NEW YORK – Although researchers don't expect to report final results from a UK-based randomized prospective study of Grail's blood-based multi-cancer screening test for about a year, debate over the results has already begun.

纽约——尽管研究人员预计要大约一年的时间才能从英国一项关于 Grail 公司基于血液的多癌症筛查测试的随机前瞻性研究中报告最终结果，但关于这些结果的争论已经开始。

Stakeholders gathered at Cambridge Healthtech Institute's Precision Medicine Tri-Conference (Tri-Con) last week to discuss the hurdles this new class of assays face in proving their worth, as well as the challenges to clinicians and the larger public in understanding their limitations.

上周，利益相关者聚集在剑桥健康技术研究所的精准医学三合一会议（Tri-Con）上，讨论了这类新型检测方法在证明其价值时面临的障碍，以及临床医生和广大公众在理解其局限性时所面临的挑战。

Central to the debate was the acknowledgement that the expected trial results for Grail's Galleri — a blood-based assay that measures genome-wide methylation to identify cancer-associated patterns in circulating DNA molecules — will provide at most about half of what policymakers may need or expect to render judgement..

辩论的核心是承认 Grail 的 Galleri 试验结果——一种基于血液的检测方法，通过测量全基因组甲基化来识别循环 DNA 分子中的癌症相关模式——最多只能提供政策制定者作出判断时可能需要或期望的一半信息。

The study, being conducted within the UK's National Health Service, is designed to evaluate a specific endpoint — a reduction in the number of late-stage (stage III and IV) cancers for those randomized to multi-cancer early detection (MCED) screening compared to those in the control arm. However, panelists at the Tri-Con said the historical benchmark for cancer screening tests, a reduction in mortality isn't something that can be directly or easily calculated from this stage-shift..

这项在英国国家医疗服务体系内进行的研究旨在评估一个特定的终点指标——与对照组相比，随机分配到多癌种早期检测（MCED）筛查组的晚期（III 期和 IV 期）癌症数量是否减少。然而，Tri-Con 会议上的专家小组表示，历史上的癌症筛查测试基准，即死亡率的降低，并不能从这种阶段转移数据中直接或轻松计算得出。

During a meeting session, University of Washington professor Larry Kessler, former chair of the Multi Cancer Early Detection Consortium, raised the question of whether MCED tests should be treated differently in this regard, due to the practical hurdles in pursuing trials designed to directly measure an impact on mortality, and the potential benefit to patients that could be lost..

在一次会议期间，华盛顿大学教授、多癌早期检测联盟前主席拉里·凯斯勒提出了一个问题，即由于在追求旨在直接衡量对死亡率影响的试验时面临的实际障碍，以及可能给患者带来的潜在益处的丧失，MCED测试是否应该在这方面被区别对待。

'Over 600,000 Americans die each year of cancer, and two-thirds of those die from cancers that are unlikely to ever have dedicated recommended screening tests,' Kessler estimated.

“每年有超过 60 万美国人死于癌症，其中三分之二死于不太可能有专门推荐的筛查测试的癌症，”凯斯勒估计。

The earliest that a US-based randomized trial of MCED tests with a mortality endpoint might see results would be close to a decade, he added.

他补充说，美国基于随机试验的MCED测试最早可能在接近十年内看到以死亡率为终点的结果。

The NCI

国家癌症研究所

recently announced

最近宣布

the launch

启动

of a three-year study called Vanguard, which is assessing tests developed by Guardant Health and ClearNote. But that study is only intended to investigate the feasibility of a larger randomized trial.

为期三年的先锋研究的一部分，该研究正在评估Guardant Health和ClearNote开发的测试。但该研究仅旨在探讨更大规模随机试验的可行性。

'I will tell you right now, the National Cancer Institute is not funded for [that larger] study, which … couldn't start earlier than 2028 and wouldn't have outcomes until 2034 at the earliest,' Kessler argued. 'We'll also have to see whether that happens at all, especially in this [political] climate.

“我现在就告诉你，国家癌症研究所没有资助[更大规模的]研究，这项研究……最早也要到2028年才能开始，最快也要到2034年才会有结果，”凯斯勒说道。“我们还要看看这是否真的会发生，尤其是在这种[政治]气候下。”

We'll have to see if the NCI exists in this climate by the time the Vanguard study is over.'.

