kåre Andersson Gotschalck, Noelia Tarazona, Thomas Reinert, Shruti Sharma, Amanda Frydendahl, Derrick Renner, Himanshu Sethi, and Desamparados Roda
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Adjuvant chemotherapy ,Early Relapse ,Postoperative management ,Recurrence risk ,Circulating tumor DNA ,Internal medicine ,Stage III colorectal cancer ,Adjuvant therapy ,Medicine ,business ,Selection (genetic algorithm) - Abstract
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.
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- 2021
15. 420P Minimal residual disease detection and tracking tumour evolution using ctDNA in stage I-III colorectal cancer patients
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Lene Hjerrild Iversen, Shruti Sharma, N. Tarazona, Svetlana Shchegrova, Thomas Reinert, Andrés Cervantes, Anders Husted Madsen, Antony Tin, J.A. Carbonell-Asins, M. Huerta, Alexey Aleshin, Tenna V Henriksen, Claus L. Andersen, Susana Roselló, Kåre Andersson Gotschalck, Bernhard Zimmermann, Himanshu Sethi, H.-T. Wu, and Desamparados Roda
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Oncology ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,Internal medicine ,medicine ,Hematology ,medicine.disease ,business ,Minimal residual disease - Published
- 2020
16. Circulating tumor DNA analysis for assessment of recurrence risk, benefit of adjuvant therapy, and early relapse detection after treatment in colorectal cancer patients
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Lene Hjerrild Iversen, Ole Thorlacius-Ussing, Tenna V Henriksen, Marisol Huerta, Alexey Aleshin, Claus L. Andersen, Derrick Renner, Susana Roselló, Anders Husted Madsen, Thomas Reinert, Per Vadgaard Andersen, Andrés Cervantes, Shruti Sharma, Himanshu Sethi, Uffe S. Løve, Kåre Andersson Gotschalck, J.A. Carbonell-Asins, N. Tarazona, and Desamparados Roda
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Early Relapse ,medicine.disease ,Recurrence risk ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor DNA ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adjuvant therapy ,business ,After treatment ,030215 immunology - Abstract
11 Background: Timely detection of recurrence, as well as identification of patients at high risk of recurrence after surgery and after completion of adjuvant therapy, are major challenges in the treatment of colorectal cancer (CRC). Postsurgical circulating tumor DNA (ctDNA) analysis is a promising tool for the identification of patients with minimal residual disease (MRD) and a high risk of recurrence. The objective of this prospective, multicenter study was to determine whether serial postsurgical ctDNA analysis could identify the patients at high risk of recurrence, provide an assessment of adjuvant therapy efficacy and detect relapse earlier than standard-of-care radiological imaging. Methods: The cohort comprises 265 stage I-III CRC patients, the to-date largest cohort assessed for ctDNA. All patients had the tumor resected and a subset of 62.6% (166 /265) was additionally treated with ACT. Plasma samples (n = 1503) were collected at various time points for a median follow-up of 28.4 months (range: 1.2-51.0 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic single nucleotide variants (SNVs) were identified. Personalized multiplex PCR assays were designed to track tumor-specific SNVs (Signatera, bespoke mPCR NGS assay) in each patient’s plasma sample. Results: Postoperative ctDNA status prior to ACT was assessed in 218 patients, of which 9.17% (20/218) were identified to be MRD-positive and 75% (15/20) eventually relapsed. The remaining 25% (5/20) of MRD-positive patients that did not relapse, received ACT. In contrast, only 13.6% (27/198) of MRD-negative cases relapsed (HR: 11: 95% CI: 5.7-20; p < 0.001). Longitudinal ctDNA-positive status, post-definitive therapy (n = 202) was associated with a HR of 36 (95% CI: 16-81; p < 0.001). For a subset of 155 patients postoperative CEA and ctDNA measurements were compared, wherein, ctDNA-positive status was found to be significantly associated with RFS (HR, 7.1; 95% CI, 3.4-15; P < 0.001) compared to CEA (HR, 1.2; 95% CI, 0.46-3.1; P = 0.73). Serial ctDNA analysis detected MRD up to a median of 8 months (0.56 - 21.6 months) ahead of radiologic relapse. Conclusion: Postoperative ctDNA positive status was associated with markedly reduced RFS compared to CEA. The study also shows that effective therapy can be curative in a portion of MRD-positive patients. In a longitudinal setting, ctDNA analysis predicted the risk of recurrence and is a more reliable biomarker for treatment response monitoring.
- Published
- 2021
17. IMPROVE-IT2: Implementing non-invasive circulating tumor DNA analysis to optimize the operative and postoperative treatment for patients with colorectal cancer – Intervention Trial 2. Study protocol
- Author
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Claus L. Andersen, Lene Hjerrild Iversen, Tenna V Henriksen, Jes Søgaard, Kåre Andersson Gotschalck, Jesper Nors, and Therese Juul
- Subjects
medicine.medical_specialty ,RESECTION ,Colorectal cancer ,MEDLINE ,GUIDELINES ,Circulating Tumor DNA ,030218 nuclear medicine & medical imaging ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Postoperative treatment ,law ,Internal medicine ,SURVEILLANCE ,medicine ,MANAGEMENT ,Humans ,EPIDEMIOLOGY ,Radiology, Nuclear Medicine and imaging ,Postoperative Period ,Intervention trial ,METACHRONOUS METASTASES ,RECURRENCE ,Protocol (science) ,business.industry ,COLON-CANCER ,Follow up studies ,Hematology ,General Medicine ,Prognosis ,medicine.disease ,Oncology ,Circulating tumor DNA ,030220 oncology & carcinogenesis ,CURATIVE TREATMENT ,Colorectal Neoplasms ,business ,FOLLOW-UP ,Colorectal Surgery ,Follow-Up Studies - Abstract
Death of colorectal cancer (CRC) is primarily associated to distant metastases, present at the time of diagnosis or appearing later following a cancer-free period. At time of diagnosis, 75% of pati...
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