NEW YORK – Crucial questions regarding the clinical utility of Grail's multi-cancer screening test Galleri have yet to be answered by prospective data from intended-use populations, pathologists from the Washington University School of Medicine have noted in a commentary on recently published controversial data on the assay's use in prostate cancer early detection..

纽约——华盛顿大学医学院的病理学家在最近发表的关于Grail多癌筛查试验在前列腺癌早期检测中的应用的有争议数据的评论中指出，关于Grail多癌筛查试验Galleri的临床实用性的关键问题尚未得到预期使用人群的前瞻性数据的回答。。

At the same time, the commenters offered some clarity on the purpose and scope of the study, countering earlier reactions online that focused on a lack of early-stage sensitivity.

与此同时，评论者们对研究的目的和范围提供了一些明确的信息，反驳了早期网上的反应，即缺乏早期敏感性。

Investigators from Grail, the University of Miami Miller School of Medicine, and the Vancouver Prostate Center at the University of British Columbia faced criticism following their late August publication in JCO Precision Oncology of a prostate cancer sub-analysis from the company's prior case-control CCGA study and ongoing prospective PATHFINDER trial..

Grail、迈阿密大学米勒医学院和不列颠哥伦比亚大学温哥华前列腺中心的研究人员在8月下旬发表在JCO Precision Oncology上，对该公司之前的病例对照CCGA研究和正在进行的前瞻性PATHFINDER试验中的前列腺癌亚分析发表后，受到了批评。。

In a subsequent editorial led by first author Ann Ayzman and also published in JCO Precision Oncology, the WashU oncologists voiced concerns that most data related to multi-cancer early detection (MCED) testing has largely been taken from case-control studies, including the recent reported data.

在随后由第一作者安·艾兹曼（AnnAyzman）领导并发表在JCO Precision Oncology上的社论中，华盛顿大学肿瘤学家表示担忧，大多数与多癌早期检测（MCED）测试相关的数据主要来自病例对照研究，包括最近报道的数据。

Because cancer cases in this type of study are recruited after they've already been diagnosed, there is concern that the reported sensitivity and specificity is an overestimation compared to what would be true in a real-world undiagnosed population.

由于这类研究中的癌症病例是在确诊后招募的，因此人们担心，与现实世界中未确诊的人群相比，报告的敏感性和特异性被高估了。

'Some extrapolated data suggest that in almost all screened cancer types, the positive predictive value [of MCED testing] would be [less than] 10 percent,' Ayzman and colleagues wrote, citing, among other caveats, a critique of earlier Grail data by pathologists at Toronto's Mount Sinai Hospital.

艾兹曼及其同事写道：“一些推断数据表明，在几乎所有筛查的癌症类型中，[MCED检测]的阳性预测值将[不到]10%，”除其他警告外，还引用了多伦多西奈山医院病理学家对早期Grail数据的批评。

Commenters discussing the study on LinkedIn last month expressed shock at how low Grail's test sensitivity was even in a case-control context, especially for early-stage prostate cancer. They highlighted that Galleri is marketed as an early detection test and that its ultimate clinical value rests in shifting cancer diagnoses to earlier, more treatable stages..

上个月在LinkedIn上讨论这项研究的评论者对Grail的测试敏感性如此低表示震惊，即使在病例对照的情况下，尤其是对于早期前列腺癌。他们强调，Galleri是作为一种早期检测测试进行销售的，其最终临床价值在于将癌症诊断转移到更早，更可治疗的阶段。。

The Grail study authors responded that the question of clinical utility is more complicated than that, conceding that while an MCED assay should meaningfully improve the ability to detect cancers at treatable stages, it shouldn't be expected to do this equally across all tumor types. In addition, it is important that the test avoid detecting certain early cancers, including prostate cancers, that don't need to be treated, they said.