我们得看看等先锋研究结束时，NCI是否还会存在于这种环境下。

Meanwhile, the possibility of making even a small dent in cancer mortality during the next 10 or 15 years is hard to turn away from, Kessler argued. 'I'm not saying we must [adopt tests with limited data], I'm just talking about why we might want to consider alternatives to waiting for the wheels of a large US-based randomized trial.'.

同时，凯斯勒认为，在未来10年或15年内，即使只是在癌症死亡率上取得小小的突破，这种可能性也难以忽视。“我不是说我们必须【采用数据有限的测试】，我只是在谈论为什么我们可能需要考虑替代方案，而不是等待美国大型随机试验的结果。”

Exact Sciences Chief Medical Officer Tomasz Beer also highlighted the potential harm in moving too slowly. 'If you invent something new every 10 or 20 years, taking 10 or 20 years to prove it out is not so bad,' he said.

Exact Sciences首席医学官托马斯·贝尔（Tomasz Beer）还强调了行动过于缓慢可能带来的危害。他说：“如果你每隔10年或20年发明一种新事物，花10年或20年的时间来验证它并不是那么糟糕。”

'But if you can invent something new every six months you suddenly have this gigantic bottleneck where, ultimately, we deliver to patients technologies that are not just obsolete, but many generations obsolete by the time we get to that point' he added. 'I'm cautiously optimistic that we can figure it out.'.

“但是，如果你每隔六个月就能发明一些新东西，那么我们突然遇到了一个巨大的瓶颈：最终，当我们把技术交给病人时，这些技术不仅已经过时，而且已经落后了好几代。”他补充道，“我谨慎乐观地认为，我们能够解决这个问题。”

Other alternatives include additional fast-tracked prospective studies with non-mortality endpoints, modeling, and post-market review.

其他替代方案包括额外的快速前瞻性研究、非死亡终点研究、建模和上市后审查。

'You could look at individual endpoints such as the proportion of screen-detected cancers that are amenable to treatment with curative intent,' Kessler proposed. 'You could look at health system endpoints like the economic burden over time. And you could look at cancer survival rates.'

“你可以查看个别终点，例如通过筛查检测到的癌症中适合接受治愈性治疗的比例，”凯斯勒提出。“你可以查看像经济负担随时间变化这样的卫生系统终点。你还可以查看癌症生存率。”

Ruth Etzioni, a biostatistician at the Fred Hutchinson Cancer Center and an expert in cancer screening modeling, responded to Kessler's proposition with a sobering projection of possible outcomes of the NHS Galleri study.

弗雷德·哈钦森癌症中心的生物统计学家、癌症筛查建模专家露丝·埃齐奥尼对凯斯勒的主张做出了回应，她对NHS Galleri研究的可能结果进行了令人警醒的预测。

The trial randomized 140,000 individuals, with half getting Galleri once per year over three years, and the other half receiving standard care under the NHS. Although there is a cancer-specific mortality endpoint planned, it's a secondary analysis for which the trial was not intentionally powered.

该试验随机选取了140,000人，其中一半人每年接受一次Galleri检测，连续三年，另一半人则接受NHS的标准护理。虽然计划中有针对癌症特异性死亡率的终点指标，但这属于次要分析，试验并非为此专门设计统计效力。

'I think it's very important to think about why we look at mortality,' Etzioni said. 'There were very thoughtful people at the beginning of the age of cancer screening who thought about endpoints and came to the conclusion that cancer mortality was the right endpoint, so I don't think we can just toss it out.

“我认为思考我们为什么关注死亡率这个问题非常重要，”艾佐尼说。“在癌症筛查时代的初期，有一些非常有思想的人考虑过终点问题，并得出结论认为癌症死亡率是一个正确的终点，所以我不认为我们可以轻易地把它抛开。

We have to think about what they were trying to do and whether we can do without it.'.

我们必须考虑他们试图做什么，以及我们是否可以不用它。

One major issue with looking at stage of diagnosis, she added, is that it's more subjective than mortality, although even that requires adjudication, she admitted.

她补充说，观察诊断阶段的一个主要问题是，它比死亡率更主观，尽管她承认，即使是这样也需要裁定。

'If you're going to have stage as an endpoint, then both the screen and control groups have to have access to the exact same technology and the exact same procedures to stage them,' she said. 'That has to be part of the documentation that happens and that is not happening at this point.'

