NEW YORK – The availability of AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) for treating HER2-low breast cancer has shaken up long-established HER2 expression classification categories and upended how pathologists and oncologists manage their patients.

纽约——阿斯利康（AstraZeneca）和第一三共（Daiichi Sankyo）的Enhertu（曲妥珠单抗deruxtecan）治疗HER2低乳腺癌的可用性动摇了早已确立的HER2表达分类类别，并颠覆了病理学家和肿瘤学家管理患者的方式。

Some pathologists are questioning the ability of immunohistochemistry (IHC) testing to reliably capture varying levels of HER2 expression, while oncologists are scrambling to revisit patients' earlier test results to see if those previously deemed negative for HER2 overexpression are actually low expressers who now qualify for Enhertu..

一些病理学家质疑免疫组织化学（IHC）检测是否能够可靠地捕获不同水平的HER2表达，而肿瘤学家则争先恐后地重新检查患者早期的检测结果，以确定那些先前被认为对HER2过表达呈阴性的患者是否实际上是低表达者，现在有资格获得Enhertu。。

The HER2 expression biomarker category, meanwhile, may still see further volatility as the makers of Enhertu want to see it approved in even broader patient populations — for those with very low or minuscule levels of HER2 expression. But AstraZeneca and Daiichi Sankyo don't see the current biomarker detection challenges in the HER2 space as insurmountable and believe they can be addressed by training pathologists to better interpret IHC results when tumors have low levels of HER2..

同时，HER2表达生物标志物类别可能仍会出现进一步的波动，因为Enhertu的制造商希望看到它在更广泛的患者人群中获得批准-对于HER2表达水平非常低或很低的患者。但阿斯利康（AstraZeneca）和第一三共（Daiichi Sankyo）并不认为HER2领域目前的生物标志物检测挑战是无法克服的，他们相信可以通过培训病理学家来解决这些挑战，以便在肿瘤HER2水平低时更好地解释IHC结果。。

The present situation began in 2022 when the US Food and Drug Administration approved AstraZeneca and Daiichi Sankyo's HER2-directed antibody-drug conjugate (ADC) Enhertu for HER2-low unresectable or metastatic breast cancer patients who have received prior chemotherapy in the metastatic setting or experienced recurrence within six months of adjuvant chemo.

目前的情况始于2022年，当时美国食品和药物管理局（FDA）批准阿斯利康（AstraZeneca）和第一三共（Daiichi Sankyo）的HER2定向抗体-药物偶联物（ADC）Enhertu用于HER2低不可切除或转移性乳腺癌患者，这些患者先前在转移性环境中接受过化疗或在辅助化疗后6个月内复发。

Concurrent with that approval, Roche's Pathway anti-HER2 (4B5) IHC test was approved as a companion diagnostic..

在获得批准的同时，罗氏途径抗HER2（4B5）IHC测试被批准为伴随诊断。。

Since the 1998 approval of the first HER2-targeted monoclonal antibody, Genentech's Herceptin (trastuzumab), doctors and pathologists have been using tests to identify patients eligible for these types of treatments based on if their tumors are 'HER2 positive' or 'HER2 negative'. Historically, tumors with an IHC score of 0 or 1+ have been considered HER2 negative and not likely to respond to HER2-targeted treatment, while tumors with 3+ scores are HER2 positive and considered responders.

自1998年批准第一种针对HER2的单克隆抗体基因泰克（Genentech）的赫赛汀（曲妥珠单抗）以来，医生和病理学家一直在使用测试来确定符合这些类型治疗条件的患者，基于他们的肿瘤是“HER2阳性”还是“HER2阴性”。从历史上看，IHC评分为0或1+的肿瘤被认为是HER2阴性的，不太可能对HER2靶向治疗产生反应，而评分为3+的肿瘤是HER2阳性的，被认为是应答者。

Tumors with 2+ IHC scores have traditionally been called 'equivocal' and have needed a second test like in situ hybridization (ISH) to determine whether they could respond to HER2-targeted therapy. .

具有2+IHC评分的肿瘤传统上被称为“模棱两可”，并且需要第二次测试，如原位杂交（ISH），以确定它们是否可以对HER2靶向治疗产生反应。

In the past 25 years, HER2-overexpressing breast cancer has been accepted as a subtype of the disease, and HER2 positivity and negativity is evaluated alongside estrogen and progesterone receptor status upon diagnosis. When Enhertu first came to market in 2019 for unresectable or metastatic breast cancer patients who have already received another HER2-targeted therapy, treatment eligibility was based on the traditional parameters for HER2 positivity.

