DeciBio Insights

Update on the Adoption And Utilization of Emerging Precision Medicine Biomarkers and Technologies in Routine Clinical Care

At DeciBio Consulting, our mission is to provide market intelligence and insights to advance precision medicine.  To this end, we track this space closely, especially the field of precision oncology, which represents the most clinically and commercially advanced segment of the precision medicine landscape.  While there is extensive and exciting exploration of emerging precision oncology tools, technologies, and biomarkers in translational and clinical research, ultimately, the true impact occurs when these tools, technologies, and biomarkers enter the clinic and begin influencing patient care on a daily basis.  To better understand this real-world impact, in 2018, we conducted a pulse survey of 147 oncologists, pathologists, and lab directors  to assess the adoption and utilization of emerging biomarkers and technologies in routine cancer care (i.e., regular, daily care, not clinical trials).  Since then, there have been numerous clinical, regulatory, technological, and commercial developments that have changed the face of the precision oncology landscape (see Figure 1).

Figure 1. Select Key Precision Medicine Developments; 2018 – 2020 YTD

To evaluate how these events and others have impacted the adoption of precision oncology in routine clinical care, we conducted a second wave of the pulse survey that we ran in 2018 (modified to reflect some new biomarkers and technologies).  This wave of the survey included responses from 142 oncologists, pathologists, and laboratory personnel and, similar to the first wave, focused on the extent to which emerging tools and diagnostics are being implemented into routine clinical care, how the adoption / utilization of technologies is changing over time, and which precision oncology trends stakeholders expect to be most impactful.  The distribution of survey respondents can be seen in Figure 2 below.  The results from this analysis were presented at the 2020 Companion Diagnostics Forum; the presentation video can be found here and the slide deck can be found here.

Figure 2. Breakdown of Pulse Survey Respondents by Type

Caveats: Both the 2018 and 2020 surveys were U.S.-only, so the takeaways shared here only represent a U.S. perspective.  Additionally, the survey focused on advanced-stage cancers only and does not reflect the adoption / utilization of emerging biomarkers or diagnostic modalities in earlier-stages of cancer care, which we know is an emerging area of interest.  We also acknowledge that pulse surveys like this one, in general, likely reflect selection bias due to the greater willingness of people interested in any particular subject to take a survey on that topic.  Lastly, it is important to not that these pulse surveys are not intended to be quantitatively robust research efforts; any quantitative references here are meant to highlight directional findings. 

Our analyses of the survey data, as well as comparisons to the 2018 data, reveal five key takeaways / themes:

    1. Adoption of biomarker testing has increased significantly, though stakeholders largely feel comfortable with the surge
    2. NGS is becoming the standard method for molecular testing across cancer types; though broad decentralization of NGS (and especially other emerging biomarkers and modalities) is not expected in the foreseeable future
    3. Confidence and adoption in liquid biopsies (LBx) is increasing; LBx is expected to be the most significant driving force of change in pathology / biomarker testing
    4. Digital pathology use is growing, but the full clinical and workflow value propositions are yet to be realized; expectations for the impact of digital pathology remain high with increasing development and use of artificial intelligence
    5. The role of the pathologist is changing, and pathologists of the future will need a new skillset than today’s pathologists

Here we summarize our synthesis for each of these top takeaways.

Takeaway 1: Adoption of biomarker testing has increased significantly, though stakeholders largely feel comfortable with the surge

While it is a surprise to no one that the adoption of precision medicine is increasing, the survey data show how significant the increase has been in a relatively short amount of time.  Since 2018, the precision medicine load on oncologists and pathologists / lab directors has approximately doubled, with oncologists treating 40% more advanced cancer patients annually, ordering ~25% more different biomarkers, and testing ~7% more patients (across all biomarkers) than they did in 2018.  Similarly, pathologists and lab directors exhibited a >110% increase in biomarker testing volumes and 15% increase in the size of their oncology biomarker menu offerings (see Figure 3 below).

Figure 3. Change in Biomarker Testing and Stakeholder Sentiments

As shown in Figure 3 above, most clinicians feel relatively comfortable handling the increased biomarker testing load.  When prompted about the extent to which they agree / disagree with various statements, respondents generally agreed that they feel adequately informed about current companion diagnostics (CDx) guidelines, that they feel familiar with all of the CDx options available to them, and that it is easy for them to implement new biomarkers into their care protocol or labs (with average agreement scores of 5.2 – 5.6 out of a 1.0 – 7.0 scale, where 1.0 = strongly disagree, 4.0 = neither agree nor disagree, and 7.0 = strongly agree).  Oncologists exhibited slightly higher agreement overall and showed consistent increases in average agreement scores compared to 2018 (Δ = +0.4 – 0.5; 2020 vs. 2018).  The only statement / respondent group for which there was a more neutral sentiment was that of pathologists / lab directors regarding the implementation of new biomarkers into their lab, for which they neither agreed nor disagreed that this process could be characterized as “easy”, a sentiment that is validated by other survey data.