“如果你要将舞台作为终点，那么屏幕组和对照组都必须使用完全相同的技术和程序来搭建舞台，”她说。“这必须是记录的一部分，但目前并没有做到。”

Modeling the possible outcomes of the NHS Galleri trial, Etzioni and colleagues predicted that the final results could show a reduction in late-stage diagnoses of between 6 percent and 23 percent after seven years, depending on the details of the population recruited.

Etzioni 和同事对 NHS Galleri 试验的可能结果进行了建模，预测在七年后，根据招募人群的具体细节，最终结果可能会显示晚期诊断减少 6% 到 23%。

How this would then translate into an effect on mortality is still an open question, but it infers that it may be significantly below the 20 percent reduction traditionally viewed as the goal for a screening test.

这一结果将如何转化为对死亡率的影响仍然是一个悬而未决的问题，但它暗示这一影响可能显著低于传统上被视为筛查测试目标的20%降幅。

'I will be the first person to say that every screening trial is a half a loaf,' but the NHS Galleri trial is unprecedented in its short evaluation time and surrogate endpoint, Etzioni said. The single readout next year may be more like a slice, she argued, considering how much the impact of screening can shift depending on when you assess it..

“我将是第一个说每项筛查试验都只完成了一半的人，”艾佐尼说，但NHS Galleri试验在其短暂的评估时间和替代终点上是前所未有的。她认为，考虑到筛查的影响会因你评估的时间而发生多大的变化，明年的一次读数可能更像是其中的一小部分。

When researchers try to project the outcome of a screening program, they look at a combination of what Etzioni called 'opportunity for early detection' and accuracy of early detection.

当研究人员试图预测筛查项目的结果时，他们会综合考虑艾佐尼所说的“早期检测机会”和早期检测的准确性。

Modeling the opportunity for early detection, often called the sojourn time, involves weighing the length of time individuals remain at an early stage of their cancer, how rapidly they progress through further stages, and how long they might remain asymptomatic with advanced disease.

对早期发现的机会（通常称为滞留时间）进行建模，涉及权衡个体在其癌症早期阶段停留的时间长度、他们通过后续阶段进展的速度，以及他们在晚期疾病中可能保持无症状的时间。

The modeling is complex, Etzioni said, but researchers have methods to infer probable scenarios using data from registry studies, and this is what fueled her group's projections of 6 percent, 20 percent, and 23 percent reduction in late-stage disease, based on three possible combinations of early detection opportunity and test sensitivity assumptions..

埃齐奥尼表示，建模很复杂，但研究人员有方法利用登记研究的数据推断可能的情景，这就是她的团队基于早期检测机会和测试灵敏度假设的三种可能组合，预测出晚期疾病将减少6%、20%和23%的原因。

'I don't know how things are going, but if everything goes according to plan and there is good compliance with screening follow-up, then I don't think it's unrealistic that we might see something between a 10 to 20 percent reduction,' said Etzioni.

“我不知道情况如何，但如果一切按计划进行，并且筛查后续工作得到良好遵守，那么我认为看到 10% 到 20% 的减少并非不现实，”艾佐尼说道。

'But what are we going to do then?' she added. 'When we see the headline saying that the Galleri trial lowers late-stage disease by 15 percent, I expect a lot of journalists will be really excited about this and the public will be excited about it. [A] 15 percent reduction may seem substantial, but we know that a given late-stage reduction has a variable mortality impact across cancers.'.

“但是我们接下来要做什么呢？”她补充说。“当我们看到标题说Galleri试验将晚期疾病降低了15%时，我认为很多记者会对此感到非常兴奋，公众也会对此感到兴奋。[A] 15%的降幅可能看起来很可观，但我们知道，特定的晚期疾病减少对不同癌症的死亡率影响是不同的。”

Another challenge, according to Etzioni, is that mortality impact usually grows over time before settling, so whatever is calculated for Galleri earlier on may fall short of its ultimate impact, echoing Kessler's call for stakeholders to consider the potential loss to patients, and to the healthcare system, in setting too high a bar..

据艾茨奥尼称，另一个挑战是死亡率的影响通常会随着时间的推移而增加，然后才会稳定下来，因此之前为Galleri计算的数据可能无法达到其最终影响，这也呼应了凯斯勒呼吁利益相关者在设定过高门槛时，考虑患者和医疗系统可能遭受的损失。

'I am not averse to using, with all the caveats and all the documentation and the care that you have to have, a stage-based endpoint,' Etizioni said. 'But we have to bring the … consideration and the thoughtfulness to that that our predecessors did to mortality.'

