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Mafalda Ramos,1 Mark Lamotte,1 Laetitia Gerlier,1 Per Svangren,2 Anna Miquel-Cases,3 John Haughney4 1Real World Evidence Solutions, IQVIA, 1930 Zaventem, Belgium; 2Core Respiratory, Global Product and Portfolio Strategy – Global Payer Evidence and Pricing, AstraZeneca Gothenburg R&D, SE-431 83 Mölndal, Sweden; 3Global Price and Reimbursement, Global Payer Evidence and Pricing, AstraZeneca Gothenburg R&D, Cambridge CB2 8PA, UK; 4Academic Primary Care Division of Applied Health Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK Background: While the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines advise exercise to reduce disease progression, little investment in promoting physical activity (PA) is made by health care authorities. The purpose of this study was to estimate the cost-effectiveness of regular PA vs sedentary lifestyle in people with COPD in the UK.Methods: Efficacy, quality of life, and economic evidence on the PA effects in COPD patients were retrieved from literature to serve as input for a Markov microsimulation model comparing a COPD population performing PA vs a COPD population with sedentary lifestyle. The GOLD classification defined the model health states. For the base case, the cost of PA was estimated at zero, a lifetime horizon was used, and costs and effects were discounted at 3.5%. Analyses were performed from the UK National Health Service (NHS) perspective. Uncertainty around inputs and assumptions were explored via scenario and sensitivity analyses, including a cost threshold analysis. Outcomes were cost/quality-adjusted life year (QALY) gained and cost/year gained.Results: Based on our model, the effects of PA in the UK COPD population would be lower mortality (-6%), fewer hospitalizations (-2%), gains in years (+0.82) and QALYs (+0.66), and total cost savings of £2,568. The cost/QALY and cost/year gained were dominant. PA was cost-saving at costs

Predictive biomarkers can guide treatment decisions in breast cancer. Many studies are undertaken to discover and translate these biomarkers, yet few biomarkers make it to practice. Before use in clinical decision making, predictive biomarkers need to demonstrate analytical validity, clinical validity and clinical utility. While attaining analytical and clinical validity is relatively straightforward, by following methodological recommendations, the achievement of clinical utility is extremely challenging. It requires demonstrating three associations: the biomarker with the outcome (prognostic association), the effect of treatment independent of the biomarker, and the differential treatment effect between the prognostic and the predictive biomarker (predictive association). In addition, economical, ethical, regulatory, organizational and patient/doctor-related aspects are hampering the translational process. Traditionally, these aspects do not receive much attention until formal approval or reimbursement of a biomarker test (informed by Health Technology Assessment (HTA)) is at stake, at which point the clinical utility and sometimes price of the test can hardly be influenced anymore. When HTA analyses are performed earlier, during biomarker research and development, they may prevent further development of those biomarkers unlikely to ever provide sufficient added value to society, and rather facilitate translation of the promising ones. Early HTA is particularly relevant for the predictive biomarker field, as expensive medicines are under pressure and the need for biomarkers to guide their appropriate use is huge. Closer interaction between clinical researchers and HTA experts throughout the translational research process will ensure that available data and methodologies will be used most efficiently to facilitate biomarker translation.

Objectives: To inform decisions about the design and priority of further studies of emerging predictive biomarkers of high-dose alkylating chemotherapy (HDAC) in triple-negative breast cancer (TNBC) using value-of-information analysis. Methods: A state transition model compared treating women with TNBC with current clinical practice and four biomarker strategies to personalize HDAC: 1) BRCA1-like profile by array comparative genomic hybridization (aCGH) testing; 2) BRCA1-like profile by multiplex ligation-dependent probe amplification (MLPA) testing; 3) strategy 1 followed by X-inactive specific transcript gene (XIST) and tumor suppressor p53 binding protein (53BP1) testing; and 4) strategy 2 followed by XIST and 53BP1 testing, from a Dutch societal perspective and a 20-year time horizon. Input data came from literature and expert opinions. We assessed the expected value of partial perfect information, the expected value of sample information, and the expected net benefit of sampling for potential ancillary studies of an ongoing randomized controlled trial (RCT; NCT01057069). Results: The expected value of partial perfect information indicated that further research should be prioritized to the parameter group including “biomarkers’ prevalence, positive predictive value (PPV), and treatment response rates (TRRs) in biomarker-negative patients and patients with TNBC” (€639 million), followed by utilities (€48 million), costs (€40 million), and transition probabilities (TPs) (€30 million). By setting up four ancillary studies to the ongoing RCT, data on 1) TP and MLPA prevalence, PPV, and TRR; 2) aCGH and aCGH/MLPA plus XIST and 53BP1 prevalence, PPV, and TRR; 3) utilities; and 4) costs could be simultaneously collected (optimal size = 3000). Conclusions: Further research on predictive biomarkers for HDAC should focus on gathering data on TPs, prevalence, PPV, TRRs, utilities, and costs from the four ancillary studies to the ongoing RCT.

