Background

Claims that genomic and biomarker technologies will transform healthcare have been central to visions of a new era of personalised or precision medicine. However, the advent of prognostic assays in clinical care has coincided with growing regulatory scrutiny of new diagnostic technologies [1]. Thus it is perhaps unsurprising that the scale and pace of the genomic revolution has been less dramatic than promised, and that some of the most hyped applications, such as polygenic risk scores and pharmacogenetic testing, have failed to convince sceptics. Much of the debate about these technologies has centred on issues of what is increasingly referred to as clinical utility, a concept that was introduced two decades ago as part of a broader framework for the evaluation of genetic tests [2]. Clinical utility potentially encompasses clinical, comparative and cost effectiveness and its potential breadth has generated its own controversy, with continued debate about the scope of the term [3,4]. Thus debates about the value of genomic and biomarker technologies are often also debates about how to evaluate prognostic assays, and efforts to demonstrate the clinical utility of specific tests are often simultaneously attempts to define clinical utility. Our paper addresses this intersection of ideas and interests in one of the most widely adopted of these technologies: breast cancer prognostics.

Prognostic assays are being positioned as increasingly important tools for physicians to use in the cancer treatment decision-making process [5,6]. These assays are algorithm-based tools that examine a tumor’s gene expression or biomarkers to assess prognosis and, in some cases, predict patients likely response to a specific therapy (for example, adjuvant chemotherapy) [5,7,8]. Currently, these assays are most commonly used in breast cancer prognostics [9,10] with the majority being proprietary products (Oncotype Dx (Exact Sciences), Mammaprint (Agendia), Prosigna (Nanostring), Breast Cancer Index (Biothernostics) and Endopredict (Myriad).

Chemotherapy is a common, yet complex treatment option for breast cancer. This treatment provides effective results for many cancers, but includes significant toxicity and side effects. Due to the myriad factors that influence cancer’s progression, physicians often prescribe chemotherapy to treat breast cancer without definitive knowledge that the chemotherapy will be effective to treat the type of cancer the patient has and therefore may provide no benefit to patients. Research has begun to investigate these issues and has attributed a decrease in the use of unwarranted chemotherapy to the use of “precision medicine” algorithms and assays [11–14]. Prognostic assays purport to reduce overtreatment as they aim to assess the risk of recurrence and response to treatment. For example, research on OncotypeDX – the most commonly used prognostic assay – has reported that the test results altered chemotherapy treatment recommendations in 30–60% of patients [15,16]. As these assays receive reimbursement from public and private payers and are integrated into healthcare services, it has been observed that patients and providers have begun to rely heavily on these results to make decisions about whether or not to undergo chemotherapy [17]. This technology has created a profound shift in cancer care treatment decision-making and processes.

These new tools offer a new conceptualization of value and utility in the cancer care space [18–22]. Recent research has demonstrated that clinical utility of these assays increasingly includes non-traditional factors such as physician confidence, patient anxieties and ‘decision impact’ [23]. Adding the outcome of ‘reducing overtreatment’ as an element of clinical utility for a health technology is a novel idea. When exploring the utility of prognostic assays, attention must be given to the influence of industry on the promotion and positioning of diagnostic and prognostic technologies [1,20,23]. Previous research has highlighted the extensive involvement of industry in producing studies that aim to establish value and demonstrate the clinical utility of these assays and has questioned efforts to generate evidence that might justify the typically high cost of these tools [20,21,23,24]. The clinical utility of a health technology is a key factor for reimbursement decision-making [8,18,20–22,24–28]. For these, often expensive prognostic assays, obtaining reimbursement is critical to integrating them into standard cancer care practices.