Grail研究的作者回答说，临床实用性的问题比这更复杂，他们承认，虽然MCED检测应该有意义地提高在可治疗阶段检测癌症的能力，但不应该期望在所有肿瘤类型中都这样做。此外，他们说，重要的是该测试应避免检测到某些不需要治疗的早期癌症，包括前列腺癌。

Grail didn't add comments of its own but highlighted the same points in its initial announcement of the publication..

Grail没有添加自己的评论，但在最初发布的出版物中强调了相同的观点。。

Ayzman and her coauthors noted along the same lines that the Grail study did provide some clarity on Galleri's strengths. For one, the data cement earlier suggestions from the company that Galleri preferentially detects deadlier cancers and is thus unlikely to lead to overdiagnosis.

艾兹曼和她的合著者也指出，圣杯研究确实为加莱里的优势提供了一些清晰的线索。首先，该数据巩固了该公司早期的建议，即Galleri优先检测致命的癌症，因此不太可能导致过度诊断。

'The data suggest that a positive result would be unlikely to detect indolent disease and should prompt ordering clinicians to obtain further diagnostic workup,' the editorial authors wrote. 'Notably, roughly one-third of detected cases in the CCGA cohort had nonmetastatic disease that was potentially amenable to cure.'.

社论作者写道：“数据表明，阳性结果不太可能检测出无痛性疾病，应该促使临床医生进行进一步的诊断检查。”值得注意的是，CCGA队列中大约三分之一的检测病例患有非转移性疾病，可能可以治愈。

In an email, Brandon Mahal, lead investigator on the Grail prostate cancer study and an oncologist at University of Miami's Sylvester Comprehensive Cancer Center, stressed that the goals of his team's analysis were not to provide evidence for clinical sensitivity in an intended-use population.

圣杯前列腺癌研究的首席研究员、迈阿密大学西尔维斯特综合癌症中心的肿瘤学家布兰登·马哈尔在一封电子邮件中强调，他的团队分析的目的不是为预期用途人群的临床敏感性提供证据。

'A common concern we hear around MCED testing is that it may contribute to overdiagnosis of cancers. That is, we may be detecting cancers that would not grow or spread enough to cause harm over the course of an individual's lifetime,' he said.

“我们在MCED测试中听到的一个共同担忧是，它可能会导致癌症的过度诊断。他说，也就是说，我们可能检测到的癌症不会在一个人的一生中发展或扩散到足以造成伤害的程度。

'Prostate cancer is one cancer type that has a notably high proportion of indolent cancers and is very common in the intended-use population for MCED tests … [so] we were particularly interested in understanding how Galleri test performed in detecting various grades and stages of this disease.'

“前列腺癌是一种癌症类型，其惰性癌症的比例非常高，在MCED测试的预期使用人群中非常常见……[因此]我们特别有兴趣了解Galleri测试如何检测这种疾病的各个等级和阶段。”

Mahal said that 'threading the needle' therapeutically is a particular challenge for prostate cancer. 'We want to detect cancers before they metastasize, while at the same time, we do not want to over-detect early-stage cancers that may not ever metastasize.'

马哈尔说，“穿针法”治疗前列腺癌是一个特殊的挑战我们希望在癌症转移之前检测到癌症，同时，我们不想过度检测可能永远不会转移的早期癌症。”

In the study, Mahal and his coauthors analyzed Galleri's performance across different prostate cancer Gleason grade groups and clinical stages in 420 patients from the CCGA, a three-part case-control study that established the Galleri assay format, also noting performance thus-far in the ongoing PATHFINDER prospective trail..

在这项研究中，Mahal和他的合著者分析了来自CCGA的420名患者中Galleri在不同前列腺癌Gleason分级组和临床阶段的表现，CCGA是一项由三部分组成的病例对照研究，建立了Galleri分析格式，也注意到目前为止在正在进行的PATHFINDER前瞻性试验中的表现。。

In the CCGA prostate cancer patients, the test detected only 3 percent of stage I disease, about 5 percent of stage II cancers, 15 percent of stage III, and more than 80 percent of stage IV cases. In PATHFINDER, one cancer has thus far been detected and one missed.