在过去的25年中，HER2过表达的乳腺癌已被认为是该疾病的一种亚型，在诊断时，HER2阳性和阴性与雌激素和孕激素受体状态一起进行评估。当Enhertu于2019年首次上市治疗已接受另一种HER2靶向治疗的不可切除或转移性乳腺癌患者时，治疗资格基于HER2阳性的传统参数。

.

.

And while the traditional HER2 testing parameters remain, for now, for breast cancer subtyping, for guiding other HER2-targeted drugs, and for the above Enhertu indication, the release of the DESTINY-Breast04 trial data in 2022 threw a wrench into established biomarker testing workflows with the introduction of HER2 low as a category.

虽然传统的HER2检测参数仍然存在，但目前，对于乳腺癌亚型，指导其他HER2靶向药物以及上述Enhertu适应症，2022年DESTINY-Breast04试验数据的发布为已建立的生物标志物检测工作流程带来了冲击，引入了HER2-low作为一个类别。

This new category includes tumors with an IHC 2+ score and a negative ISH result or an IHC 1+ score, denoting either weak-to-moderate complete staining for the presence of HER2 expression or faint, partial staining of the membrane in greater than 10 percent of the cancer cells. In DESTINY-Breast04, Enhertu showed efficacy in this HER2-low subgroup, demonstrating improvements in survival outcomes compared to physician's choice of chemotherapy..

这一新类别包括IHC 2+评分和ISH阴性结果或IHC 1+评分的肿瘤，表示HER2表达的弱至中度完全染色或大于10%的癌细胞中膜的微弱部分染色。在DESTINY-Breast04中，Enhertu在这个HER2低亚组中显示出疗效，与医生选择的化疗相比，生存结果有所改善。。

With this approval, AstraZeneca and Daiichi Sankyo significantly expanded the number of breast cancer patients eligible for the HER2-directed therapy. Using the traditional definition of HER2 positive, between 10 percent to 20 percent of breast cancers were eligible for Enhertu. HER2-low patients, meanwhile, make up nearly 60 percent of breast cancer patients, according to one estimate..

有了这一批准，阿斯利康和第一三共显着扩大了符合HER2定向治疗条件的乳腺癌患者数量。使用HER2阳性的传统定义，10%至20%的乳腺癌符合Enhertu的条件。同时，据估计，HER2低的患者占乳腺癌患者的近60%。。

Enhertu, as an ADC, is designed to bind to the HER2 protein on the surface of tumor cells and release a cytotoxic payload, a DNA topoisomerase I inhibitor. That cytotoxic payload, however, is highly membrane permeable and can kill neighboring tumor cells that may not be overexpressing HER2, using a mechanism dubbed the 'bystander effect.' AstraZeneca and Daiichi Sankyo announced this year that a Phase III trial has shown their drug has activity in breast cancers with ultralow HER2 expression and the firms are also exploring Enhertu's activity in HER2-negative breast tumors..

Enhertu作为一种ADC，旨在与肿瘤细胞表面的HER2蛋白结合，并释放细胞毒性有效载荷，即DNA拓扑异构酶I抑制剂。然而，这种细胞毒性有效载荷具有高度的膜渗透性，可以通过一种称为“旁观者效应”的机制杀死可能不过度表达HER2的邻近肿瘤细胞阿斯利康（AstraZeneca）和第一三共（Daiichi Sankyo）今年宣布，一项III期临床试验表明，他们的药物对HER2表达超低的乳腺癌具有活性，两家公司也在探索Enhertu在HER2阴性乳腺肿瘤中的活性。。

'Part of the ADC works through binding to a target, but part of the ADC also works without requirement for a target,' said Paolo Tarantino, a breast medical oncologist at Dana-Farber Cancer Institute. 'There is this release of chemotherapy that is prolonged, more prolonged than traditional chemo, and it does not require antigen expression.

达纳法伯癌症研究所乳腺肿瘤内科医师保罗·塔伦蒂诺（PaoloTarantino）说，ADC的一部分通过与靶标结合而起作用，但ADC的一部分也不需要靶标这种化疗的释放时间比传统化疗延长，并且不需要抗原表达。

It's possible that there is activity of the drugs in HER2 0, HER2-null breast cancer due to the release of chemo irrespective of the antigen.'.

由于化学物质的释放，HER2 0，HER2无效乳腺癌中可能存在药物活性，而与抗原无关。”。

Measuring the biomarker

测量生物标志物

As AstraZeneca and Daiichi Sankyo try to broaden the market for Enhertu by reframing the HER2 biomarker from a binary, positive or negative, category to a spectrum based on IHC scores, providers on the ground are worried that, using currently available test methodologies, they won't be able to reliably identify patients who will benefit from treatment.

