Purpose of the study: Molecular tests have the potential to improve current non-invasive faecal immunochemical test (FIT) screening for colorectal cancer (CRC) and advanced precancerous lesions. We examined the performance of a panel of faecal DNA (sDNA) markers and FIT in archival samples from an invitational CRC screening population. Methods: Whole stool samples were prospectively collected from individuals participating an invitational primary colonoscopy-screening program (COCOS trial). Only participants that provided stool, performed FIT (OC-Sensor) and underwent colonoscopy were selected. The sDNA panel included quantitative molecular assays for KRAS mutations and for aberrant NDRG4 and BMP3 methylation. The performance of the sDNA plus FIT panel was compared to the FIT results alone, by Receiver Operator Characteristic (ROC) analyses. Results: A total of 1047 individuals (51% male) with a median age of 60 years (range 50-75) were included, of which 7 (0.7%) had colorectal cancer and 104 (9.9%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps ≥ 1 cm). The combination of sDNA and FIT was more sensitive than FIT alone for detecting advanced precancerous lesions (49% (50/102) and 25% (26/102), respectively). Specificities among individuals with non-advanced or negative findings (controls) were 89% and 96% for sDNA and FIT testing, respectively. ROC analysis of CRC and advanced precancerous lesions compared to controls revealed an Area Under the Curve (AUC) of 0.75 for the sDNA plus FIT test, compared to 0.68 for FIT alone. At an equal specificity of 95%, advanced precancerous lesions were detected with a higher sensitivity by the sDNA plus FIT test compared to FIT alone (36% vs 28%, p = 0.08). Conclusions: In an invitational colorectal cancer screening cohort, combining stool DNA markers with FIT detected more advanced neoplasia than FIT alone, primarily due to detecting more advanced adenomas. Citation Format: Linda J.W. Bosch, Veerle Melotte, Sandra Mongera, Kathleen L.J. Daenen, Veerle H.M. Coupe, Sietze T. van Turenhout, Esther M. Stoop, Thomas R. de Wijkerslooth, Chris J.J. Mulder, Ernst J. Kuipers, Evelien Dekker, Michael Domanico, Graham P. Lidgard, Barry M. Berger, Beatriz Carvalho, Manon van Engeland, Gerrit A. Meijer. Advanced neoplasia detection in colorectal cancer screening using multiple stool DNA markers and haemoglobin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4338.
Background: Most colorectal cancer (CRC) deaths are caused by metastatic disease (mCRC). Therapeutic approaches include treatment with monoclonal antibodies (mAbs) against EGFR and VEGF. There is an urgent clinical need to stratify mCRC patients for optimal treatment. Cell-free circulating tumor DNA (ctDNA) derived from blood plasma is expected to improve stratification by early detection of therapy resistance and disease progression. Aim: The general aim of this study is to advance towards clinical implementation of ctDNA-based tests as molecular biomarkers to improve disease management of mCRC patients. We will investigate added value of liquid biopsy ctDNA-based gene mutation analyses compared to: 1) tissue-based tests for RAS mutation status as determined in standard clinical care setting; and 2) monitoring of disease progression by computed tomography (CT) imaging. Methods: CAIRO5 is a multicenter, randomized, phase 3 clinical trial of the Dutch Colorectal Cancer Group (DCCG) and includes patients with initially unresectable, liver-only mCRC, as confirmed by a central panel of liver surgeons/radiologists based on CT imaging. This study involves nation-wide longitudinal collection of liquid biopsies (blood samples) using cell-save tubes and CT imaging from up to 564 patients. Hotspot mutations in ctDNA will be analyzed by droplet digital PCR (ddPCR), and mutations in a panel of genes by targeted error correction sequencing (TEC-seq). Clinical, imaging, biobanking, and molecular data will be collected using standardized data fields and data formats and integrated for querying and viewing in tranSMART, making use of the national Health-RI research IT infrastructure. Results: The nation-wide multi-center logistics for longitudinal blood sample collection and plasma processing has been established, with participation of more than 40 Dutch hospitals. At present (Nov 2017), over 220 patients have been included from whom more than 550 blood samples and 330 CT images were obtained. Proof of concept for the validity of this workflow was obtained by successful subjection of 11 plasma samples to ctDNA mutation analysis by TEC-seq (Phallen et al., 2017). Discussion: Implementation of ctDNA-based tests as molecular biomarkers to improve disease management of mCRC patients requires collection of information from large, well-defined studies with longitudinal patient follow-up. This translational research project will provide the data that are needed to determine cost-effectiveness analysis of ctDNA mutation analyses by health technology assessment, yielding recommendations for clinical implementation of ctDNA applications. Citation Format: Iris van 't Erve, Jillian Phallen, Karen Bolhuis, Joost Huiskens, Nicole C. van Grieken, Veerle Coupé, Annegien Broeks, Daan van den Broek, Alessandro Leal, Victor E. Velculescu, Cornelis J. Punt, Gerrit A. Meijer, Remond J. Fijneman. Liquid biopsy analyses of cell-free circulating tumor DNA as predictive and prognostic biomarker for colorectal cancer patients with metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1588.
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