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      Do cancer biomarkers make targeted therapies cost-effective? A systematic review in metastatic colorectal cancer

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      Journal: PLoS ONE
      Publisher: Public Library of Science

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          Abstract

          Background

          Recent advances in targeted therapies have raised expectations that the clinical application of biomarkers would improve patient’s health outcomes and potentially save costs. However, the cost-effectiveness of biomarkers remains unclear irrespective of the cost-effectiveness of corresponding therapies. It is thus important to determine whether biomarkers for targeted therapies provide good value for money. This study systematically reviews economic evaluations of biomarkers for targeted therapies in metastatic colorectal cancer (mCRC) and assesses the cost-effectiveness of predictive biomarkers in mCRC.

          Methods

          A literature search was performed using Medline, Embase, EconLit, NHSEED. Papers published from 2000 until June 2018 were searched. All economic evaluations assessing biomarker-guided therapies with companion diagnostics in mCRC were searched. To make studies more comparable, cost-effectiveness results were synthesized as per biomarker tests and corresponding therapies. Methodological quality was assessed using the Quality of Health Economic Studies (QHES) instrument.

          Results

          Forty-six studies were included in this review. Of these, 17 studies evaluated the intrinsic value of cancer biomarkers, whereas the remaining studies focused on assessing the cost-effectiveness of corresponding drugs. Most studies indicated favourable cost-effectiveness of biomarkers for targeted therapies in mCRC. Some studies reported that biomarkers were cost-effective, while their corresponding therapies were not cost-effective. A considerable number of economic evaluations were conducted in pre-defined genetic populations and thus, often failed to fully capture the biomarker’s clinical and economic values. The average QHES score was 73.6.

          Conclusion

          Cancer biomarkers for targeted therapies in mCRC were mostly found to be cost-effective; otherwise, they at least improved the cost-effectiveness of targeted therapies by saving some costs. However, this did not necessarily make their corresponding therapies cost-effective. While companion biomarkers reduced therapy costs, the savings were not sufficient to make the corresponding agents cost-effective. Evaluation of biomarkers was often restricted to the cost of tests and did not consider their clinical values or biomarker prevalence.

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          Most cited references56

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          Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer.

          Helena Linardou, Issa Dahabreh, Dimitra Kanaloupiti … (2008)
          Somatic mutations of the k-RAS oncogene have been assessed as a mechanism of de-novo resistance to epidermal growth factor receptor (EGFR) tyrosine-kinase inhibition in patients with non-small-cell lung cancer (NSCLC), and to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). The aim of this systematic review and meta-analysis was to assess if k-RAS mutations represent a candidate predictive biomarker for anti-EGFR-targeted therapeutic strategies in mCRC and NSCLC. We systematically identified articles pertaining to k-RAS mutational status in patients with NSCLC treated with tyrosine-kinase inhibitors (TKI), and patients with mCRC treated with any anti-EGFR-based regimens. Eligible studies had to report complete responses (CR) and partial responses (PR), stratified by k-RAS mutational status. Potential between-study heterogeneity was accommodated by use of random-effects models for bivariable meta-analysis of sensitivity and specificity (the primary endpoints). The positive and negative likelihood ratios (+LR and -LR, respectively) of k-RAS mutations for predicting an absence of response were considered as secondary endpoints and were calculated by use of pooled estimates for sensitivity and specificity. Of 252 retrieved manuscripts, 17 were deemed eligible for the NSCLC meta-analysis (165 of 1008 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to TKIs (sensitivity=0.21 [95% CI 0.16-0.28], specificity=0.94 [0.89-0.97]; +LR=3.52; -LR=0.84). Of 68 retrieved manuscripts reporting on anti-EGFR monoclonal-antibody-based treatment of mCRC, eight studies were deemed eligible for the final analysis (306 of 817 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments (sensitivity=0.47 [0.43-0.52]; specificity=0.93 [0.83-0.97]; +LR=6.82; -LR=0.57). This analysis provides empirical evidence that k-RAS mutations are highly specific negative predictors of response (de-novo resistance) to single-agent EGFR TKIs in advanced NSCLC; and similarly to anti-EGFR monoclonal antibodies alone or in combination with chemotherapy in patients with mCRC. The low sensitivity and relatively high -LR of k-RAS mutations for determining non-responsiveness clearly shows that additional mechanisms of resistance to EGFR inhibitors exist.
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            On the origin of cancer metastasis.

