Background Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. Methods/design MEDOCC-CrEATE follows the ‘trial within cohorts’ (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. Discussion The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. Trial registration Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281
Identification of non-metastatic colorectal cancer (CRC) patients with a high risk of recurrence after tumor resection is important to select patients who might benefit from adjuvant treatment. Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analyses after surgery are promising biomarkers to predict recurrence in these patients. However, these analyses face several challenges and do not allow guidance of neoadjuvant treatment, which might become a novel standard option in colon cancer treatment. The prognostic value of cfDNA/ctDNA before surgery is unclear. This systematic review aims to provide an overview of publications in which the prognostic value of presurgery cfDNA/ctDNA in non-metastatic CRC patients was studied and is performed according to PRISMA guidelines. A total of 29 out of 1233 articles were included and categorized into three groups that reflect the type of approach: measurement of cfDNA, ctDNA somatic alterations, and ctDNA methylation. Overall, a clear association between presurgery cfDNA/ctDNA and the outcome was not observed, but large studies that primarily focus on the prognostic value of presurgery cfDNA/ctDNA are lacking. Designing and performing studies that focus on the value of presurgery cfDNA/ctDNA is needed, in addition to standardization in the reporting of cfDNA/ctDNA results according to existing guidelines to improve comparability and interpretation among studies.
IMPORTANCE Triplet chemotherapy with fluorouracil, folinic acid, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-B) is an effective first-line treatment option for patients with metastatic colorectal cancer (mCRC). However, the degree of implementation of FOLFOXIRI-B in daily practice is unknown. OBJECTIVES To evaluate the current adoption rate of FOLFOXIRI-B in patients with mCRC and investigate the perspectives of medical oncologists toward this treatment option. DESIGN, SETTING, AND PARTICIPANTS This 1-week, multicenter, cross-sectional study in the Netherlands used a flash mob design, which facilitates ultrafast data generation (flash) through the engagement of numerous researchers (mob). During the study week (March 1-5, 2021), patient data were retrieved from electronic health records of 47 hospitals on patients with mCRC who were referred to a medical oncologist between November 1, 2020, and January 31, 2021. Interviews were simultaneously conducted with 101 medical oncologists from 52 hospitals who regularly treat patients with mCRC. EXPOSURE First-line systemic treatment as determined by the treating physician. MAIN OUTCOMES AND MEASURES The FOLFOXIRI-B prescription rate was the main outcome. Current practice was compared with prescription rates in 2015 to 2018. Eligibility for treatment with FOLFOXIRI-B was estimated. An exploratory outcome was medical oncologists' reported perspectives on FOLFOXIRI-B. RESULTS A total of 5948 patients in the Netherlands (median age [interquartile range], 66 [57-73] years; 3503 [59%] male; and 3712 [62%] with left-sided or rectal tumor) were treated with first-line systemic therapy for synchronous mCRC. A total of 282 patients with mCRC underwent systemic therapy during the study period (2021). Of these 282 patients, 199 (71%) were treated with intensive first-line therapy other than FOLFOXIRI-B, of whom 184 (65%) were treated with oxaliplatin doublets with or without bevacizumab; 14 (5%) with irinotecan doublets with or without bevacizumab, panitumumab, or cetuximab; and 1 (0.4%) with irinotecan with bevacizumab. Fifty-four patients (19%) were treated with fluoropyrimidine monotherapy with or without bevacizumab, 1 patient (0.4%) with panitumumab monotherapy, and 3 (1%) with immune checkpoint inhibitors. In total, 25 patients (9%; 95% CI, 6%-12%) were treated with first-line FOLFOXIRI-B compared with 142 (2%; 95% CI, 2%-3%) in 2015 to 2018. During the study period, 21 of 157 eligible patients (13.4%) in the Netherlands were treated with FOLFOXIRI-B. A total of 87 medical oncologists (86%) reported discussing FOLFOXIRI-B as a treatment option with eligible patients. A total of 47 of 85 (55%) generally communicated a preference for a chemotherapy doublet to patients. These oncologists (continued)
Tropomyosin receptor kinase (TRK) inhibitors have been approved for metastatic solid tumors harboring NTRK fusions, but the detection of NTRK fusions is challenging. International guidelines recommend pan-TRK immunohistochemistry (IHC) screening followed by next generation sequencing (NGS) in tumor types with low prevalence of NTRK fusions, including metastatic colorectal cancer (mCRC). RNA-based NGS is preferred, but is expensive, time-consuming, and extracting good-quality RNA from FFPE tissue is challenging. Alternatives in daily clinical practice are warranted. We assessed the diagnostic performance of RNA-NGS, FFPE-targeted locus capture (FFPE-TLC), fluorescence in situ hybridization (FISH), and the 5′/3′ imbalance quantitative RT-PCR (qRT-PCR) after IHC screening in 268 patients with microsatellite-instability-high mCRC, the subgroup in which NTRK fusions are most prevalent (1–5%). A consensus result was determined after review of all assay results. In 16 IHC positive tumors, 10 NTRK fusions were detected. In 33 IHC negative samples, no additional transcribed NTRK fusions were found, underscoring the high sensitivity of IHC. Sensitivity of RNA-NGS, FFPE-TLC, FISH, and qRT-PCR was 90%, 90%, 78%, and 100%, respectively. Specificity was 100% for all assays. Robustness, defined as the percentage of samples that provided an interpretable result in the first run, was 100% for FFPE-TLC, yet more limited for RNA-NGS (85%), FISH (70%), and qRT-PCR (70%). Overall, we do not recommend FISH for the detection of NTRK fusions in mCRC due to its low sensitivity and limited robustness. We conclude that RNA-NGS, FFPE-TLC, and qRT-PCR are appropriate assays for NTRK fusion detection, after enrichment with pan-TRK IHC, in routine clinical practice.
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: 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.
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