Introduction: Surgery followed by adjuvant chemotherapy (ACT) is standard of care in stage III colon cancer. However, 50% of the patients would be cured by surgery alone and are being overtreated, while 30-35% will experience a recurrence despite adjuvant treatment, resulting in only 15-20% of the patients benefitting from ACT. Therefore, there is a need for prognostic biomarkers to better stratify this group of patients for ACT decisions. Recent observational and interventional studies in non-metastatic colon cancer have shown that detection of cell-free circulating tumor DNA (ctDNA) in blood after surgery is highly prognostic for development of recurrence. Hence, ctDNA analysis is a promising approach to guide treatment decisions in stage III colon cancer, but studies with large well-defined patient cohorts are needed to prove clinical utility. Aim: Determine the prognostic value of ctDNA in stage III colon cancer patients treated with ACT to reduce futile treatment. Methods: 241 stage III colon cancer patients treated with ACT were included in the prospective observational study “PROVENC3” (PROgnostic Value of Early Notification by Ctdna in Colon Cancer stage 3), a substudy of the Prospective Dutch Colorectal Cancer cohort (PLCRC). The PLCRC infrastructure accrued patients with colorectal cancer in 23 participating hospitals in the Netherlands. After informed consent, blood was collected pre-surgery, post-surgery, post-ACT and every six months up to 3 years. Tumor-informed detection of ctDNA was performed through integrated whole genome sequencing (WGS) analyses of formalin-fixed paraffin-embedded tumor tissue DNA (80x), germline DNA (40x), and plasma cell-free DNA (30x). Results: Patient accrual was completed in 2021, with a median follow-up of 35.6 months. In total, 1090 blood samples have been collected to date. Analytical studies demonstrated a limit of detection of the test of 0.005% ctDNA utilizing contrived reference models derived from six independent cell lines, with a specificity of 99.6% across 119 noncancerous donor plasma specimens. From the PROVENC3 study, ctDNA analyses are ongoing for pre-surgery (n=68) and post-surgery (n=241 patients) blood samples. Preliminary results demonstrated a ctDNA detection rate of 93.4% pre-surgery and 17.1% post-surgery, which was associated with disease recurrence. Final analysis will enable determination of: 1) the proportion of ctDNA-positive/negative patients after surgery and the corresponding recurrence rates; 2) the prognostic value of post-surgery ctDNA; and 3) the lead time between post-surgery ctDNA detection and recurrence. Future Perspective: Ultimately, the results of this study will be used to model and design a ctDNA-guided interventional trial in stage III colon cancer patients, to reduce futile ACT and its associated side-effects. Citation Format: Carmen Rubio-Alarcon, Steven L. Ketelaars, Ingrid A. Franken, Sietske C. van Nassau, Dave E. van der Kruijssen, Suzanna J. Schraa, Theodora C. Linders, Pien Delis-van Diemen, Maartje Alkemade, Anne Bolijn, Marianne Tijssen, Margriet Lemmens, Miranda van Dongen, Mirthe Lanfermeijer, Annegien Broeks, Lana Meiqari, Linda J. Bosch, Victor E. Velculescu, Amy Greer, Samuel V. Angiuoli, Andrew Georgiadis, David Riley, James R. White, Christopher Greco, Liam Cox, Daan van den Broek, Cornelis J. Punt, Veerle M. Coupé, Miriam Koopman, Jeanine Roodhart, Gerrit A. Meijer, Mark Sausen, Geraldine R. Vink, Remond J. Fijneman. PLCRC-PROVENC3: assessing the prognostic value of post-surgery liquid biopsy cell-free circulating tumor DNA in stage III colon cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3358.