“我并不反对使用基于阶段的终点指标，同时考虑到所有的警告、所有的文档记录以及必须具备的谨慎态度，”埃齐奥尼说。“但是，我们必须像我们的前辈对待死亡率那样，对此进行深思熟虑。”

'That is work that really has to be done, and it's not about publishing more papers,' she argued.

“这是必须要完成的工作，而不是发表更多的论文，”她争辩道。

An early report from the UK Galleri trial last year was met with some anxiety amongst investors, when the

去年英国Galleri试验的一份早期报告让投资者感到有些焦虑，当时

NHS reported

NHS 报告显示

that, at the sensitivity seen, it was

在所见的敏感性下，它是

not going to exercise an option

不打算行使期权

to roll out commercial Galleri screening then and there.

在那里和当时推出商业性的Galleri筛查。

Kessler, who was part of the committee that looked at the interim data and advised the NHS, said that he couldn't share details, but noted that labeling the decision 'not to immediately buy a million tests' as a bad omen was not warranted.

凯斯勒是审查中期数据并为 NHS 提供建议的委员会的一员，他表示自己不能分享细节，但指出将“不立即购买一百万份测试”的决定标记为不祥之兆是没有根据的。

'We set an extremely high threshold because the NHS and Grail did not want to … jump the shark. They did not want to have a middling result, buy a bunch of tests, and later discover that the trial was not so successful.' The mark would have been 'very hard if not impossible' to achieve, Kessler said..

“我们设定了一个非常高的门槛，因为 NHS 和 Grail 不想……贸然行事。他们不想得到一个平庸的结果，买了一堆测试，然后后来发现试验并不那么成功。”凯斯勒说，这个目标“即使不是不可能，也很难”实现。

Megan Hall, Grail's VP of medical and corporate affairs, added that the early readout was not an official interim analysis of the study and reiterated that the company is 'cautiously optimistic about the three years of screening having an impact.'

梅根·霍尔（Megan Hall），Grail公司医疗和企业事务副总裁，补充道，早期数据并非该研究的正式中期分析，并重申公司“对三年筛查产生影响持谨慎乐观态度”。

Kessler raised the question of whether a 20 percent reduction in mortality should be the cutoff point for assessing the value of a MCED test, noting that the public may have a different risk tolerance that policymakers should consider.

凯斯勒提出了一个问题，即20%的死亡率降低是否应该作为评估MCED测试价值的临界点，并指出公众可能有不同的风险承受能力，这是政策制定者应该考虑的。

'You could determine the degree to which the public might be more comfortable accepting some degree of evidentiary uncertainty in exchange for earlier detection of cancer and the possibility of clinical benefit,' he said. 'There's room for discussion and debate.'

“你可以确定公众在多大程度上可能更愿意接受一定程度的证据不确定性，以换取更早发现癌症和可能的临床益处，”他说。“这有讨论和辩论的空间。”

The same point was raised by a meeting attendee, leading to debate between panelists. Etzioni highlighted the fact that although the lay public may have a different risk tolerance, they also have a different understanding of the harms and benefits of early detection that can make them vulnerable.

与会者提出了同样的观点，引发了专家小组之间的辩论。艾茨欧尼强调，尽管普通公众可能有不同的风险承受能力，但他们对早期发现的危害和益处也有不同的理解，这可能使他们变得脆弱。

For example, 'if you take those 70 percent of cancer deaths that come from cancers for which we don't have a screening test, and we're able to save 20 percent of them [that might sound really exciting] but  62 percent of cancer deaths will still come from those cancers,' Etzioni said.

例如，“如果拿走那 70% 死于我们无法进行筛查的癌症的患者，而我们能够拯救其中 20% 的人 [这听起来真的很令人兴奋]，但仍有 62% 的癌症死亡将来自这些癌症，”艾茨奥尼说。

That's not because they don't have a screening test, but because of their aggressiveness, their prevalence, and a lack of treatments. 'Screening isn't going to make up for that,' she said.