The survey data suggest that recent drug / companion biomarker approvals are significant drivers of the uptake of precision oncology in the past two years; nearly all of the most significant increases in biomarker adoption among oncologists can be linked to new drug / diagnostic approvals or clinical or regulatory developments in the since 2018 (Figure 4).

Figure 4. Biomarker Adoption Rates (Absolute Rate and Change Since 2018) Among Oncologists (% of oncologists that order each marker)

These data support the oncologist sentiment that it is not a significant challenge to implement a new biomarker into their practices.  Oncologists also indicted that, while guideline recommendations remain the primary driver of adoption, they are increasingly willing to adopt new biomarkers based on clinical data (e.g., as shared at conferences) and availability of validated assays, even prior to guideline recommendations or regulatory approval.  This results in an increasing base of “early adopters” for new assays / biomarkers / technologies.

Despite this apparent ease in the adoption of new markers, it is clear from Figure 3 that familiarity, knowledge, and implementation gaps remain, and these gaps may only widen as new biomarkers, technologies, and data integration come online.  Continued investment by industry players in clinician education and the development of accessibility models that lower the barriers to new biomarker / technology adoption are essential to maximizing access to the precision diagnostics, technologies, and therapies of the future.

Takeaway 2: NGS is becoming the standard method for molecular testing across cancer types; though broad decentralization of NGS is not expected in the foreseeable future

A key consequence of this increase in precision medicine adoption is the technological shift playing out with respect to genetic biomarker testing.  Historically, when there were only a handful of genetic biomarkers for therapy selection and rarely more than 1 or 2 for any given indication, biomarker testing was performed using single-marker assays, such as PCR or FISH, which was often done in-house at hospital labs due to the availability of such equipment in-house and experience with these protocols.  However, with the approval of multiple different biomarker-drug combinations, including multiple pan-tumor approvals, genetic testing is shifting significantly towards NGS, which enables the simultaneous assessment of all known potentially-clinically-relevant markers.  In 2018, we observed that NGS already comprised a large share of genetic biomarker testing volumes among our oncologist respondents, and in 2020 we see that share expand to even greater levels, especially via comprehensive genomic profiling (CGP).  Among our respondents in 2020, CGP accounted for and estimated 55% of genetic testing orders, while single-biomarker assays accounted for <15% (Figure 5).  While these numbers likely reflect the influence of selection bias in this survey, the magnitude of this change is still likely indicative of direction in which things are trending.

Figure 5. Estimated Share of Genetic Biomarker Testing by Modality and Tumor-Agnostic Biomarker Testing Behaviors; as Reported by Oncologists

Among multiple potential reasons, one of the key potential drivers of NGS and CGP utilization is the shifting behavior related to tumor-agnostic biomarker testing (e.g., those biomarkers which inform treatment based on molecular status, regardless of tumor type, such as MSI, NTRK, and TMB).  In 2018, <20% of oncologists indicated that they do or plan to implement tumor-agnostic biomarker testing into their routine clinical care prior to the first line of therapy, while >35% indicated that they did not intend to test for these markers at all.  By 2020, however, the story flipped, with >35% of respondents testing for these markers prior to the first line of treatment, and <15% indicating no intention of testing for these markers (Figure 5).  Prior research with lab directors / pathologists suggested that 3 – 4 biomarkers represents the threshold at which it becomes more resource, cost, and time efficient to conduct a single NGS test rather than 3 – 4 individual biomarker tests.  With at least 3 tumor-agnostic markers approved, multiple indications with multiple additional tumor-specific markers, and an ever-growing pipeline of precision oncology clinical trials, the shift to NGS is logical and it seems like we are approaching the clinical NGS inflection point.  As one respondent put it, “…The expansion of molecular targets and genomic understanding of carcinogenesis is redefining precision medicine to the extent that protein/gene analysis is being performed for nearly every advanced cancer. NGS is at an inflection point, where it no longer serves as a last resort when all standard therapies have failed but is required before initiating the first systemic therapy for a metastatic cancer…”

– Oncologist, Private Community Practice

This shift to NGS testing is likely to impact the commercial and logistical infrastructure of diagnostic testing as well as competitive dynamics in the marketplace.  While the cost of sequencers and sequencing continues to decrease, the assay validation requirements and bioinformatics infrastructure requirements and costs remain prohibitively high for many labs, resulting in relatively high centralization of NGS testing.  Both in 2018 and 2020, respondents indicated that they expect the majority of NGS testing to be outsourced to large academic centers and commercial reference labs (and they expect even higher levels of centralization for other emerging technologies).  We also expect that increasing utilization of sequencing in routine care will add to the deluge of information that clinicians have to manage, making data clarity a key point of differentiation among genomics providers.  Lastly, increasing utilization of NGS will also likely drive competition, putting cost and turnaround time pressures on testing providers (particularly service providers), especially as NGS becomes more widely used in first-line settings.