Introduction: Stage III colon cancer patients are offered surgery followed by adjuvant chemotherapy (ACT) according to Dutch clinical guidelines. However, only 15-20% of the patients benefit from ACT: 50% would be cured by surgery alone and are thus being overtreated, while 30-35% will experience a recurrence despite adjuvant treatment. Therefore, there is a need for prognostic biomarkers to better stratify this group of patients for ACT. Recent studies in non metastatic colorectal cancer have shown that detection of cell-free circulating tumor DNA (ctDNA) in blood after surgery indicates presence of minimal residual disease, and is highly prognostic for relapse. Hence, ctDNA based liquid biopsies could be a promising approach to guide post-surgery treatment decisions in stage III colon cancer. Aim: Determine the prognostic value of post-surgery ctDNA in stage III colon cancer patients treated with ACT in order to reduce futile treatment. Study design and Methods: The Prospective Dutch Colorectal Cancer Cohort study PLCRC (www.PLCRC.nl) offers a nationwide infrastructure to accrue colorectal cancer patients in nearly all (>60) hospitals in the Netherlands. Patients give informed consent for collection of clinical data, tissue and blood samples. “PROVENC3” (PROgnostic Value of Early Notification by Ctdna in Colon Cancer stage 3) is a prospective observational subcohort of PLCRC consisting of 267 stage III colon cancer patients treated with ACT,open for patient accrual in 25 hospitals. Blood samples are collected pre-surgery, post-surgery, post-ACT and longitudinally every six months up to 3 years. We will apply tumor-informed detection of ctDNA mutations by integrated analysis of targeted sequencing of a panel of 30 genes in cfDNA (PGDx elio plasma resolveassay) with a panel of 500 genes in DNA from formalin-fixed paraffin-embedded tumor tissue (PGDx elio tissue complete assay). The clinical, pathological, and molecular data will be integrated in cBioPortal. Results and future directions: 267 patients have been included. Approximately 950 blood samples have been collected to date. Once sequencing data is obtained, multivariate Cox regression analysis will be used to assess the association between post-surgery ctDNA detection and progression-free and overall survival. Ultimately, the results of this study will be used to design an ethically acceptable and cost-effective ctDNA-guided interventional trial in stage III colon cancer patients, in order to improve the risk stratification and reduce futile ACT and its associated side-effects. Citation Format: Carmen Rubio Alarcon, Dave E. van der Kruijssen, Suzanna J. Schraa, Sietske C. Nassau, Leticia G. León, Lana Meiqari, Linda J. Bosch, John K. Simmons, Mark Sausen, Amy Greer, Samuel V. Angiuoli, Jeanine M. Roodhart, Victor E. Velculescu, Daan van den Broek, Cornelis J. Punt, Veerle M. Coupé, Miriam Koopman, Gerrit A. Meijer, Geraldine R. Vink, Remond J. Fijneman. Prognostic value of post-surgery liquid biopsy cell-free circulating tumor DNA in stage III colon cancer patients - PLCRC-PROVENC3 study [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 536.
Introduction: Stage III colon cancer patients undergo surgery followed by adjuvant chemotherapy (ACT) according to clinical guidelines. However, 50% would be cured by surgery alone and are being overtreated, while 30-35% will relapse despite adjuvant treatment. This means that only 15-20% of the patients benefit from ACT. Therefore, there is a need for better prognostic biomarkers to stratify patients for ACT. Detection of cell-free circulating tumor DNA (ctDNA) in blood after surgery is indicative of minimal residual disease and highly prognostic for disease recurrence. Hence, detecting liquid biopsy ctDNA is a promising approach to guide treatment decisions in stage III colon cancer. Aim: Determine prognostic value of ctDNA in stage III colon cancer patients treated with ACT in order to reduce futile treatment. Methods: 315 stage III colon cancer patients treated with ACT will be included in the prospective observational study “PROVENC3” (PROgnostic Value of Early Notification by Ctdna in Colon Cancer stage 3). The Prospective Dutch Colorectal Cancer Cohort (PLCRC) infrastructure organizes accrual of colorectal cancer patients in more than 50 hospitals in the Netherlands, among which 25 hospitals that accrue patients for PROVENC3. If informed consent is provided, blood is collected at baseline, post-surgery, post-ACT and every six months up to 3 years, and shipped to a central location. Tumor-informed detection of mutations in ctDNA will be performed by combined analysis of targeted sequencing of a panel of >30 genes in cfDNA (PGDx elio plasma test) and a panel of >500 genes in DNA from formalin-fixed paraffin-embedded tumor tissue (PGDx elio tissue complete assay). The clinical, pathological, and molecular data will be handled according to the FAIR (findable, accessible, interoperable and reusable) principles and integrated in cBioPortal. Results and future directions: Around 125 patients and 400 blood samples included to date. Once sequencing data are obtained we will determine: 1) the proportion of ctDNA-positive and ctDNA-negative patients after surgery and the corresponding recurrence rates; 2) the prognostic value of ctDNA pre-surgery; and 3) the lead time between ctDNA detection and recurrence. Ultimately, the results of this study will be used to model and design an ethically acceptable and cost-effective ctDNA-guided interventional trial, to reduce futile ACT and its associated side-effects in stage III colon cancer patients. Citation Format: Carmen Rubio Alarcón, Dave E. van der Kruijssen, Lana Meiqari, Linda J. Bosch, John K. Simmons, Victor E. Velculescu, Daan van den Broek, Cornelis J. Punt, Veerle M. Coupé, Miriam Koopman, Gerrit A. Meijer, Geraldine R. Vink, Remond J. Fijneman. Liquid biopsy cell-free circulating tumor DNA as prognostic biomarker for stage III colon cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3096.