在CCGA前列腺癌患者中，该测试仅检测到3%的I期疾病，约5%的II期癌症，15%的III期和80%以上的IV期病例。在PATHFINDER中，迄今为止已经检测到一种癌症，而错过了一种。

Overall, Mahal said, the results show that individuals with a positive Galleri test and a tumor origin prediction of prostate cancer are likely to have a clinically significant cancer that merits rapid workup and treatment.

马哈尔说，总的来说，结果表明，加莱里试验阳性和前列腺癌肿瘤起源预测的个体很可能患有临床意义重大的癌症，需要快速检查和治疗。

He also noted that low sensitivity to early-stage prostate cancer does not mean Galleri would necessarily show low sensitivity for all early-stage cancers. In other words, conclusions about the test's overall clinical value shouldn't rest on this specific sub-analysis.

他还指出，对早期前列腺癌的低敏感性并不意味着Galleri对所有早期癌症都必然表现出低敏感性。换句话说，关于测试总体临床价值的结论不应基于这种特定的子分析。

Because most of the data they analyzed was retrospective, Mahal and his team didn't have the ability to look at clinical outcomes for cancers detected by Galleri versus those the test missed. But as a surrogate, they compared the overall survival of patients in the CCGA cohort with historical records from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database..

因为他们分析的大多数数据都是回顾性的，所以Mahal和他的团队没有能力观察Galleri检测到的癌症与未检测到的癌症的临床结果。但作为替代指标，他们将CCGA队列中患者的总生存率与美国国家癌症研究所的监测，流行病学和最终结果（SEER）数据库的历史记录进行了比较。。

Patients that Galleri missed had about three times higher overall survival rates than the SEER population, while those it did detect had similar survival rates to the overall historical average.

Galleri遗漏的患者的总生存率是SEER人群的三倍左右，而那些确实检测到的患者的生存率与总体历史平均水平相似。

'Survival comparisons with SEER data may not be definitive, but they can provide critical insights,' Mahal wrote. 'We found that participants with prostate cancers not detected by the MCED test were three times more likely to survive than would be expected. This result strongly suggests that those cancers not detected by the MCED test are likely indolent cases that would not cause harm.'.

马哈尔写道：“与SEER数据的生存率比较可能并不确定，但可以提供重要的见解。”我们发现，MCED测试未检测到的前列腺癌患者的生存率是预期的三倍。这一结果强烈表明，MCED测试未检测到的癌症可能是不会造成伤害的惰性病例。”。

Moreover, about a third of the Galleri-detected cases in the CCGA group were both high-grade and pre-metastatic, 'the types of cases we want to detect,' Mahal said, because they are both high risk and potentially curable.

此外，CCGA组中约三分之一的Galleri检测到的病例都是高级别和转移前的，“我们想检测的病例类型”，Mahal说，因为它们都是高风险且可能治愈的。

In their commentary, Ayzman and colleagues stressed that regardless of its implications, the current analysis should be held with caution because the number of cases detected in the study was relatively low.

艾兹曼及其同事在评论中强调，无论其影响如何，目前的分析都应谨慎进行，因为研究中发现的病例数量相对较少。

Another important limitation, they wrote, is that 85 percent of patients in the cohort self-reported as White, non-Hispanic. 'Prostate cancer is notorious for disproportionately affecting Black men,' who face 'higher incidence rates, more aggressive disease, and double the mortality risk compared with their White counterparts.' .

他们写道，另一个重要的限制是，队列中85%的患者自我报告为白人，非西班牙裔。”。

Future efforts would benefit from greater inclusion of the true population that stands to benefit from MCED screening, they argued.

他们认为，未来的努力将受益于更多地纳入真正的人群，这些人群将从MCED筛查中受益。