随着阿斯利康（AstraZeneca）和第一三共（Daiichi Sankyo）试图通过将HER2生物标志物从二元，阳性或阴性类别重新定义为基于IHC评分的光谱来拓宽Enhertu的市场，当地的供应商担心，使用目前可用的测试方法，他们将无法可靠地识别将从治疗中受益的患者。

Clinical guidelines bodies and many pathologists have not fully embraced the HER2-low category amid concerns that the lower limit of HER2-low expression, like tumors with IHC 1+ scores, cannot be reliably determined using IHC..

临床指南机构和许多病理学家尚未完全接受HER2低表达类别，因为担心使用IHC无法可靠地确定HER2低表达的下限，如IHC 1+评分的肿瘤。。

Several studies have explored reproducibility and inter- and intra-reader concordance for HER2 IHC results, but findings have varied widely, said David Rimm, a professor of pathology in the departments of pathology and oncology at Yale University School of Medicine.

耶鲁大学医学院病理学和肿瘤学系的病理学教授David Rimm说，一些研究已经探索了HER2 IHC结果的可重复性以及读者之间和读者内部的一致性，但发现差异很大。

'There are studies showing that we're pretty good at [distinguishing IHC] 3+ versus 2+ [tumors], but we're not so good at 0 versus 1,' Rimm said, adding that these studies have shown that pathologists tend to score low HER2 expression quite differently. 'That's pretty concerning that whether or not you get the drug depends on your pathologist.'.

里姆说：“有研究表明，我们很擅长[区分IHC]3+和2+[肿瘤]，但我们不擅长0对1，”他补充说，这些研究表明，病理学家往往对HER2低表达的评分有很大不同。”。

One international study from 2023 reported 'moderate' inter-observer agreement for HER2-low IHC scores, but the researchers acknowledged that separating cases between IHC 1+ and 2+ cases was 'problematic' in their study. When pathologists scored IHC 1+ and 2+ together as one HER2-low category, agreement was higher, at about 74 percent..

2023年的一项国际研究报告称，HER2低IHC评分的观察者之间存在“中等”的一致性，但研究人员承认，在他们的研究中，将IHC 1+和2+病例分开是“有问题的”。当病理学家将IHC 1+和2+评分为一个HER2低类别时，一致性更高，约为74%。。

Validation studies conducted by Roche for its Pathway companion diagnostic concluded that the assay was 'precise and reproducible for scoring HER2-low status,' the authors wrote. The validation study, which was based on more than 1,000 samples collected within DESTINY-Breast04, found that concordance between local and central labs in determining HER2-low tumors — those with scores of IHC 1+ or IHC 2+ and ISH-negative — was 77.6 percent.

作者写道，罗氏针对其Pathway companion诊断进行的验证研究得出结论，该测定法“对于HER2低状态的评分是精确且可重复的”。该验证研究基于DESTINY-Breast04中收集的1000多个样本，发现当地和中央实验室在确定HER2低肿瘤（IHC 1+或IHC 2+评分和ISH阴性）方面的一致性为77.6%。

.

.

The validation study also found that there was higher agreement between individual readers when it came to determining non-HER2-low specimens — grouped together as tumors with IHC 0 and 3+ scores — than the HER2-low specimens. Pathologist agreement was 99.7 percent for IHC 0 scores and 98.9 percent for IHC 3+ scores in the study.

验证研究还发现，当确定非HER2低标本（归类为IHC 0和3+评分的肿瘤）时，个体读者之间的一致性高于HER2低标本。在该研究中，病理学家对IHC 0评分的同意率为99.7%，对IHC 3+评分的同意率为98.9%。

The most scoring variability in the HER2-low category was with IHC 1+ slides. The majority of the discordance in this category, according to researchers, was due to readers scoring IHC 1+ tumors as IHC 2+. .

HER2低类别中得分变化最大的是IHC 1+载玻片。据研究人员称，这一类别中的大多数不一致是由于读者将IHC 1+肿瘤评分为IHC 2+。

However, the validation study did not explore the readers' ability to discern between IHC 0 and IHC 1+, a critical flaw in the study's design in Rimm's view, since research from him and others has suggested that distinguishing between the lower IHC scores is more difficult, and therefore, IHC 0and 3+ readings shouldn't have been grouped together.

然而，验证研究并没有探索读者辨别IHC 0和IHC 1+的能力，这是Rimm认为该研究设计中的一个关键缺陷，因为他和其他人的研究表明，区分较低的IHC分数更困难，因此，IHC 0和3+读数不应该分组在一起。

In Rimm's research, the overall percent agreement for reading IHC 0 results across 18 pathologists was only 25 percent. When asked to score IHC 1+ and 2+ slides separately, agreement among pathologists was also low. For IHC 1+ readings, agreement was less than 1 percent, reflecting the fact that pathologists agreed on only one IHC1+ case out of 102 in the study.