Looking slightly more towards the future, survey respondents were asked to rank which technological trends they expected would impact precision oncology the most, and there was clear consensus among the top trends (Figure 6), with some minor variation by stakeholder type and setting.

Figure 6. Ranking of Most Impactful Trends in Precision Oncology

Liquid biopsy for biomarker testing emerged as the top overall trend, scoring highly among both oncologists and pathologists / lab directors.  Among pathologists, digital pathology was scored as the top overall trend.  Clinico-genomic RWD and liquid biopsy for early detection were also cited as key trends, while others were noted as interesting and potentially impactful, but too early in their development to foresee a significant clinical impact.  Focusing on the top trends for each stakeholder group (i.e., liquid biopsy and digital pathology) leads to the next key takeaways:

Takeaway 3: Confidence and adoption in liquid biopsies (LBx) is increasing; LBx is expected to be the most significant driving force of change in pathology / biomarker test

While liquid biopsies for solid-tumor biomarker testing have been available and covered by payors for a few years now, only a few months ago did the two industry leading offerings (i.e., Guardant’s Guardant360 and Foundation Medicine’s FoundationOne Liquid CDx) become FDA approved.  Despite only recent approvals, oncologist confidence in liquid biopsy for biomarker testing is already relatively high, with nearly 60% of respondents agreeing to some extent that liquid biopsy is as clinically actionable as tissue-based testing (Figure 7).  While confidence in liquid biopsy for biomarker testing seems to be high, the same cannot be said yet for the confidence in liquid biopsy for monitoring, as only ~35% of respondents agree to some extent that ctDNA load is as clinically actionable as imaging for response monitoring.  Given the relatively nascent nature of solid-tumor MRD clinical research, however, we expect that this figure may rise in the near-mid term.

Figure 7. Oncologist Confidence in Liquid Biopsies for Biomarker Testing and Monitoring (distribution of agreement ratings)

Open-ended respondent feedback clearly indicates that the minimal invasiveness and the streamlined diagnostic workflow are the liquid biopsy value propositions that are resonating strongest with clinicians and diagnostic stakeholders:

“…Less invasive and more precise testing is needed to limit the burden on patients, so liquid biopsies, followed by single cell analyses, will most likely have the edge…”

– Laboratory Director, Oncology Lab, Academic Medical Center

“…Less invasive procedures such as liquid biopsy will become the norm for testing. Easy collection and testing process…”

– Pathologist, Molecular Pathology Lab, Integrated Delivery Network

“…Liquid biopsy, if sensitive and specific enough, should provide non-invasive and maybe more accurate results of mutations due to e.g., tumor heterogeneity…”

– Laboratory Director, Molecular Diagnostics Lab, Academic Medical Center

“…I hope that liquid biopsies are ultimately proven to be as actionable as they are so much more convenient…”

– Medical Oncologist, Academic Medical Center

While confidence, optimism, and growth for LBx are high (e.g., >140% share growth from 2018 to 2020), the absolute share of LBx utilization across all biomarkers remains relatively limited, with blood-based testing for soluble markers accounting for only ~12% of test order volumes in 2020 (up from ~5% in 2018; Figure 8).

Figure 8. Biomarker Testing Distribution by Sample Type, All Tumors

Given the enthusiastic feedback from respondents, we consider the relatively low current penetration of liquid biopsy more as an opportunity for significant growth, rather than an indicator of limited clinical potential / utility, and expect to see an increasing shift of genetic testing (for which spatial context is less important) to liquid-based tests.  Additionally, we expect that as clinicians become increasingly comfortable with liquid biopsy for biomarker testing, and the liquid biopsy testing infrastructure grows more robust, that this will pave the way for adoption of other liquid-based testing such as MRD and early detection, opening up substantial market opportunity for liquid biopsy companies.

