A cost-consequence model of using the 21-gene assay to identify patients with early-stage node-positive breast cancer who benefit from adjuvant chemotherapy in the Netherlands.

BACKGROUND: Patients with early-stage hormone receptor positive, human epidermal growth factor receptor-2 (HER2) negative invasive breast cancer with 1-3 positive lymph nodes (N1) often undergo surgical excisions followed by adjuvant chemotherapy (ACT). Many patients have no benefit from ACT and receive unnecessary, costly treatment often associated with short- and long-term adverse events (AEs). Gene expression profiling (GEP) assays, such as the 21-gene assay (i.e. the Oncotype DX assay), can identify patients at higher risk for recurrence who may benefit from ACT. However, the budgetary consequence of using the Oncotype DX assay versus no GEP testing in the Netherlands is unknown. Our study therefore assessed it using a cost-consequence model. METHODS: A validated model was used to create the N1 model. The model compared the costs and consequences of using the Oncotype DX assay versus no GEP testing and MammaPrint, and subsequent ACT use with corresponding costs for chemotherapy, treatment of AEs, productivity losses, GEP testing, and treatment of recurrences, according to the Oncotype DX results. The model time horizon was 5 years. RESULTS: Costs for the total population amounted to €8.0 million (M), €16.2 M, and €9.5 M, and cost per patient amounted to €13,540, €27,455, and €16,154 for using the Oncotype DX assay, no GEP testing, and MammaPrint, respectively. Total cost savings of using the Oncotype DX assay amounted to €8.2 M versus no GEP testing and €1.5 M versus MammaPrint. Using the Oncotype DX assay would result in fewer patients receiving ACT and thus fewer AEs, sick days, and hospitalizations, leading to overall cost savings compared with no GEP testing and MammaPrint. CONCLUSIONS: Implementing Oncotype DX testing in this population can prevent unnecessary overtreatment, reducing clinical and economic burden on the patient and Dutch healthcare system.

Early-stage invasive breast cancer patients often undergo surgery followed by adjuvant chemotherapy. However, many of these patients have no benefit from adjuvant chemotherapy and thus receive unnecessary and costly treatment often associated with side-effects. Patients who may benefit from adjuvant chemotherapy can be identified by analyzing the genomic profile of the patients' tumors using a molecular diagnostic test called the 21-gene assay (also known as Oncotype DX assay). However, the budgetary consequences of using Oncotype DX for this purpose in the Netherlands are currently unknown and, therefore, assessed using a health-economic model. The model compared the costs and consequences of using the Oncotype DX assay versus no molecular diagnostic testing and an alternative molecular diagnostic test called MammaPrint. The three diagnostic testing strategies resulted in different costs in terms of several different costing categories and were compared with one another. The total costs were lowest for the diagnostic strategy using the Oncotype DX assay, as it would result in fewer patients receiving adjuvant chemotherapy compared with no molecular diagnostic testing and MammaPrint. Implementing the Oncotype DX assay as a molecular diagnostic test can identify the right patient who benefits from chemotherapy (prevent over- and undertreatment) and lead to cost-savings, reducing the clinical and economic burden on the patient and Dutch healthcare system.

Cost and Clinical Benefits Associated with Oncotype DX® Test in Patients with Early-Stage HR+/HER2- Node-Negative Breast Cancer in the Netherlands.

Objectives: Patients with early-stage HR+/HER2- N0 breast cancer may receive adjuvant chemotherapy in combination with surgery. However, chemotherapy does not always lead to improved survival and incurs high healthcare costs and increased adverse events. To support decision-making regarding adjuvant chemotherapy, genomic profile testing performed with tests such as the Oncotype DX® test can help healthcare practitioners decide whether chemotherapy provides any benefit to these patients. As such, a cost-consequence model was developed with the aim to estimate the economic impact of using different gene expression tests or no testing, in patients with node-negative early-stage breast cancer. Methods: A cost-consequence model was developed to estimate the economic impact of three different scenarios in the Dutch setting: (1) Oncotype DX® test, (2) MammaPrint®, and (3) and no genomic profile testing. The model included chemotherapy costs, administration costs, short- and long-term adverse event costs, productivity loss, genomic profiling testing costs, cost of cancer recurrence, and hospitalization costs. Results: A treatment paradigm with Oncotype DX resulted in average savings per patient of €6,768 vs. a paradigm with MammaPrint and €13,125 vs. a paradigm with no genomic testing. Furthermore, due to less patients receiving adjuvant chemotherapy through better targeting by the Oncotype DX test, fewer adverse events, sick days, practice visits, and hospitalizations were required compared to MammaPrint and no genomic profiling. Conclusions: Testing with Oncotype DX test in Dutch clinical practice in patients with early-stage breast cancer proved to be cost-saving versus MammaPrint and no genomic profiling tests. Introducing the Oncotype DX test to the Dutch setting will likely reduce the economic resources that are required.

2-Year Real-World Outcomes with Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: Literature Review and Meta-analysis of Patient-Relevant Outcomes.