在Rimm的研究中，18位病理学家阅读IHC 0结果的总体一致率仅为25%。。对于IHC 1+读数，一致性不到1%，这反映了病理学家在研究中102例IHC1+病例中仅同意一例。

Agreement for IHC 2+ scoring was 3.6 percent..

IHC 2+评分的一致性为3.6%。。

However, when the researchers combined the 1+ and 2+ scores into one category, which reflects Enhertu's current HER2-low indication, pathologist agreement reached 27 percent. In comparison, agreement on IHC 3+ scores in the study was much higher, with half of pathologists scoring the same samples as IHC 3+.

然而，当研究人员将1+和2+分数合并为一个类别时，这反映了Enhertu目前的HER2低适应症，病理学家的一致性达到了27%。相比之下，研究中对IHC 3+评分的一致性要高得多，一半的病理学家评分与IHC 3+相同。

There was even higher agreement, 87 percent, when pathologists were asked to determine whether a sample was either IHC 3+ or not, reflecting the traditional HER2-positive category..

当病理学家被要求确定样本是否为IHC 3+时，更高的一致性为87%，反映了传统的HER2阳性类别。。

Rimm criticized the studies Enhertu's sponsors submitted to the FDA for the Pathway HER2 companion diagnostic, specifically the decision in these studies to measure precision and reproducibility between readers in two categories, IHC 1+/2+ and IHC 0/3+. He argued that the agency should have evaluated whether pathologists could use the assay to distinguish 0 from 1+, especially since many other studies have shown this to be more difficult..

Rimm批评了Enhertu赞助商提交给FDA的HER2伴侣诊断途径的研究，特别是这些研究中决定测量两类读者（IHC 1+/2+和IHC 0/3+）之间的精确度和可重复性。他认为，该机构应该评估病理学家是否可以使用该测定法来区分0和1+，特别是因为许多其他研究表明这更困难。。

One study exploring HER2 IHC scoring concordance among 16 pathologists found that the cases with the lowest agreement on HER2 IHC scores were all HER2-low or HER2-ultralow. The highest agreement, 86 percent, occurred when IHC categories were clustered into IHC 0 versus all others. Another study exploring agreement on HER2 IHC scoring on two different assays across six pathologists found a higher level of agreement in scoring HER2 IHC 0 from IHC 1+, 78.1 percent with Agilent's HercepTest and 72.2 percent with the Pathway anti-HER2 assay, but the researchers noted agreement was higher when pathologists were asked to distinguish IHC 2+ and IHC 3+, 91.9 percent for HercepTest and 86.3 percent with the Pathway anti-HER2 assay..

一项在16位病理学家中探索HER2 IHC评分一致性的研究发现，HER2 IHC评分最低的病例均为HER2低或HER2超低。当IHC类别与所有其他类别相比被归类为IHC 0时，最高的一致性为86%。。。

'[The companies] grouped the 3+, which we're really good at, with the 0, [with the rationale that] those are the patients that aren't qualified for the drug and the 1+ and 2+ patients are qualified,' he said. '[The FDA] didn't require the company to do what the pathologists actually have to do when they sit there in front of the slide.'.

他说，“（这些公司）将我们非常擅长的3+和0分组，[理由是]这些患者不符合该药物的资格，而1+和2+患者符合资格。”（FDA）没有要求该公司做病理学家坐在幻灯片前实际必须做的事情。

To make matters more challenging for pathologists, the American Society of Clinical Oncology and the College of American Pathologists haven't fully incorporated HER2-low into their joint guidelines as a new category. In 2023, nearly a year after Enhertu's US approval in HER2-low breast cancer, ASCO and CAP updated their recommendations for HER2 testing in breast cancer to acknowledge that there was a new indication for Enhertu as an option for breast cancers that don't overexpress HER2.

为了使病理学家更具挑战性，美国临床肿瘤学会和美国病理学家学院尚未将HER2-low作为一个新类别完全纳入其联合指南。2023年，在Enhertu获得美国HER2低乳腺癌批准近一年后，ASCO和CAP更新了他们对乳腺癌HER2检测的建议，以承认Enhertu作为不过度表达HER2的乳腺癌的一种选择有了新的指征。

However, they also concluded that there were limited data on the efficacy of HER2-targeted ADCs in IHC 0 tumors, and therefore it was premature to change the traditional HER2-positive/negative categories and add a new HER2-low or ultralow category. .

然而，他们还得出结论，关于HER2靶向ADC在IHC 0肿瘤中的疗效的数据有限，因此改变传统的HER2阳性/阴性类别并添加新的HER2低或超低类别为时过早。

Given Enhertu's approval for HER2-low breast cancer, however, the organizations recommended that the best practice for measuring the biomarker is for pathologists to report whether a patient's tumor is positive or negative for HER2 overexpression using the traditional categories, but then, include the semiquantitative IHC score and a footnote explaining how eligibility for Enhertu can be determined using IHC 1+ and 2+ scores.

