The presence of high expressing epithelial cell adhesion molecule (EpCAMhigh) circulating tumor cells (CTC) enumerated by CellSearch® in blood of cancer patients is strongly associated with poor prognosis. This raises the question about the presence and relation with clinical outcome of low EpCAM expressing CTC (EpCAMlow CTC). In the EU-FP7 CTC-Trap program, we investigated the presence of EpCAMhigh and EpCAMlow CTC using CellSearch, followed by microfiltration of the EpCAMhigh CTC depleted blood. Blood samples of 108 castration-resistant prostate cancer patients and 22 metastatic breast cancer patients were processed at six participating sites, using protocols and tools developed in the CTC-Trap program. Of the prostate cancer patients, 53% had ≥5 EpCAMhigh CTC and 28% had ≥5 EpCAMlow CTC. For breast cancer patients, 32% had ≥5 EpCAMhigh CTC and 36% had ≥5 EpCAMlow CTC. 70% of prostate cancer patients and 64% of breast cancer patients had in total ≥5 EpCAMhigh and/or EpCAMlow CTC, increasing the number of patients in whom CTC are detected. Castration-resistant prostate cancer patients with ≥5 EpCAMhigh CTC had shorter overall survival versus those with <5 EpCAMhigh CTC (p = 0.000). However, presence of EpCAMlow CTC had no relation with overall survival. This emphasizes the importance to demonstrate the relation with clinical outcome when presence of CTC identified with different technologies are reported, as different CTC subpopulations can have different relations with clinical outcome.

BackgroundFor rational decision making, assessing the cost-effectiveness and budget impact of new drugs and comparing the costs of drugs already on the market is required. In addition to value frameworks, such as the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology–Magnitude of Clinical benefit Scale, this also requires a transparent overview of actual drug prices. While list prices are available, evidence on treatment cost is not. This paper aims to synthesise evidence on the reimbursement and costs of high-cost breast cancer drugs in The Netherlands (NL).MethodsA literature review was performed to identify currently reimbursed breast cancer drugs in the NL. Treatment costs were determined by multiplying list prices with the average length of treatment and dosing schedule.ResultsComparing list prices to the estimated treatment cost resulted in substantial differences in the ranking of costliness of the drugs. The average mean treatment length was unknown for 11/31 breast cancer drugs (26.2%). The differences in the 15 highest-cost drugs were largest for Bevacizumab, Lapatinib and everolimus, with list prices of €541, €158, €1,168 and estimated treatment cost of €174,400, €18,682 and €31,207, respectively. The lowest-cost (patented) targeted drug is €1,818 more expensive than the highest-cost (off-patent) generic drug according to the estimated drug treatment cost.ConclusionsA lack of evidence on the reimbursement and cost of high-cost breast cancer drugs complicates rapid and transparent evidence synthesis, necessary to focus strategies aiming to limit the increasing healthcare costs. Interestingly, the findings show that off-patent generics (such as paclitaxel or doxorubicin), although substantially cheaper than patented drugs, are still relatively costly. Extending standardisation and increasing European and national regulations on presenting information on costs per cancer drug is highly recommended.

Objectives: As survival outcomes improve for patients with diffuse large B-cell lymphoma (DLBCL), it is increasingly important to understand costs and humanistic burden to evaluate the need for new treatments. We conducted systematic reviews to understand the health-related quality of life (HRQoL) of patients with DLBCL and costs associated with treatment. MethOds: MEDLINE, EMBASE, EconLit,

Objectives: Bootstrapping is often used to assess uncertainty in outcomes of randomized controlled trials (RCTs) due to sampling variation and limited sample sizes. Although guidance is available on two-stage bootstrapping for cluster-RCTs, specific guidance is lacking on sampling clusters within bootstrap samples to address the uncertainty in variation across clusters. This study assesses the impact of using different selection approaches to sample clusters in two-stage bootstrapping in a case study on procalcitonin-based antibiotic treatment in IC patients with sepsis. MethOds: The case study was a cluster-RCT including 16 hospitals (4 academic, 12 non-academic) with on average 48 patients per hospital (range n: 1-185). Five cluster sampling approaches were investigated, based on random sampling of: 1) the intended number of patients, 2) 16 hospitals, 3) 16 hospitals maintaining the original ratio academic/non-academic hospitals, 4) as method 2 while maintaining the total number of patients, 5) as method 3 while maintaining the total number of patients. Additionally, a scenario analysis using half of the data was performed. Incremental cost differences and corresponding 95%CIs were determined based on 10,000 bootstrap samples. Results: Different approaches of bootstrapping resulted in variation in the incremental costs per patient (data mean: € 16, bootstrap range: € -24 -€ 183), with approach 5 deviating most from the observed mean incremental cost. 95%CIs also varied in size (smallest 95%CI: € -5,123 -€ 5,986 [method 5], largest 95%CI: € -5,699 -€ 6,566 [method 2]). Differences in outcomes were more pronounced when using half of the data. cOnclusiOns: Using different approaches for sampling clusters in two-stage bootstrapping may influence the mean outcomes and 95%CIs. Determining the most appropriate sampling method based on outcomes and 95%CIs is dependent on the approach for selection used in the real-world trial. When the inclusion strategy is unknown, sensitivity analysis is recommended to assess uncertainty arising from this unknown cluster inclusion process.

Chapter 1-General Introduction Chapter 2-Evidence on the cost of breast cancer drugs is required for rational decision making Chapter 3-Real world data on discordance between estrogen, progesterone and HER2 receptor expression on diagnostic tumor biopsy versus tumor resection material Chapter 4-Treatment choices for neo-and adjuvant systemic therapy following repeated assessment of estrogen, progesterone and HER2 in tumor biopsy and resection in invasive breast cancer patients Chapter 5-Detecting blood based biomarkers in metastatic breast cancer: A systematic review of their current status and clinical utility Chapter 6-Health Economic Impact of Liquid Biopsies in Cancer Management Chapter 7-Rapid assessment of the health economic impact of using CTCs to guide systemic therapy in metastatic breast cancer-an online tool to inform the design of prospective biomarker studies Chapter 8-Health economic impact of using CTCs to guide systemic therapy in metastatic ER+ HER2-breast cancer patients-Results from a randomized controlled multicenter trial