Background Accurate detection of patients with minimal residual disease (MRD) after resection of localized colon cancer remains an unmet clinical need as these patients might benefit from adjuvant chemotherapy (ACT). For stage II colon cancer, ACT is only indicated in patients with a pT4 tumor without a deficient mismatch repair system (dMMR), according to Dutch guidelines. However, recurrence rate (RR) in stage II colon cancer is still 15-20%. Circulating tumor DNA (ctDNA), consisting of small fragments of DNA containing tumor-specific mutations, has been shown to be a promising biomarker for MRD and a strong predictor for recurrent disease when detectable after resection. The MEDOCC-CrEATE trial investigates how many stage II colon cancer patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces RR in these patients. Methods The MEDOCC-CrEATE study follows the ‘trials within cohorts' (TwiCs) design. Patients with colorectal cancer are included in the Prospective Dutch ColoRectal Cancer (PLCRC) cohort study and give informed consent for collection of clinical data and biomaterials, including tissue and blood samples. Additionally, patients are invited to give their consent for future randomization without being informed when allocated to the control group receiving standard of care. In MEDOCC-CrEATE 1320 stage II colon cancer patients without an indication for ACT will be included and randomized 1:1 into an experimental and a control arm. In the experimental arm, tissue and blood samples are analyzed after surgery for tissue-informed detection of plasma ctDNA, using the PGDx elio™ Platform. Patients with detectable ctDNA after surgery will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin. Patients in the experimental arm without detectable ctDNA and patients in the control arm receive standard follow-up. The primary endpoint is the proportion of patients accepting ACT when ctDNA is detectable after resection. Most important secondary endpoint is 2-year RR, but also includes 5-year RR, disease free and overall survival, time to recurrence, quality of life and cost-effectiveness of the ctDNA-based treatment strategy. Data will be analyzed by intention to treat. To our knowledge, MEDOCC-CrEATE is the first trial in which a ctDNA guided strategy for adjuvant chemotherapy in colon cancer is investigated. The first patient was enrolled in August 2020. MEDOCC-CrEATE is now open for inclusion in 8 hospitals in the Netherlands. So far, 9 patients have been randomized. The number of participating hospitals will be expanded to 20-25 hospitals to include all 1320 patients within 3 years. MEDOCC-CrEATE has been registered in the Netherlands Trial Register: NL6281/NTR6455. Citation Format: Suzanna J. Schraa, Karlijn L. Van Rooijen, Dave E. Van Der Kruijssen, Carmen Rubio Alarcón, Jillian Phallen, John Simmons, Sam Angiuoli, Amy E. Greer, Veerle M. Coupé, Helma M. Van Grevenstein, Sjoerd Elias, Helena M. Verkooijen, Miranda M. Van Dongen, Linda J. Bosch, Daan Van Den Broek, Gerrit A. Meijer, Victor E. Velculescu, Remond J. Fijneman, Geraldine R. Vink, Miriam Koopman. MEDOCC-CrEATE trial in progress: effectiveness of adjuvant chemotherapy in stage II colon cancer patients with positive circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT251.
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