。

.

.

The groups also recommended best practices for pathologists to distinguish IHC 1+ from IHC 0, which includes examining HER2 IHC-stained slides at high-power magnification of at least 40x; getting a second review from another pathologist when results are close to the 1+/0 threshold; validating tests using controls with a range of HER2 expression; and paying careful attention to the pre-analytic conditions during the processing of breast cancer tissue samples..

该小组还为病理学家推荐了最佳实践，以区分IHC 1+和IHC 0，其中包括以至少40倍的高倍放大率检查HER2 IHC染色的载玻片；当结果接近1+/0阈值时，从另一位病理学家那里获得第二次审查；使用具有一系列HER2表达的对照验证测试；并在乳腺癌组织样品处理过程中仔细注意预分析条件。。

For their part, AstraZeneca, Daiichi Sankyo, and their companion diagnostic partner Roche have mounted a large-scale education and training effort around gauging HER2-low based on the best practices outlined by ASCO and CAP. 'We understand [the challenge] because for the last 20 to 25 years, everybody was used to reading HER2 in one way,' said Shalini Singh, chief medical partner of oncology at Roche Diagnostics.

阿斯利康（AstraZeneca）、第一三共（Daiichi Sankyo）和他们的伴侣诊断合作伙伴罗氏（Roche）根据ASCO和CAP概述的最佳实践，围绕测量HER2-low展开了大规模的教育和培训工作罗氏诊断公司（RocheDiagnostics）肿瘤学首席医学合伙人沙利尼·辛格（ShaliniSingh）说：“我们理解（这一挑战），因为在过去的20至25年中，每个人都习惯于以某种方式阅读HER2。”。

'Everybody knows HER2 but this is a little bit of a shift [in the scoring method] and that's why the training is there. With [the training], I'm pretty confident that it can be done.'.

“每个人都知道她2岁，但这（在得分方法上）有点转变，这就是为什么要进行训练。通过[训练]，我非常有信心做到这一点。”。

The companies have taken several approaches to their training efforts, said Dan Switzer, head of Daiichi Sankyo's US oncology business division, using national commercial and medical field teams to conduct one-on-one engagements with oncologists; employing third-party training programs for pathologists; offering company-sponsored educational programs at larger oncology centers; and disseminating dozens of videos, resource guides, and case study walkthroughs of HER2-low cases by oncologists and pathologists through educational websites.

Daiichi Sankyo美国肿瘤学业务部门负责人Dan Switzer表示，这些公司已经采取了几种培训方式，利用国家商业和医疗领域团队与肿瘤学家进行一对一的接触；为病理学家采用第三方培训计划；在较大的肿瘤中心提供公司赞助的教育计划；并通过教育网站传播肿瘤学家和病理学家对HER2低病例的数十段视频，资源指南和案例研究演练。

.

.

The goal of these programs is two-fold: to raise awareness for the new category so pathologists know to more precisely score HER2 IHC results and to train pathologists on how to recognize HER2-low results.

这些计划的目标有两个：提高对新类别的认识，使病理学家能够更准确地对HER2 IHC结果进行评分，并培训病理学家如何识别HER2低结果。

Switzer said that one of the educational websites, HER2know.com, has reached more than 25,000 pathologists and that the companies are partnering with Roche to train pathologists on HER2-low scoring at the 25 largest labs in the US. The Roche Pathway HER2 assay is used by about 80 percent of the US lab market, he estimated..

Switzer说，其中一个教育网站HER2know.com已经接触到25000多名病理学家，这些公司正在与罗氏合作，在美国25个最大的实验室对病理学家进行HER2低分培训。他估计，美国大约80%的实验室市场使用罗氏途径HER2检测。。

'Those [25 high-volume] labs represent almost half of the market share in the country,' Switzer said. 'We're pretty fortunate the testing landscape is very concentrated so we can get to the high-volume labs relatively easily.'

斯威策说，这些（25个高容量）实验室几乎占全国市场份额的一半

The two main pillars of the companies' HER2-low awareness efforts, according to Switzer, are encouraging oncologists to ask pathologists to reevaluate patient samples, even older samples previously deemed HER2 negative, in light of the HER2-low category; and encouraging pathologists to get second opinions if they're unsure about an IHC result..

根据Switzer的说法，公司HER2低意识努力的两个主要支柱是鼓励肿瘤学家要求病理学家根据HER2低类别重新评估患者样本，甚至是以前被认为HER2阴性的较旧样本；并鼓励病理学家在不确定IHC结果时获得第二意见。。

Finally, the companies are also continuing to generate evidence supporting the HER2-low and ultralow categories that may be used to inform future clinical guidelines, said Omar Perez, head of medical diagnostics and US medical affairs for oncology at AstraZeneca. In December, Perez said that AstraZeneca researchers plan to report additional data on HER2-ultralow scoring..