Takeaway 4: Digital pathology use is growing, but the full clinical and workflow value propositions are yet to be realized; expectations for the impact of digital pathology remain high with increasing development and use of artificial intelligence

Digital pathology has long been considered a “trend” in pathology (e.g., for >10 years), though progress in implementing digital pathology in routine laboratory diagnostics has been slow.  However, new regulatory approvals (e.g., for primary diagnosis and the use of AI for image analysis) in recent years, as well as the expanded use of digital pathology due to the SARS-CoV-2 pandemic, has stimulated progress.

Over half of all laboratory respondents surveyed indicated the adoption of a digital slide scanner, which is the minimum requirement for digital pathology (Figure 9).  Less than a quarter of respondents, however, indicated use of a computational image analysis solution (many scanners come with image viewers or analysis solutions with basic annotation capabilities, but these differ from computational image analysis solutions, which are often provided by third parties).

Figure 9. Adoption of Digital Pathology Solutions Among Pathologists / Lab Directors

Users of digital pathology in this survey (N = 44) indicated that there is some utilization in routine clinical care, but that the full clinical potential of the technology is not yet realized.  Figure 10 below shows that among digital pathology users, only ~16% use it for the majority of their cases for either primary diagnosis or specialty stain analysis, while slightly larger shares of respondents use digital pathology for a minority of their cases or for other clinical applications.  On the other hand, non-clinical applications, such as the use of digital pathology for remote consultations / second opinions and as a tool to facilitate tumor board meetings, is common.  For the clinical applications, respondents cited particular utility for the automated assessment of breast cancer markers and well as FISH analyses.

Figure 10. Digital Pathology Utilization by Application (share of dig. path. users)

Overall, despite what seems to be somewhat limited clinical utilization today, respondents generally perceive the implementation of digital pathology favorably, with nearly all respondents indicating that the adoption of digital pathology has had a neutral or positive impact on their lab from financial, clinical, and workflow perspectives (Figure 11).  Of note, multiple respondents cited that their adoption of digital pathology has been recent (e.g., due to the SARS-CoV-2 pandemic), and that they are still evaluating the full impact of the technology in their labs.

Figure 11. Perceived Financial, Clinical, and Workflow Value / Impact of Digital Pathology

Ultimately, laboratory stakeholders acknowledge that the greatest impact from digital pathology is expected to come from AI-enabled image analysis solutions.  This, however, will require additional technological, clinical, regulatory, and market development efforts before the impact is felt in routine clinical care.  Until then, digital pathology may continue to be a useful, but perhaps not quite transformational, tool for pathologists, unless providers can more convincingly communicate and demonstrate a stronger value proposition.

Takeaway 5: The role of the pathologist is changing, and pathologists of the future will need a new skillset than today’s pathologists

It is clear that the evolving technological landscape (e.g., molecular-, liquid-, and digital-based technologies) is significantly changing the role of the pathologist in precision medicine, and there are mixed perspectives among pathologists on how their role is expected to evolve as a result.  Respondents were asked, open-ended, to describe how they expect the role of the pathologist to change, and three schools of thought emerged (Figure 12):

Figure 12. Spectrum of Perspectives on the Changing Role of the Pathologist in Precision Medicine

As seen in Figure 12, a small share of pathologists (~11% of those surveyed), expect emerging technologies to replace much of what the pathologist does in precision medicine, leaving little left for the pathologist to do.  The most common sentiment (~48% of respondents), however, was one of neutrality, but acknowledgement that pathologists will need to embrace, master, and implement these technologies to stay relevant.  Lastly, a sizeable share of pathologists (~41% of respondents) expressed optimism that their role in precision medicine is increasing.  This perspective is largely based on the presumption that pathologists are the stewards of patient data, and that, as more and more molecular, clinical, and other types of real-world data are generated, it will be the role of the pathologist to integrate this information and leverage it to inform patient care.  Ultimately, the clear takeaway is that pathologist training, both at the point of medical school and continuing career education, needs to prioritize molecular-, liquid-, and digital technologies as fundamental piece of the curriculum to prepare pathologists for the future.

Collectively, these survey data and analyses underscore how rapidly the field of oncology is changing, and how impactful emerging diagnostic tools and technologies can and will be on routine patient care.  For the developers of precision medicine tools, technologies, and solutions, tracking and understanding the evolution of this landscape will be critical to developing the products, strategies, and business models that will resonate with oncology stakeholders in the future.  We at DeciBio will continue to track these developments closely in pursuit of our mission to advance precision medicine through strategy, insights, and information.

 

This work was powered by DeciBio’s Dexter and BioTrack platforms.  To learn more about about how these platforms can empower your precision medicine primary research, landscape monitoring, and competitive intelligence efforts, or to inquire about DeciBio’s consulting capabilities, please contact me at [email protected]

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Andrew Aijian

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