Nadia Øgaard1, Thomas Reinert2, Tenna V Henriksen3, Amanda Frydendahl4, Emilie Aagaard5, Mai-Britt W Ørntoft6, Marie Ø Larsen7, Anders R Knudsen8, Frank V Mortensen9, Claus L Andersen10. 1. Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark. Electronic address: n.oegaard@clin.au.dk. 2. Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark. Electronic address: thomas.reinert@clin.au.dk. 3. Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark. Electronic address: tvh@clin.au.dk. 4. Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark. Electronic address: amandafbj@clin.au.dk. 5. Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark. 6. Department of Surgery, Section for Upper Gastrointestinal and Hepatico-Pancreatico-Biliary Surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. Electronic address: mwo@clin.au.dk. 7. Department of Surgery, Section for Upper Gastrointestinal and Hepatico-Pancreatico-Biliary Surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. 8. Department of Surgery, Section for Upper Gastrointestinal and Hepatico-Pancreatico-Biliary Surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. Electronic address: andeknud@rm.dk. 9. Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark; Department of Surgery, Section for Upper Gastrointestinal and Hepatico-Pancreatico-Biliary Surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. Electronic address: franmort@rm.dk. 10. Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark. Electronic address: cla@clin.au.dk.
Abstract
PURPOSE: Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. EXPERIMENTAL DESIGN: 499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test 'TriMeth'. RESULTS: Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). CONCLUSIONS: Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.
PURPOSE: Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. EXPERIMENTAL DESIGN: 499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test 'TriMeth'. RESULTS: Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). CONCLUSIONS: Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.
Authors: Hamza AlGhamdi; Jennifer Dhont; Mohammad Krayem; Pauline De Bruyn; Benedikt Engels; Dirk Van Gestel; Robbe Van den Begin Journal: Cancers (Basel) Date: 2022-04-18 Impact factor: 6.575