A Micro-Costing Framework for Circulating Tumor DNA Testing in Dutch Clinical Practice

Abstract

Circulating tumor DNA (ctDNA) is a promising new biomarker with multiple potential applications in cancer care. Estimating total cost of ctDNA testing is necessary for reimbursement and implementation, but challenging because of variations in workflow. We aimed to develop a micro-costing framework for consistent cost calculation of ctDNA testing. First, the foundation of the framework was built, based on the complete step-wise diagnostic workflow of ctDNA testing. Second, the costing method was set up, including costs for personnel, materials, equipment, overhead, and failures. Third, the framework was evaluated by experts and applied to six case studies, including PCR-, mass spectrometry–, and next-generation sequencing–based platforms, from three Dutch hospitals. The developed ctDNA micro-costing framework includes the diagnostic workflow from blood sample collection to diagnostic test result. The framework was developed from a Dutch perspective and takes testing volume into account. An open access tool is provided to allow for laboratory-specific calculations to explore the total costs of ctDNA testing specific workflow parameters matching the setting of interest. It also allows to straightforwardly assess the impact of alternative prices or assumptions on the cost per sample by simply varying the input parameters. The case studies showed a wide range of costs, from €168 to €7638 ($199 to $9124) per sample, and generated information. These costs are sensitive to the (coverage of) platform, setting, and testing volume. Circulating tumor DNA (ctDNA) is a promising new biomarker with multiple potential applications in cancer care. Estimating total cost of ctDNA testing is necessary for reimbursement and implementation, but challenging because of variations in workflow. We aimed to develop a micro-costing framework for consistent cost calculation of ctDNA testing. First, the foundation of the framework was built, based on the complete step-wise diagnostic workflow of ctDNA testing. Second, the costing method was set up, including costs for personnel, materials, equipment, overhead, and failures. Third, the framework was evaluated by experts and applied to six case studies, including PCR-, mass spectrometry–, and next-generation sequencing–based platforms, from three Dutch hospitals. The developed ctDNA micro-costing framework includes the diagnostic workflow from blood sample collection to diagnostic test result. The framework was developed from a Dutch perspective and takes testing volume into account. An open access tool is provided to allow for laboratory-specific calculations to explore the total costs of ctDNA testing specific workflow parameters matching the setting of interest. It also allows to straightforwardly assess the impact of alternative prices or assumptions on the cost per sample by simply varying the input parameters. The case studies showed a wide range of costs, from €168 to €7638 ($199 to $9124) per sample, and generated information. These costs are sensitive to the (coverage of) platform, setting, and testing volume. Our increasing knowledge of tumor biology has enabled a transition from one-size-fits-all to tailored treatment of patients with cancer. Molecular profiling of the tumor DNA in tissue samples has become routine in cancer care. In our circulation, cell-free DNA (cfDNA) fragments derived from all cells in our body are found. Recent proof-of-concept studies have demonstrated the diagnostic potential of the analysis of circulating tumor-derived DNA (ctDNA) fragments as a tumor biomarker supporting clinical decision making.1Wan J.C.M. Massie C. Garcia-Corbacho J. Mouliere F. Brenton J.D. Caldas C. Pacey S. Baird R. Rosenfeld N. Liquid biopsies come of age: towards implementation of circulating tumour DNA.Nat Rev Cancer. 2017; 17: 223-238Crossref PubMed Scopus (1484) Google Scholar, 2Osumi H. Shinozaki E. Yamaguchi K. Zembutsu H. Clinical utility of circulating tumor DNA for colorectal cancer.Cancer Sci. 2019; 110: 1148-1155Crossref PubMed Scopus (84) Google Scholar, 3Heitzer E. Haque I.S. Roberts C.E.S. Speicher M.R. Current and future perspectives of liquid biopsies in genomics-driven oncology.Nat Rev Genet. 2019; 20: 71-88Crossref PubMed Scopus (722) Google Scholar These ctDNA fragments can be analyzed using liquid biopsy approaches in blood plasma and urine among others. Major advantages of testing ctDNA compared with tumor tissue are the possibility to analyze ctDNA longitudinally and the fact that obtaining the sample is less invasive, and as such associated with a lower risk of complications.4Rolfo C. Cardona A.F. Cristofanilli M. Paz-Ares L. Diaz Mochon J.J. Duran I. Raez L.E. Russo A. Lorente J.A. Malapelle U. Gil-Bazo I. Jantus-Lewintre E. Pauwels P. Mok T. Serrano M.J. ISLBChallenges and opportunities of cfDNA analysis implementation in clinical practice: perspective of the International Society of Liquid Biopsy (ISLB).Crit Rev Oncol Hematol. 2020; 151: 102978Crossref PubMed Scopus (62) Google Scholar ctDNA testing can address multiple diagnostic needs, across many cancer types, including clinical applications, like early detection of cancer, detection of minimal residual disease, molecular target profiling, surveillance for recurrences, prediction and monitoring of treatment response, and early detection of resistance.1Wan J.C.M. Massie C. Garcia-Corbacho J. Mouliere F. Brenton J.D. Caldas C. Pacey S. Baird R. Rosenfeld N. Liquid biopsies come of age: towards implementation of circulating tumour DNA.Nat Rev Cancer. 