阿斯利康医学诊断和美国肿瘤医学事务负责人奥马尔·佩雷斯（OmarPerez）表示，最后，这些公司还继续提供支持HER2低和超低类别的证据，这些证据可能用于为未来的临床指南提供信息。12月，佩雷斯表示，阿斯利康研究人员计划报告有关HER2超低评分的其他数据。。

However, before the field has a chance to become comfortable gauging HER2-low, the testing landscape may get even more complicated if AstraZeneca and Daiichi Sankyo gain FDA approval for Enhertu in the HER2-ultralow breast cancer setting. The FDA is expected to decide whether to approve Enhertu for treating HER2-ultralow advanced or metastatic breast cancer patients in the first quarter of 2025.

然而，在该领域有机会舒适地测量HER2低之前，如果阿斯利康和第一三共在HER2超低乳腺癌环境中获得FDA批准Enhertu，测试环境可能会变得更加复杂。。

The ultralow group would expand the Enhertu's eligibility to tumors with an IHC 0 result with faint, incomplete membrane staining for HER2 expression in less than 10 percent of tumor cells, also defined as an IHC score greater than 0 and less than 1. .

超低组将扩大Enhertu对IHC 0结果的肿瘤的资格，在不到10%的肿瘤细胞中HER2表达的微弱，不完全的膜染色，也被定义为IHC评分大于0且小于1。

'If approved [in HER2-ultralow], it will require a higher recognition of the IHC 0 to be truly 0,' Perez said. 'That will necessitate the separation of what is IHC 0 versus IHC 0 with some membrane staining. That category will [need] to be split and recognized by pathologists.'

佩雷斯说：“如果（在HER2 ultralow中）获得批准，将需要对IHC 0的认可度更高，才能真正达到0。”这将需要用一些膜染色分离IHC 0与IHC 0。这一类别[需要]被病理学家分割和认可。”

Exploratory data from the HER2-ultralow subgroup who received Enhertu in the DESTINY-Breast06 trial was presented earlier this year and demonstrated similar efficacy to the HER2-low subgroup, which had a median progression-free survival of 13.2 months on Enhertu.

在DESTINY-Breast06试验中接受Enhertu治疗的HER2超低亚组的探索性数据于今年早些时候公布，并显示出与HER2低亚组相似的疗效，HER2低亚组的中位无进展生存期为13.2个月。

If approved, Switzer noted that Daiichi Sankyo plans to take a similar education approach for the ultralow category at launch. The firm plans to emphasize using the companion diagnostic, which Roche is also developing, to diagnose patients and distinguish between IHC 0 and IHC 1 tumors. 'We feel we take a lot of responsibility and accountability to help pathology and oncology adopt these new practices as quickly as possible,' Switzer said, acknowledging that the companies have heard from pathologists that distinguishing HER2-ultralows from IHC 0s 'can be really challenging.' The closer a sample is to 'hugging that 0,' the more important it is to get second opinions, he stressed.

如果获得批准，Switzer指出，第一三共计划在推出超低级别时采取类似的教育方法。斯威策说，我们觉得我们承担了很大的责任和义务，以帮助病理学和肿瘤学尽快采用这些新做法，并承认这些公司从病理学家那里听说，区分HER2超低和IHC 0s“确实具有挑战性”他强调，样本越接近“拥抱0”，获得第二意见就越重要。

.

.

In Perez's view, scientific advances in the HER2-directed ADC space are happening quickly, and it may take some time for guidelines bodies to update testing recommendations to reflect the ultralow category if Enhertu is approved in that setting. 'It will require the separation of the IHC 0 category into two new categories, and given the fast pace of science, it does take some time to deploy [those changes], but hopefully with our partners, we'll be able to do that very quickly,' Perez said..

佩雷斯认为，HER2定向ADC空间的科学进步正在迅速发生，如果Enhertu在这种情况下获得批准，指导机构可能需要一些时间来更新测试建议，以反映超低类别。”佩雷斯说，这将需要将IHC 0类别分为两个新类别，鉴于科学的快速发展，部署（这些变化）确实需要一些时间，但希望与我们的合作伙伴一起，我们能够很快做到这一点。。

Rimm is more skeptical about the ability to reliably measure HER2-ultralow as many studies of HER2 IHC scoring have shown the highest discordance between scores of IHC 0 and 1+. Even the validation study of Roche's Pathway anti-HER2 (4B5) IHC test approved with Enhertu's approval in HER2-low breast cancer showed that distinguishing between 0 and 1+ was more challenging than other scores.