Explicating these complex factors of reducing overtreatment, redefining clinical utility and reimbursement are all critical to understanding the value and use of prognostic assays in breast cancer care. Building on a critical body of research that has examined the definition of clinical utility for diagnostic and prognostic tool reimbursement [20,24,25] and evidentiary standards [20,29,30], we further investigate the perceived value and utility of these assays. We also leverage critical scholarship that has investigated the role of industry in defining benefit and promoting their use [20,23,25]. Finally, our study builds on the important work done by diverse scholars [31–34] by extending qualitative inquiry into reducing chemotherapy overtreatment and redefining the clinical utility of diagnostics in breast cancer care.

Study objective

The objective of this study was to explore key opinion leader’s perspectives on the value, clinical utility, and integration of breast cancer prognostic assays in clinical care.

Methods

This paper presents data collected during the execution of a larger study on diagnostic innovation. The results presented here build on findings from a scoping review [10] and bibliometric analysis [23].

Results

Fifteen participants from nine different countries were included in this study. Participants were researchers and physicians/scientists (oncologists (n = 6), surgeons (n = 5), other (e.g., pathologists, cell biologists) (n = 4)) and had used 4 different breast cancer prognostic assays in their practice and/or research (see participant characteristics in Tables 1 and 2). Participants from this study were drawn from our larger study on diagnostic innovation. Recruitment for the larger study included 90 email invitations of which: 55 did not respond, 12 declined and 23 participated. Of those 23 participants, the 15 breast cancer prognostic assay participants were included in this study.

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Table 1. Participant nationality.

https://doi.org/10.1371/journal.pone.0322509.t001

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Table 2. Prognostic assay discussed.

https://doi.org/10.1371/journal.pone.0322509.t002

The analysis resulted in three themes: 1. role of prognostic assays in identifying overtreatment; 2. integration of assays into clinical use; and 3. jurisdictional variation in use and value. The results are presented according to these themes.

Discussion

In this study we aimed to explore key opinion leader’s perspectives on the integration of and use of prognostic assays in breast cancer care. Our results illuminate the impact of the positioning of this technology on identifying overtreatment, standard care processes, and the jurisdictional variation in perceived value and use of these assays.

Research has identified that breast cancer is currently often overtreated [14,34,41]. Providers have begun to address this issue and prognostic assays have become prevalent tools in efforts to identify inappropriate chemotherapy use. The integration of these assays into standard practice presents clinical and ethical shifts for providers as these assays redefine cornerstone cancer treatments and treatment decision-making. This shift contravenes the “imperative to treat” [34] often felt by patients and providers [9,34]. Our participants identified reducing overtreatment as the primary purpose of these assays. They described the impact of believing chemotherapy was not the best treatment option, but, without more information, and being influenced by their training, they overtreated patients as standard practice. Our findings align with Ross and colleagues who observed that prognostic assays “appeared to make a rejection of the treatment imperative an acceptable choice, due to its positioning as a ‘scientific’, ‘advanced’ and ‘state of the art’ technique which reduced uncertainty” [34]. While some studies have reported that oncologist have felt uneasy about recommending against chemotherapy, because they practice in the “context of a ‘dose culture’” and are “trained to believe in chemotherapy” [9]; our participants reported that the assays provided definitive results which provided confidence – for both patients and providers – in deciding whether to undergo chemotherapy treatment.

Our participants provided rich data on the emerging challenge created by a tool that reduces downstream overtreatment, while potentially creating a new issue of over testing. Integrating these assays into standard care therefore reducing overtreatment with toxic drugs, but increasing laboratory testing creates a unique situation for providers and patients to navigate. Bombard and colleagues (2015) raise this issue in their study of the use of gene expression profiling and note that indiscriminate use of these assays is not only costly, but contributes to the significant health system issue of overuse of laboratory testing [32]. This issue necessitates a weighing of benefits, harms and patient outcomes. The authors call for clinical practice guidelines to standardize genomic test ordering – to mitigate potential laboratory overuse while realizing the benefits of reducing unnecessary chemotherapy [32]. While participants in our study did not raise the issue of over testing – emphasis was placed on the negatives of side effects and the significant benefits of not inappropriately treating with chemotherapy – this emerging issue necessitates further investigation.

