Cost Saving Opportunities in NSCLC Therapy by Optimized Diagnostics.

Ilija Nenadić,Susanne Dreier,Janine Staber,Oliver Schildgen,Guus Simons,Michael Brockmann,Verena Schildgen

doi:10.3390/cancers9070088

Abstract

With an incidence of 68 new cases per 100,000 people per year, an estimated total number of up to 350,000 new non-small-cell lung cancer (NSCLC) cases are diagnosed each year in the European Union. Up to 10% of NSCLC patients are eligible for therapy with novel ALK (anaplastic lymphoma kinase) inhibitors, as they have been diagnosed with a mutation in the gene coding for ALK. The ALK inhibitor therapy costs add up to approx. 9000 € per patient per month, with treatment durations of up to one year. Recent studies have shown that up to 10% of ALK cases are misdiagnosed by nearly 40% of pathologic investigations. The current state-of-the-art ALK diagnostic procedure comprises a Fluorescent in situ Hybridization (FISH) assay accompanied by ALK inhibitor therapy (Crizotinib). The therapy success ranges between a full therapy failure and the complete remission of the tumor (i.e., healing), but the biomedical and systemic reasons for this range remain unknown so far. It appears that the variety of different ALK mutations and variants contributes to the discrepancy in therapy results. Although the major known fusion partner for ALK in NSCLC is the Echinoderm microtubule-associated protein-like 4 (EML4), of which a minimum of 15 variants have been described, an additional 20 further ALK fusion variants with other genes are known, of which three have already been found in NSCLC. We hypothesize that the wide variety of known (and unknown) ALK mutations is associated with a variable therapy success, thus rendering current companion diagnostic procedures (FISH) and therapy (Crizotinib) only partly applicable in ALK-related NSCLC treatment. In cell culture, differing sensitivity to Crizotinib has been shown for some fusion variants, but it is as yet unknown which of them are really biologically active in cancer patients, and how the respective variants affect the response to Crizotinib treatment. Moreover, it has been demonstrated that translocated ALK genes can also be observed in healthy tissues and are not compulsorily associated with tumors. Therefore, it is important to keep in mind that even for the known variants of ALK fusion genes, the biological function is not known for all variants, and that no information is available on the homogeneity of ALK fusion variants within a single tumor. These facts, in concert with data for ALK mutation prevalence and therapy outcomes of a German cohort of NSCLC patients, support the hypothesis that, by using novel companion diagnostic tools in combination with therapy outcome predictions, massive cost savings could be possible in European Health Care systems without a loss of patient care.

Highlights

In the era of personalized medicine, the molecular diagnostics of non-small cell lung cancer (NSCLC) have become more and more complex, and therapeutic interventions nowadays are highly targeted, and sometimes restricted to narrow clinical entities [1,2,3,4,5,6]
Taking into account that ALK fusion mutations can theoretically occur with up to 21 fusion partner genes, of which even Echinoderm microtubule-associated protein-like 4 (EML4) can form up to variants, this latter fact implies that an optimized diagnostic algorithm accompanied by a prediction software tool that correlates the likelihood of therapy response of a variant is capable of saving enormous therapy costs by excluding those variants that are not susceptible to tyrosine kinase inhibitor (TKI)
Institute (RKI) data on NSCLC in Germany, approximately 35,000 male and 20,300 female patients are newly diagnosed with lung cancer per year, with a low five year survival rate of 21% for female and

Summary

Introduction

In the era of personalized medicine, the molecular diagnostics of non-small cell lung cancer (NSCLC) have become more and more complex, and therapeutic interventions nowadays are highly targeted, and sometimes restricted to narrow clinical entities [1,2,3,4,5,6]. Taking into account that ALK fusion mutations can theoretically occur with up to 21 fusion partner genes, of which even EML4 can form up to variants, this latter fact implies that an optimized diagnostic algorithm accompanied by a prediction software tool that correlates the likelihood of therapy response of a variant (as determined in vitro) is capable of saving enormous therapy costs by excluding those variants that are not susceptible to TKI therapy. Based on these considerations, we addressed the question of how much the development of such an assay would cost, how much the assay itself would cost, and how much could be saved in healthcare reimbursement budgets by such an assay. We have extrapolated data from our own clinical cohort of NSCLC patients with FISH-confirmed ALK mutation and epidemiological data reported to and published by the Robert-Koch-Institute

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