Rimm对可靠测量HER2超低的能力更加怀疑，因为许多关于HER2 IHC评分的研究表明，IHC 0和1+评分之间的不一致性最高。即使是经Enhertu批准用于HER2低乳腺癌的罗氏途径抗HER2（4B5）IHC测试的验证研究也表明，区分0和1+比其他分数更具挑战性。

In that study, nearly 20 percent of samples were scored HER2-low in local labs but later determined to be IHC 0 by central testing, versus only around 3 percent of samples deemed HER2-low locally and later determined to be HER2-positive centrally..

在该研究中，近20%的样本在当地实验室中被评为HER2低，但后来通过中心测试确定为IHC 0，而只有约3%的样本在当地被认为HER2低，后来被确定为HER2阳性。。

'Pathologists are doing their best, we're not trying to make mistakes here,' Rimm said. 'We're just asked to do the impossible.'

里姆说：“病理学家正在竭尽全力，我们不想在这里犯错。”我们只是被要求做不可能的事。”

The testing uncertainty has spilled over into the oncologists' workflow and challenging how they determine which patients to give Enhertu. ASCO and CAP recommended considering HER2 IHC results from multiple tissue samples, including previously collected samples, multiple primary tumor samples, or metastatic tissue samples.

测试的不确定性已经扩散到肿瘤学家的工作流程中，并挑战他们如何确定哪些患者给予Enhertu。ASCO和CAP建议考虑来自多个组织样本的HER2 IHC结果，包括先前收集的样本，多个原发性肿瘤样本或转移组织样本。

The organizations noted there may be heterogeneity in HER2 expression levels within these samples..

这些组织指出，这些样本中HER2表达水平可能存在异质性。。

Dana-Farber's Tarantino noted that there is a lot of confusion around HER2-low as pathologists adapt to reading these low IHC scores. Amid this confusion and in light of the latest guidelines, oncologists are now looking for HER2 expression in any patient biopsy, new or old.

达纳·法伯（DanaFarber）的塔伦蒂诺（Tarantino）指出，随着病理学家适应阅读这些较低的IHC分数，围绕HER2-low存在很多困惑。在这种混乱中，根据最新的指南，肿瘤学家现在正在寻找任何新的或旧的患者活检中HER2的表达。

'The way patients were enrolled in the trials was that they were required have one biopsy to test as HER2-low, but in our case, our patients often have several biopsies in the past, some of which are HER2-low, some of which are IHC 0, ' Tarantino said. 'There is a lot of discordance in this, and so usually we accept any biopsy that has proven to be HER2-low to use [Enhertu], which is a very broad usage.'.

塔伦蒂诺说：“患者参加试验的方式是，他们需要进行一次活检以检测HER2低，但在我们的病例中，我们的患者过去经常进行多次活检，其中一些是HER2低，一些是IHC 0。”这方面存在很多不一致之处，因此通常我们接受任何已被证明是HER2低的活检[Enhertu]，这是一种非常广泛的用法。

At Dana-Farber, he noted that their labs are beginning to report whether samples are IHC 0 with some membrane staining in anticipation of the potential HER2-ultralow approval for Enhertu. Most labs are not doing this yet, however, in the absence of Enhertu's approval in this setting or guidelines supporting it, he noted..

在Dana Farber，他指出，他们的实验室正在开始报告样本是否为IHC 0，并进行了一些膜染色，以预期Enhertu可能获得HER2超低批准。然而，他指出，大多数实验室还没有这样做，因为在这种情况下没有得到恩赫图的批准，也没有支持它的指导方针。。

Given the rapidly changing parameters for patients' eligibility for Enhertu, Tarantino said he's taking an 'open-minded' approach to prescribing the drug. 'If we find any sign of HER2 expression somewhere, we use the drug [Enhertu],' he said. 'If we don't find it, we try to do a new biopsy to see if we can find it.'.

塔伦蒂诺说，考虑到患者是否有资格服用恩赫图的参数迅速变化，他正在采取“开放的”方法开药他说：“如果我们在某处发现HER2表达的任何迹象，我们就会使用这种药物（Enhertu）。”如果我们没有找到它，我们会尝试进行新的活检，看看是否能找到它。”。

What's next for HER2 breast cancer management?

HER2乳腺癌管理的下一步是什么？

While AstraZeneca and Daiichi Sankyo used IHC to stratify patients in Enhertu trials, the companies are keeping an eye on advances in digital pathology and even new assays that may be used to refine patient selection.

虽然阿斯利康（AstraZeneca）和第一三共（Daiichi Sankyo）在Enhertu试验中使用IHC对患者进行分层，但两家公司正在关注数字病理学的进展，甚至可能用于改进患者选择的新检测方法。

'For the most patients to benefit from this targeted agent right now, we wanted to leverage what's currently available in practice and used, and it is well established in clinical practice that IHC, particularly in breast cancer, is widely utilized,' Perez said. 'That's not to say that other modalities can't be introduced, however with any new technology there is an adoption period.'.