2017; 17: 223-238Crossref PubMed Scopus (1484) Google Scholar,3Heitzer E. Haque I.S. Roberts C.E.S. Speicher M.R. Current and future perspectives of liquid biopsies in genomics-driven oncology.Nat Rev Genet. 2019; 20: 71-88Crossref PubMed Scopus (722) Google Scholar,5Otandault A. Anker P. Al Amir Dache Z. Guillaumon V. Meddeb R. Pastor B. Pisareva E. Sanchez C. Tanos R. Tousch G. Schwarzenbach H. Thierry A.R. Recent advances in circulating nucleic acids in oncology.Ann Oncol. 2019; 30: 374-384Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 6van der Leest P. Hiddinga B. Miedema A. Aguirre Azpurua M.L. Rifaela N. Ter Elst A. Timens W. Groen H.J.M. van Kempen L.C. Hiltermann T.J.N. Schuuring E. Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors.Mol Oncol. 2021; 15: 2910-2922Crossref PubMed Scopus (12) Google Scholar, 7Tie J. Cohen J.D. Lahouel K. Lo S.N. Wang Y. Kosmider S. Wong R. Shapiro J. Lee M. Harris S. Circulating tumor DNA analysis guiding adjuvant therapy in PubMed Scopus Google Scholar the of ctDNA testing in cancer for the detection of minimal residual has promising as the of ctDNA is associated with a and a lower risk of H. Shinozaki E. Yamaguchi K. Zembutsu H. Clinical utility of circulating tumor DNA for colorectal cancer.Cancer Sci. 2019; 110: 1148-1155Crossref PubMed Scopus (84) Google J. Cohen J.D. Lahouel K. Lo S.N. Wang Y. Kosmider S. Wong R. Shapiro J. Lee M. Harris S. Circulating tumor DNA analysis guiding adjuvant therapy in PubMed Scopus Google Scholar, J. Wang Y. C. L. S. I. N. M. Wong M. Kosmider S. I. Wong R. M. B. J. I. A. T. Diaz N. B. P. Circulating tumor DNA analysis minimal residual and in patients with PubMed Scopus Google Scholar, J. Cohen J.D. Wang Y. M. K. Lee M. Wong R. Kosmider S. S. J. Lee B. I. J. M.J. N. L. L. C. N. B. P. Circulating tumor DNA as of risk and of adjuvant therapy for Oncol. 2019; PubMed Scopus Google Scholar that ctDNA be to patients are risk for of tumor and from adjuvant In lung cancer, a promising of ctDNA is target is a tissue and ctDNA S. J. A. T. T. G. S. J. M. A. Kempen I. to plasma testing in clinical Oncol. 2020; PubMed Scopus Google Scholar ctDNA testing has in the as a diagnostic in case tissue samples are for molecular C. Cardona A.F. Cristofanilli M. Paz-Ares L. Diaz Mochon J.J. Duran I. Raez L.E. Russo A. Lorente J.A. Malapelle U. Gil-Bazo I. Jantus-Lewintre E. Pauwels P. Mok T. Serrano M.J. ISLBChallenges and opportunities of cfDNA analysis implementation in clinical practice: perspective of the International Society of Liquid Biopsy (ISLB).Crit Rev Oncol Hematol. 2020; 151: 102978Crossref PubMed Scopus (62) Google C. S. K. M. J.A. L. R. B. E. Y. molecular testing for the of lung cancer patients for treatment with from the of the International for the of and the for Molecular 20: Full Text Full Text PDF PubMed Scopus Google Hiltermann T.J.N. B. K. van M. V. Schuuring E. van van der J. L. of molecular for lung cancer in The to with increasing Oncol. 2019; PubMed Scopus Google Scholar of clinical utility for applications of ctDNA is and the implementation of ctDNA testing in clinical is J.D. C. M. P. N. P. Circulating tumor DNA analysis in patients with Society of Clinical and of Oncol. PubMed Scopus Google Scholar In to the on clinical has the costs of ctDNA testing. for cfDNA and detection of ctDNA with and in N. S. liquid biopsies into treatment and 2019; PubMed Scopus Google Scholar the costs of ctDNA testing all costs associated with the diagnostic from sample collection to diagnostic test result. is a of in diagnostic and the have A. K. I. J. J. R. Lee J. L. K. M. J. K. L. L.C. for the of next-generation ctDNA a of the 2020; PubMed Scopus Google Scholar, R. M. J.A. F. J.A. C. N. Schuuring E. from the cfDNA on the minimal for clinical ctDNA 2019; PubMed Scopus Google Scholar, V. S. The of cell-free DNA as a molecular for cancer 2019; 17: PubMed Scopus Google Scholar of the applications approaches and for ctDNA testing of and to result. and have become in the for in the workflow of ctDNA R. M. J.A. F. J.A. C. N. Schuuring E. from the cfDNA on the minimal for clinical ctDNA 2019; PubMed Scopus Google Scholar to many variations in diagnostic among applications and and the total costs of ctDNA testing. into the total costs of ctDNA testing is to the and In the costs of ctDNA testing is for of ctDNA testing. the ctDNA is and the diagnostic and costs of ctDNA testing cost can become specific cost for and diagnostic workflow be of the costs of ctDNA applications, platforms, and diagnostic aimed to develop a framework with a cost calculation including all costs of the diagnostic workflow of framework a consistent calculation method and can be to explore the total costs of diagnostic and platforms, into the of samples that are analyzed testing It can in clinical as as the calculation of the costs of ctDNA testing for future is as of the Dutch the to in the that to the implementation of ctDNA testing in routine clinical First, the diagnostic workflow was in with ctDNA experts and as the foundation of the Second, the costing method and cost calculation tool of the framework Third, the framework and cost calculation tool with experts and evaluated by the cost calculation tool to six case studies with approaches and The diagnostic workflow for ctDNA testing was in with including in clinical molecular clinical in molecular and ctDNA from blood sample collection to diagnostic test result. was and the diagnostic workflow was into J.J. 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