            Thomas Seyfried, Leanne Huysentruyt (2013)
            Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis. These involve an epithelial mesenchymal transition, an accumulation of mutations in stem cells, a macrophage facilitation process, and a macrophage origin involving either transformation or fusion hybridization with neoplastic cells. Many of the properties of metastatic cancer cells are also seen in normal macrophages. A macrophage origin of metastasis can also explain the long-standing "seed and soil" hypothesis and the absence of metastasis in plant cancers. The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management.
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              Examining the Value and Quality of Health Economic Analyses: Implications of Utilizing the QHES

              Joshua J. Ofman, Sean D. Sullivan, Peter J. Neumann … (2003)
              OBJECTIVES: To examine the increasing use of health economic studies and practical implications of evaluating their quality utilizing the Quality of Health Economic Studies (QHES) instrument. METHODS: We first reviewed secondary references to examine ways in which health economic analyses are used in different health care settings, the manner in which these data are appraised and evaluated, and their relevance and value in decision making. The QHES, a new instrument designed to support fast, accurate initial assessments of study quality, was then introduced and validated. A case study was performed using the QHES to score the quality of 30 cost-effectiveness studies in gastroesophageal reflux disease (GERD) published since 1985. Areas where additional research could guide efforts to identify and enhance the use of higher-quality cost-effectiveness studies were suggested. RESULTS: Results from the published validation study of the QHES demonstrated the validity of this new instrument. The resulting QHES scores in the case study of GERD papers ranged from 43 to 91 with a mean of 63.6 (SD=14.7). Approximately 27% of the studies rated had scores less than 50, and 27% had scores above or equal to 75. All 30 studies made conclusions and recommendations and justified them based on their study results. Most studies used appropriate cost and health outcome measures. Very few studies stated the perspective of their analysis and reasons for its selection. The majority of the studies did not perform incremental analysis. CONCLUSIONS: An examination of the QHES validation study and the case study in GERD suggests that there is a rationale and potential utility to use a quality scoring system for cost-effectiveness studies. The QHES may play an important role in discriminating higher-quality cost-effectiveness information to enhance decision making. The QHES can also serve as a guideline for conducting and reporting future cost-effectiveness studies, as an aid in the editorial process, and for stratification in systematic reviews. Complex decisions regarding resource allocation rarely rely solely on economic considerations but do increasingly use health economic analyses. To the extent that such analyses are used, the QHES may help ensure that higher-quality analyses receive more analytic attention and greater weight in the decision-making process.
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                Author and article information

                Contributors
                Mikyung Kelly Seo:
                ORCID: http://orcid.org/0000-0003-4746-2264
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Project administrationRole: Writing – original draft
                John Cairns:
                ORCID: http://orcid.org/0000-0001-6442-0440
                Role: ConceptualizationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Aamir Ahmad: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 26 September 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 9
                Electronic Location Identifier: e0204496
                Affiliations
                [1 ] Department of Health Services Research and Policy, Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom
                [2 ] Centre for Cancer Biomarkers, Faculty of Medicine, University of Bergen, Bergen, Norway
                University of South Alabama Mitchell Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-4746-2264
                http://orcid.org/0000-0001-6442-0440
                Article
                Publisher ID: PONE-D-18-05107
                DOI: 10.1371/journal.pone.0204496
                PMC ID: 6157891
                PubMed ID: 30256829
                SO-VID: 19e9a68a-2f1c-4aef-864a-ba5f45c0d122
                Copyright © © 2018 Seo, Cairns
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 15 February 2018
                Date accepted : 10 September 2018
                Page count
                Figures: 2, Tables: 4, Pages: 23
                Funding
                MKS received a PhD studentship from Centre for Cancer Biomarkers (CCBIO), Centre of Excellence at the Faculty of Medicine and Dentistry, University of Bergen.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Biomarkers
                Subject: Social Sciences
                Subject: Economics
                Subject: Economic Analysis
                Subject: Cost-Effectiveness Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Probability Theory
                Subject: Markov Models
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Social Sciences
                Subject: Economics
                Subject: Health Economics
                Subject: Medicine and Health Sciences
                Subject: Health Care
                Subject: Health Economics
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Therapy
                Subject: Chemotherapy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Colorectal Cancer
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Genotyping
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Genotyping
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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