Our findings further illustrate the complexity of determining clinical utility for novel diagnostics [20–22,24,26]. The participant’s perspectives on chemotherapy overuse, and the role of assays to address this, highlights that the assays have been framed as an integral tool to address the problem of overtreatment. In doing so, these assays add a novel patient-focused outcome that exists outside the traditional scope of clinical utility outcomes. The participants conveyed this extended definition of clinical utility – identifying overtreatment – as the key purpose of the tests. Our recent research has demonstrated that the integration of these new ideas has been significantly supported by evidence creation and marketing done by the producers of the assays [23]. All of our participants had conducted research on the ‘decision impact’ of these assays and expressed this extended definition of clinical utility. These perspectives reinforce that these assays are advancing the novel role of prognostic assays to identify overtreatment, thereby extending boundaries of clinical utility in this space. Our earlier scholarship has critiqued this elaboration of clinical utility [1,20,23], the uncertainty around the evidentiary standards [1,20,21,24] and industry’s role in these activities [20,23]. Industry developing and promoting new technologies (and required testing processes) to address overtreatment adds financial and commercial factors into the treatment decision-making process.

The cost of the assays and varied reimbursement schemes were a significant area of discussion. A number of participants who thought the high cost was justified and had conducted a cost analysis, reported that while the assay is expensive, the downstream savings, with patient outcomes and healthcare savings, justified the cost. On the contrary, other participants describe the cost as prohibitive and argued that currently chemotherapy drugs are generic and these costs are low relative to the cost of the assay. These disparate perspectives reflect the vastly different health systems within which providers practice. If the assays were fully or partially reimbursed had significant impact on the costs of the assays and subsequently their perceived value in their local context. This disparity sometimes lead to a ‘physician’s paradox’, continuing to overtreat patients because the assay was not available or too expensive. The gravity of the issue – severity of overtreatment – also varied depending on the system within which care is provided. Within these contexts the issue of price can become an epilogue to broader systemic issues that create scenarios where overtreating a patient is the cheaper option because the high cost of a prognostic assay.

The impact of the health system on costs and subsequent use leads to a novel and unexpected theme in our findings. The participants discussed jurisdictional variation in perceived value and use for cancer treatment and how this adds to the complexity of these new conceptualizations of overtreatment, clinical utility, and standard care. The perspectives described illuminate the subjectivity of cancer treatment and the contested nature of the space within which these assays attempt to add value. While overtreatment in breast cancer is occurring all over the world, our international participants shed light on the geographic variability of overtreatment and the important implications this variability has for the value add of these assays. Participants describe a “US/UK school of thought” dichotomy where US training is described as using chemotherapy more liberally, and UK training using endocrine therapy more frequently. While our participants were from nine different countries, this dichotomy in training was referenced frequently and participants spoke of how Latin and South American countries followed the US paradigm; while Australia and most European countries aligned with the UK school of thought. These varied approaches to cancer treatment, and varied use of chemotherapy as the dominant cancer treatment created disparate perceptions of value for the assays. In countries where chemotherapy was used more judiciously, therefore overtreatment with chemotherapy was less, the perceived value of the assay was not high. In some countries, such as Brazil, where overuse of chemotherapy has been reported to be as high as 60% [42]; the potential to reduce overtreatment with chemotherapy was significant. While research has begun to explore jurisdictional variation in cancer diagnosis, treatment and specifically chemotherapy use [43–46], much work needs to be done in this area. Our study extends this analysis to highlight the role of entrenched jurisdictional perspectives on cancer and treatment on the value of the assay.

Conclusion

The results of this study provide insights into the integration of prognostic assays into clinical decision-making processes. These assays are extending the boundaries of their clinical utility through identifying overtreatment and unnecessary care. Efforts to integrate these assays and justify their high prices are explored. Finally, these results illuminate the subjectivity of cancer treatment and the contested space within which these tools attempt to add value.

Supporting information

Acknowledgments

The authors would like to thank Lena Saleh for her valuable assistance.