Abstract 3358: PLCRC-PROVENC3: assessing the prognostic value of post-surgery liquid biopsy cell-free circulating tumor DNA in stage III colon cancer patients
Authors: Rubio-Alarcon Carmen , Ketelaars Steven L. , Franken Ingrid A. , van Nassau Sietske C. , van der Kruijssen Dave E. , Schraa Suzanna J. , Linders Theodora C. , Diemen Pien Delis-van , Alkemade Maartje , Bolijn Anne , Tijssen Marianne , Lemmens Margriet , van Dongen Miranda , Lanfermeijer Mirthe , Broeks Annegien , Meiqari Lana , Bosch Linda J. , Velculescu Victor E. , Greer Amy , Angiuoli Samuel V. , Georgiadis Andrew , Riley David , White James R. , Greco Christopher , Cox Liam , Broek Daan van den , Punt Cornelis J. , Coupé Veerle M. , Koopman Miriam , Roodhart Jeanine , Meijer Gerrit A. , Sausen Mark , Vink Geraldine R. , Fijneman Remond J. 
Published: April 2023

Abstract
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.