Background: While the GOLD guidelines advise exercise to reduce disease progression, little investment in promoting physical activity (PA) is made by healthcare authorities. Objective: To estimate the cost-effectiveness of regular PA vs sedentary lifestyle in COPD patients of the UK. Methods: Efficacy, quality of life, and economic evidence on the PA effects in COPD patients was retrieved from literature. These data served as input for a Markov microsimulation model comparing a COPD population performing PA vs a COPD population with a sedentary lifestyle. The GOLD classification defined the model health states. For the base case, the cost of PA was estimated at zero, a lifetime horizon was used and costs and effects were discounted at 3.5%. Analyses were performed from the UK NHS perspective. Uncertainty around inputs and assumptions was explored via scenario and sensitivity analyses, including a cost threshold analysis. Outcomes were cost/quality-adjusted-life-year (QALY) gained and cost/year gained. Results: In the base case, PA resulted in lower mortality (-6%) and number of hospitalisations (-2%), gains in years (+0.82) and QALYs (+0.66), and savings in total costs (-£2,568). The cost/QALY and cost/year gained were dominant. PA was cost-saving at costs Conclusions: Including PA in the management of COPD patients of the UK leads to long-term clinical benefits. If the NHS only promotes exercise via medical advice, this would lead to healthcare costs savings. If the NHS chose to fund PA, it would still likely lead to a cost-effective intervention.

Purpose: Triple negative breast cancers (TNBC) with a BRCA1-like profile may benefit from high dose alkylating chemotherapy (HDAC). This study examines whether BRCA1-like testing to target effective HDAC in TNBC patients can be more cost-effective than treating all patients with standard chemotherapy. Additionally, we estimated the minimum required prevalence of BRCA1-like and the required positive predictive value (PPV) for a BRCA1-like test to become cost-effective. Methods: Our Markov model compared 1) the incremental costs; 2) the incremental number of respondents; 3) the incremental number of Quality Adjusted Life Years (QALYs); and 4) the incremental cost-effectiveness ratio (ICER) of treating TNBC women with personalized HDAC based on BRCA1-like testing vs. standard chemotherapy, from a Dutch societal perspective and a 20-year time horizon, using probabilistic sensitivity analysis. Furthermore, we performed one-way sensitivity analysis (SA) to all model parameters, and two-way SA to prevalence and PPV. Data were obtained from a current trial (NCT01057069), published literature and expert opinions. Results: BRCA1-like testing to target effective HDAC would presently not be cost-effective at a willingness-to-pay threshold of €80.000/QALY (€81.981/QALY). SAs show that PPV drives the ICER changes. Lower bounds for the prevalence and the PPV were found to be 58.5% and 73.0% respectively. Conclusion: BRCA1-like testing to target effective HDAC treatment in TNBC patients is currently not cost-effective at a willingness-to-pay of €80.000/QALY, but it can be when a minimum PPV of 73% is obtained in clinical practice. This information can help test developers and clinicians in decisions on further research and development of BRCA1-like tests.

Monitoring therapeutic response to neoadjuvant chemotherapy(NAC) is likely to improve NAC effectiveness in breast cancer(BC). Imaging performance seems to vary per tumour subtype(by ER and HER2 status), therefore we performed a systematic review on subtype specific imaging performance in monitoring NAC in BC. Studies examining imaging performance in predicting pathologic complete response(pCR) during NAC in BC subtypes were selected. Per study, negative- and positive predictive value, sensitivity(se) and specificity(sp), AUC and accuracy were derived. Fifteen/106 articles were included. Inter-study variability was revealed in: monitoring interval, response and pCR definitions. In ER-positive/HER2-negative BC, 181F FDG-PET/CT showed se/sp of 38%–89%/74%–100%, MRI showed se/sp of 35%–37%/87%–89%. In triple negative BC, 181F FDG-PET/CT showed se/sp of 0%–79%/95%–100%. 181F FDG-PET/CT showed in ER-positive/HER2-positive BC se/sp of 59%/80% and in ER-negative/HER2-positive 27%/88%. Evidence on imaging performance in monitoring NAC according BC subtypes is lacking. Consensus should be reached in: definitions of pCR, response and monitoring interval before starting well-designed studies.

