EUnetHTA Joint-Action 1. HTA Core Model Application for Diagnostic Technologies (1.1). Prognostic tests for breast cancer recurrence (uPA/PAI-1 [FEMTELLE], MammaPrint, Oncotype DX). Ethical analysis

From the ethical point of view, the foundation of any medical act – including the utilisation of prognostic tests for breast cancer recurrence (PTBCRs) – is the evaluation of (and respect for) the clinical (diagnostic/therapeutic) benefit for patients. At the moment, the available literature shows the following. In this context, clinical utility is the likelihood that using a PTBCR to guide management in patients with diagnosed early-stage breast cancer will significantly improve health-related outcomes. Clinical utility is assessed by investigating the balance of benefits (reduced adverse events due to low-risk women avoiding chemotherapy) and harms (cancer recurrence that might have been prevented) associated with the use of the test compared with the use of alternative management strategies. Direct evidence was not found linking any of the three tests to improved outcomes, but there are studies about the components of clinical utility that might provide indirect evidence for clinical utility. There is encouraging indirect evidence for Oncotype DX®, and plausibility for potential use of MammaPrint® and, possibly, the uPA/PAI-1 test. It seems plausible that more women will benefit (i.e., to avoid unnecessary chemotherapy), but there is the potential for significant harms among a small number of low or intermediate risk women (who might have benefited from chemotherapy) who are moved to a lower level of risk as a result of using these tests, possibly resulting in breast cancer recurrence or death. There are currently insufficient data to confidently estimate these risks and benefits. In addition, it is difficult to determine the proportion of women with moderate to high risk, based on conventional risk assessments, that will have a “low enough” score to affect their decision about chemotherapy. These new tests raise the question of the extent to which patients are prepared to participate in informed decision making about their care. Information from these tests about the risk of breast cancer recurrence should play a significant role in women’s breast cancer treatment decisions. But few studies indicate whether patients understand genomic and similar tests and their results adequately to be informed decision makers when using them. The results of the studies underscore the comparative weight that participants placed on their physicians’ recommendations and the importance of patient education regarding how clinicians incorporate genomic risk of recurrence information into treatment decision-making. Indeed, the value placed on testing by the physician and how this is conveyed will likely be critical to patients’ decision-making processes. Some studies show that health literacy is fundamental to understanding women’s capacity to learn about the new PTBCRs as well as their desire for active participation in medical care: women with lower health literacy recalled less of the information provided about the recurrence risk test than women with higher health literacy. Studies show that most patients prefer to be involved in medical decisions that affect their care and that patients who are active participants in their medical decisions are better adjusted psychologically, report being more satisfied with their decisions, and are more likely to adhere to their treatment regimens. These new tests raise important new issues for the clinicians about how to communicate with patients about their recurrence risks. Acknowledgement by clinicians of the potential problems and subsequent clarification of any misconceptions should prevent or relieve patients’ anxiety and help them to cope with the situation. Physicians should explain the difference between genomic signatures and genetic testing, the clinical meaning of the result of the test with the standard clinicopathological criteria and the expressions that relate to technical problems of these tests. Improving the quality of the information with which patients are provided about these new methods – by taking more time to explain what they involve, favouring discussions and eliciting feedback from the patients – will enable them to play an active role in the decision-making process about their treatment. In general, the physician should be a skilful guide for the patient, on the grounds of scientific knowledge and personal experience. Choosing a prognostic test for breast cancer recurrence balancing between risks and benefits pertains to the physician, followed by the patient’s free consent based on adequate information. Particularly, the use of uPA/PAI-1, Oncotype or MammaPrint affect the patient’s autonomy and play an important role in the decision-making process about their treatment. Finally, distributive justice needs to be faced by health policy makers. In general, the main question for our project is the evaluation of the cost-effectiveness of the tests while assuring that economic and organisational feasibility is maintained. From the point of view of distributive justice, following the specific available literature shows that: - Up to now, through the studies available, it is not possible to evaluate the consequences of using these tests on a large scale within a healthcare system because the clinical efficacy data are still insufficient and heterogeneous for these three tests. In addition, the three tests so far have had different frequencies of use in the USA and Europe; - The few studies available suggest that, although both Oncotype DX and MammaPrint are costly and have high incremental cost-effectiveness ratios (ICERs), it is reasonable to presume a willingness to pay for testing strategies that are likely to yield reduced expenditures for payers, health systems, patients, and society in the long term. Unfortunately, however, these studies are at an early stage, and are, so far, inconclusive.