这并不是因为他们没有筛查测试，而是因为它们的侵袭性、普遍性以及缺乏治疗方法。她表示：“筛查无法弥补这一点。”

Guardant Health Chief Medical Officer Craig Eagle argued that 20 percent mortality reduction is not necessarily an ideal threshold, and there should be a broader effort at shared decision-making to determine what that should be. 'If you think about it, there are many diseases and interventions we spend a lot of effort on, even advanced cancer, where you don't get a significant mortality reduction,' he said.

Guardant Health首席医疗官克雷格·伊格尔认为，20%的死亡率降低并不一定是一个理想的阈值，应该在共享决策方面做出更广泛的努力来确定这个阈值应该是多少。他说：“如果你仔细思考，会发现有很多疾病和干预措施，我们投入了大量精力，甚至是晚期癌症，也没有显著降低死亡率。”

'20 percent is a really high bar.'.

“20%是一个非常高的门槛。”

Exact Sciences' Beer said that he came to the panel prepared for this question, and had looked up meta-analyses of both cholesterol treatment and blood pressure medications, which showed a 7 percent and 9 percent reduction in mortality respectively.

Exact Sciences的比尔表示，他来参加讨论小组时已准备好回答这个问题，并查阅了关于胆固醇治疗和降血压药物的荟萃分析，结果显示死亡率分别降低了7%和9%。

'None of this, by the way, was demonstrated in a prospective randomized control trial,' he added. 'Only when the meta-analyses were done could we speak to the mortality benefits, so 20 percent is a wonderful goal, but we might want to zoom out and take a look at other areas of health where decisions were made differently.'.

“顺便说一句，这些都没有在前瞻性随机对照试验中得到证实，”他补充说。“只有当荟萃分析完成时，我们才能谈论对死亡率的益处，所以20%是一个很好的目标，但我们也可能需要放大视野，看看其他健康领域，那里的决策方式有所不同。”

Kessler reiterated that some of the uncertainty faced by tests like Galleri could be addressed with post-market surveillance.

凯斯勒重申，像 Galleri 这样的测试所面临的一些不确定性可以通过上市后监测来解决。

'A large number of medical devices are classically put on the market with only half the evidence,' he said, citing hip implants as an example.

“大量的医疗器械在上市时，通常只有半数的证据支持，”他举例说，髋关节植入物就是这样的例子。

'Hip implants are expected to last in your body anywhere from 10 to 15 years, sometimes more, but no trial for hip implants is made to last more than three years,' Kessler said. At that point, the US Food and Drug Administration will clear or approve an implant with a post-market requirement to look for failure rates.

凯斯勒说：“髋关节植入物预计在体内可以维持10到15年，有时更长，但髋关节植入物的试验从未持续超过三年。” 在那个阶段，美国食品和药物管理局将通过一项上市后要求来监测失败率，从而批准或认可该植入物。

.

。

'Sometimes you get high failure rates, and those products can be pulled off the market,' he added. 'It's different than a cancer screening test, but it's an example of the way in which we use post-market data to facilitate putting products in the market before all the information is in.'

“有时失败率会很高，那些产品可能被撤出市场，”他补充说。“这和癌症筛查测试不同，但这是一个例子，说明我们如何利用上市后的数据，在所有信息尚未完备之前，将产品推向市场。”

According to Hall, Grail is also optimistic about the real-world evidence it is sitting on. 'I think that's going to be a big indicator outside of a clinical trial setting as to what we could expect,' she said.

据哈勒介绍，Grail 对其掌握的真实世界证据也持乐观态度。“我认为这将成为临床试验环境之外的一个重要指标，可以让我们了解未来的期望，”她表示。

She also stressed that the company is trying to be responsible in how it has implemented Galleri in the clinic as a laboratory-developed test, including an effort to follow up on 'every single positive test result' that it gets, to track whether those results transition to a cancer diagnosis or not, as well as any issues with follow-up diagnostic workups..

她还强调，该公司在诊所中将Galleri作为实验室开发的测试来实施时，正努力采取负责任的态度，包括跟进“每一个阳性测试结果”，以追踪这些结果是否转变为癌症诊断，以及后续诊断评估中可能出现的任何问题。

'Knock on wood so far, based on voluntary data that's reported to us … we're seeing that it's doing what we think it should be doing and what we've predicted that it would,' Hall said.

霍尔说：“根据向我们报告的自愿数据，到目前为止，情况正如我们所预期和预测的那样发展。”