BACKGROUND: The 96 weeks' assessment from the VIEW studies provided insights into the long-term efficacy of intravitreal aflibercept (IVT-AFL) in neovascular age-related macular degeneration (nAMD) and demonstrated that it was possible to maintain long-term outcomes while moving from a fixed bimonthly regimen in Year 1 to a variable dosing regimen in Year 2. The aim of this analysis was to perform a literature review and meta-analysis assessing the use of IVT-AFL and real-world outcomes in treatment-naïve patients with nAMD treated with IVT-AFL for 2 years, as per label. METHODS: A literature review and meta-analysis were performed to provide an overview of the baseline characteristics of the population, the 2-year outcomes, the associated treatment burden, and safety. RESULTS: Eleven publications providing data from patients with nAMD who had treatment initiated with IVT-AFL between 2012 and 2016 were identified. The mean baseline age of patients was 78.62 years, with a baseline best-corrected visual acuity (BCVA) of 57.73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Patients reported a mean BCVA at 2 years of 62.55 ETDRS letters, with 47.39% of patients having a BCVA ≥ 70 ETDRS letters. Mean gain in BCVA versus baseline was + 4.49 ETDRS letters for the combined population (+ 5.91 letters for patients treated with a treat-and-extend regimen). Over the 2 years of the study, patients received an average of 12.34 injections, with a reduction in injections in Year 2 versus Year 1. The qualitative assessment of the safety data suggested that no new safety signals were identified. CONCLUSION: Patients treated with IVT-AFL reported significant gains in visual acuity versus baseline after 2 years. The evidence identified indicates that the visual gains achieved during the first year of treatment are maintained through the second year and that these were achieved with a reduction in the mean number of IVT-AFL injections administered in Year 2 of treatment.

The burden of amputation in patients with peripheral arterial disease in the Netherlands.

INTRODUCTION: Peripheral arterial disease (PAD) can lead to severe cases of critical limb ischemia (CLI), which in turn might lead to amputation. Amputation can have substantial consequences for patients. This publication aims to give a better understanding of the amputation-related burden in patients with PAD in the Netherlands. EVIDENCE ACQUISITION: A systematic review and grey literature searches were conducted followed by qualitative interviews with a multidisciplinary team of clinical experts in amputation. Subsequently, IQVIA's Dutch hospital claims data were analyzed. EVIDENCE SYNTHESIS: Twenty-seven publications were identified. Dutch claims data identified claims for 2328 patients after amputation for PAD. Data for the following topics were found: incidence, mortality, complications, mobility, daily functioning, quality of life, utilities, length of stay (LoS), costs, and resource use. Annually, 90% of the 3300 amputations carried out in the Netherlands were due to vascular disease. One-year mortality in patients with an amputation ranged from 49.6% (above-the-knee amputation) to 9% (specialized care). Patients' quality of life was substantially affected and utility of post-major amputation for PAD was 0.54. LoS after amputation varied from 11.4 (general rehabilitation) to 53.4 days (amputation of the leg). Total budget incurred based on frequently claimed DBC's from Dutch claims data in patients with PAD undergoing an amputation over 2012 to 2016 was € 136,651,374. Mean cost per patient was € 17,821. CONCLUSIONS: Amputation leads to substantial burden in patients with PAD in the Netherlands. Identified results give a better understanding of the specific Dutch burden of amputation.

A novel nonribose agonist, LUF5834, engages residues that are distinct from those of adenosine-like ligands to activate the adenosine A(2a) receptor.

The recent publication of both the antagonist- and agonist-bound structures of the adenosine A(2A) receptor have revealed much about how a ligand may bind to a receptor and cause the conformational changes associated with agonist-mediated activation. In particular, the agonist-bound structure revealed key interactions between the ribose group of adenosine-derived agonists and amino acids in the receptor binding pocket that lead to receptor activation. However, agonists without a ribose group also exist, and we wondered whether such compounds occupy the same agonist binding site. Therefore we used a mutagenesis approach in this study to investigate the mode of binding of 2-amino-4-(4-hydroxyphenyl)- 6-(1H-imidazol-2-ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (LUF5834), a potent partial agonist without a ribose moiety, compared with the adenosine-derived reference agonist 2-[p-(2-carboxyethyl)phenyl-ethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). Mutation of the orthosteric residue Phe168 to alanine abrogated the function of both agonists. However, mutation to alanine of residues Thr88 and Ser277 shown by the crystal structures to interact with the ribose group of adenosine-like ligands had no effect on the potency of LUF5834. Furthermore, alanine mutation of Asn253, which makes a hydrogen-bonding interaction with the exocyclic nitrogen of the adenine ring, had minimal effect on LUF5834 affinity but removed agonist activity of this ligand. Mutation of other residues, such as the highly conserved Trp246 or Glu13, had significant deleterious effects on the function of CGS21680 but little effect on LUF5834. In summary, our findings suggest that this class of agonist interacts with distinct residues to activate the receptor compared with classic adenosine derived agonists.