COMMENTARY

'Stepping Back From the Hype': A Critical Look at Next-Gen Sequencing

H. Jack West

Disclosures

December 13, 2017

In an effort to expedite the transition into a world of molecular oncology and precision medicine, the US Food and Drug Administration (FDA) recently approved Foundation Medicine's next-generation sequencing (NGS)-based in vitro diagnostic test, FoundationOnc CDx (F1CDx), which can detect genetic mutations in 324 genes and two genomic signatures in any solid tumor type.[1] Moreover, the Centers for Medicare & Medicaid Services (CMS) also proposed coverage for the F1CDx test.[1] We can certainly expect this to lead to a transformation in cancer care and a greater frequency of detection of potentially actionable targets. At the same time, however, it is important to recognize the limitations and potential negative, unintended consequences of this change as well.

In the interests of full disclosure, I have previously expressed skepticism about universal genomic sequencing,[2] on the basis of the absence of prospective, population-based evidence that genomic testing improves any clinically significant outcomes. This is not to say that molecular testing has no role, particularly for patients with cancers for which we have well-established and biomarker-dependent targeted therapies. My concerns about universal broad genomic testing have not intended to question the utility of "precision medicine."

We should step back from the unfettered hype.

Instead, my view is that we should step back from the unfettered hype to question the presumption, still based on anecdotal or very biased retrospective data combined with an inherent belief or bias in favor of NGS testing, that identifying more targets is inherently better, especially if most of these identified targets have little or no clinical data to guide an arguably optimal targeted therapy toward them.

But regardless of whether or not there is a benefit to identifying rare mutations with potential but unproven therapies, NGS testing represents a more efficient use of limited tissue and becomes increasingly cost-effective as the number of targets clearly worth testing for a given cancer grows. For lung cancer, where EGFR, ALK, ROS1, and BRAF B600E are all indicated tests in addition to PD-L1 expression, and with another handful of emerging biomarkers for associated targeted therapies for which there is a critical mass of phase 2 clinical evidence, NGS testing is a clearly compelling option. For other cancers, in which there are few or no current molecular markers with established utility, the benefit of testing for a wide range of markers is more speculative.

There is good reason to be concerned that more is not necessarily better in this setting. Although the cost of broad NGS testing itself is often cited as a significant concern, this expense of several thousand dollars per test is little more than a drop in the bucket in a time when we have become inured to treatment costs often exceeding $15,000 per month. This is especially true as technology improves and NGS testing costs may well decline. Our bigger concern should be the financial and clinical consequences of treatment decisions made for molecular targets without an associated targeted therapy.

There is good reason to be concerned that more is not necessarily better in this setting.

Although many respected leading figures in oncology and healthcare presume that treatments based on molecular testing will lead to better outcomes, this conclusion is devoid of prospective evidence. Dr William Halsted was a renowned, commanding figure who fostered the eminence-based dogma that disfiguring radical mastectomies were the appropriate treatment for resectable breast cancer, and this edict was broadly accepted as self-evident rather than subjected to critical testing for decades—to the great harm of generations of women with breast cancer. Unfortunately, even after centuries of what should be humility-inspiring illustrations of our hubris, the medical community remains all too willing to grant a pass to bias-driven conclusions from respected luminaries who speak with authority but weak evidence. Precision medicine needs to move beyond dramatic anecdotal cases without denominators of the population tested, or retrospective studies working backward from collections of patients with readily targetable lesions.

Despite the reflexive promotion of broad NGS testing as the party line by so many of its proponents, the fact remains that a large fraction of potential biomarkers identified by NGS testing create dark tunnels that are just as likely to be rabbit holes leading nowhere as they are to be previously unrecognized gold mines of remarkably beneficial and effective therapies for new or future targets. In an effort to provide treatment options and justify the cost of testing that all too often delivers no evidence-based therapy recommendations, NGS reports from Foundation Medicine and many others offer treatment options based on very early clinical trials or even preclinical data. Whether broad genomic testing becomes a beneficial inflection point for improving cancer care or a key moment where treatment costs come off the rails depends entirely on whether the reported results are interpreted judiciously or with an uncritical, gravitational pull toward molecularly defined therapies.

At a time when we face difficult decisions about how to cover the societal costs of very expensive cancer treatments with well-established benefits, we should be wary of increasing these challenges by selecting very expensive therapies devoid of strong clinical evidence. A few months of completely speculative, low-yield treatment with a targeted therapy that costs tens of thousands of dollars on the basis of a preclinically driven premise has the potential to create a societal financial nightmare if we expect these costs to be borne by insurers, who will invariably pass the costs on to their subscribers, now unwittingly forced to bankroll ill-advised decisions.

But the potential harm is not merely financial and indirectly borne by society. First, these targeted therapies may have significant adverse effects and lead to unexpected detrimental effects. Nobody in the lung cancer community expected gefitinib to be associated with a significantly detrimental effect after chemotherapy and radiation that amounted to a 12-month shorter survival than with placebo,[3] even if we might have thought that it may or may not help. But even beyond the potential for harm from a targeted therapy compared with placebo or supportive care, I too often see colleagues displace standard-of-care, established treatments with ones inspired by NGS reports indicating benefits that should be considered more in the range of "fanciful" than "expected"-a poor trade that may lead to worse outcomes rather than better ones, especially if this decision is made in an earlier line when treatments with meaningful and proven benefits are bypassed.

The key lies in the ability of clinicians to discriminate the quality of the evidence and judge the merit of the therapeutic recommendation.

Despite these concerns, I recognize the great potential for broad genomic testing to accelerate the rate of cancer research and identify subsets of patients likely to benefit profoundly. The key lies in the ability of clinicians to discriminate the quality of the evidence and judge the merit of the therapeutic recommendation accordingly. An important model of this approach has been published[4] and distinguishes among treatments that are ranked from level 1 (FDA-approved) to level 2 (standard care), level 3 (clinical evidence), and level 4 (biological evidence). Following the threshold for these criteria makes good sense in helping to distinguish what to expect to be covered by insurers compared with other options. Those options at a higher level, with relatively weaker evidence, may still present a strong strategy in the setting of a clinical trial, compassionate use program, or self-payment for a targeted therapy; but they should be acknowledged as falling short of the standards that should compel insurance coverage or substitution for treatment options with clinical data demonstrating a benefit in treatment outcomes.

Of note, we must also maintain rigor in our endpoints and demand that the benefits measured are clinically meaningful, such as a significant improvement in overall survival, rather than manufacturing new, weak endpoints-for example, a relative gain in progression-free survival compared with ineffective alternative salvage therapies, which have been created merely as a very low bar for tested therapies to exceed. For the cost of these treatments and the promise we have offered from precision medicine approaches, we should test endpoints that do more than create meaningless feel-good victories.

We should test endpoints that do more than create meaningless feel-good victories.

Rather than continuing to debate whether broad genomic testing should be done for patients with solid tumors, I feel that ship has sailed. But whether it takes us to a new world or we end up under water depends on how we direct that ship from here.

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