Even though the idea of starting economic evaluations early in the product life cycle of medical technologies has gained popularity in the past few years, its use has not been fully exploited yet. In this thesis, we aimed to contribute to the literature on early cost-effectiveness analysis (CEA), value of information analysis and resource modeling analysis, particularly applied to medical technologies for emerging breast cancer interventions. After a short introduction (chapter 1), this thesis is divided in three parts, distinguished by the type of technologies assessed: The first part focuses on predictive biomarkers to personalize systemic treatment (chapters 2, 3, 4), the second part focuses on imaging techniques to guide the personalization of neoadjuvant chemotherapy (NACT) (chapters 5, 6, 7), and the third part focuses on imaging as a tool to detect distant metastases (chapter 8).

Objectives: 18F-FDG-PET/CT is accurate in detecting distant metastases (DM) in breast cancer patients scheduled for neoadjuvant chemotherapy. If DMs are screen-detected in an early phase, morbidity and mortality may be reduced. Because 18F-FDG-PET/CT comes at a significant cost, we compared its expected cost-effectiveness in stage II/III breast cancer patients of the UK, the US and the Netherlands (NL) vs. the gold-standard (X-thorax/liver sonography/bone scan (UK/NL) and CT-thorax-abdomen/bone scan (US)). Methods: A time-dependent Markov model compared expected Life Year (LY) and cost/Quality-adjusted Life Year (QALY) gained in four breast cancer subtypes (ER-/HER2+;ER+/HER2+;ER-/HER2-;ER+/HER2-) over a 5-year time horizon from a hospital perspective. Sensitivity and specificity of imaging and type of systemic and local treatments were derived from the Netherlands Cancer Institute. Epidemiological, survival and utility data were estimated from literature or informed by expert assumptions. Costs (2013) were derived from national tariffs (UK and NL), and from the Centres for Medicaid and Medicare Services (US). Results: 18F-FDG-PET/CT is more sensitive (53% vs. 15%) and specific (97% vs. 94%) than the gold-standard. LYs and QALYs gained were similar across subtypes, ranging from 0.025 to 0.027 and 0.0037 to 0.0044 respectively. In all countries, ER+HER2+ was the least and ER+HER2- the most costly group. 18F-FDG-PET/CT is expected to be cost-effective in the NL and the US (with highest ICERs of €165/QALY in ER+/HER2+ and $750 in ER-HER2+), with probabilities of cost-effectiveness ranging from 46-52% and 62-72% respectively, but not in the UK, with a 66-75% probability, depending on tumor subtype. Conclusions: Using 18F-FDG-PET/CT for DM screening in stage II/III breast cancer is expected to result in incremental QALY gains in all subtypes and countries. Due to costs differences between countries, 18F-FDG-PET/CT is expected to be cost-effective in the US and the NL, but not in the UK.

Background: Response-guided neoadjuvant chemotherapy (RG-NACT) with magnetic resonance imaging (MRI) is effective in treating oestrogen receptor positive/human epidermal growth factor receptor-2 negative (ER-positive/HER2-negative) breast cancer. We estimated the expected cost-effectiveness and resources required for its implementation compared to conventional-NACT. Methods: A Markov model compared costs, quality-adjusted-life-years (QALYs) and costs/QALY of RG-NACT vs. conventional-NACT, from a hospital perspective over a 5-year time horizon. Health services required for and health outcomes of implementation were estimated via resource modelling analysis, considering a current (4 %) and a full (100 %) implementation scenario. Results: RG-NACT was expected to be more effective and less costly than conventional NACT in both implementation scenarios, with 94 % (current) and 95 % (full) certainty, at a willingness to pay threshold of €20.000/QALY. Fully implementing RG-NACT in the Dutch target population of 6306 patients requires additional 5335 MRI examinations and an (absolute) increase in the number of MRI technologists, by 3.6 fte (full-time equivalent), and of breast radiologists, by 0.4 fte. On the other hand, it prevents 9 additional relapses, 143 cancer deaths, 23 congestive heart failure events and 2 myelodysplastic syndrome/acute myeloid leukaemia events. Conclusion: Considering cost-effectiveness, RG-NACT is expected to dominate conventional-NACT. While personnel capacity is likely to be sufficient for a full implementation scenario, MRI utilization needs to be intensified.