佩雷斯说：“为了让大多数患者现在都能从这种靶向药物中受益，我们想利用目前在实践中可用和使用的药物，并且在临床实践中已经确立了IHC的广泛应用，特别是在乳腺癌中。”这并不是说不能引入其他模式，但是任何新技术都有一个采用期。”。

Perez highlighted various tools that AstraZeneca's translational research teams have explored for refining the measurement of HER2 expression, such as a deep learning-based quantitative continuous scoring (QCS) method for analyzing digital whole-slide images that are IHC stained. A retrospective analysis by AstraZeneca and Daiichi Sankyo researchers of breast cancer samples from a Phase I trial of Enhertu with the QCS method found it was more precise than IHC for selecting the patients who responded to treatment with Enhertu..

佩雷斯强调了阿斯利康的转化研究团队为改进HER2表达测量而探索的各种工具，例如用于分析IHC染色的数字整张幻灯片图像的基于深度学习的定量连续评分（QCS）方法。阿斯利康（AstraZeneca）和第一三共（Daiichi Sankyo）研究人员对Enhertu I期临床试验中使用QCS方法的乳腺癌样本进行的回顾性分析发现，在选择对Enhertu治疗有反应的患者方面，它比IHC更精确。。

He added that AstraZeneca has ongoing collaborations evaluating digital pathology methods for optimizing HER2-low and HER2-ultralow detection and that the company hopes to report data from this research at upcoming meetings.

他补充说，阿斯利康正在进行合作，评估数字病理学方法，以优化HER2低和HER2超低检测，该公司希望在即将举行的会议上报告这项研究的数据。

Rimm is also advancing a new, more sensitive assay for measuring HER2 expression. The mass spectrometry-based assay was designed specifically to measure low HER2 expression in a quantitative manner. It uses quantitative immunofluorescence methods to highlight the tumor cells expressing the HER2 protein.

Rimm还提出了一种新的，更灵敏的测定HER2表达的方法。基于质谱的测定法专门设计用于定量测量低HER2表达。它使用定量免疫荧光方法来突出表达HER2蛋白的肿瘤细胞。

Rather than trying to count cells or visually inspect the sample under a microscope like in IHC, pathologists only need to indicate the boundary of tumor tissues and normal tissue, then the test uses mass spectrometry to measure HER2 expression in the tumor sample..

病理学家不需要像IHC那样在显微镜下计数细胞或目视检查样品，只需要指示肿瘤组织和正常组织的边界，然后测试使用质谱法测量肿瘤样品中HER2的表达。。

In the validation study for Rimm's assay, his team determined the low HER2 expression range,  between 2 and 20 attomols per square millimeter, and used this threshold to measure HER2 expression of 364 breast cancer cases at Yale Cancer Center. They found that 67 percent of cases fell within that low HER2 range..

在Rimm分析的验证研究中，他的团队确定了HER2的低表达范围，即每平方毫米2至20阿托摩尔，并使用该阈值测量了耶鲁大学癌症中心364例乳腺癌病例的HER2表达。他们发现67%的病例属于低HER2范围。。

Rimm's lab has partnered with Danaher subsidiaries Leica Biosystems and Cepheid to conduct clinical trials of the assay and standardize its use. Rimm currently offers the assay as a laboratory-developed test out of the CLIA lab at Yale but can only conduct about 50 tests per month. He hopes the partnership with Danaher will enable more testing with the assay to meet increasing demand..

。Rimm目前在耶鲁大学的CLIA实验室提供实验室开发的检测方法，但每月只能进行约50次检测。他希望与Danaher的合作将使更多的检测能够满足不断增长的需求。。

Rimm's lab is just one of many exploring alternative methods for measuring HER2 expression. Researchers reported this year that a liquid biopsy circulating tumor DNA assay had 89.6 percent sensitivity for determining HER2-ultralow breast cancer samples. Researchers in the Netherlands evaluated a HER2 PET imaging method to identify HER2-low expressers or those who had whole-body HER2 heterogeneity.

Rimm的实验室只是许多探索测量HER2表达的替代方法之一。研究人员今年报告说，液体活检循环肿瘤DNA检测对确定HER2超低乳腺癌样本的敏感性为89.6%。荷兰的研究人员评估了HER2 PET成像方法，以识别HER2低表达者或具有全身HER2异质性的人。

Apis Assay Technologies reported results from a study of its Breast Cancer Subtyping Kit to detect mRNA expression of standard biomarkers (ERBB2, estrogen receptor, progesterone receptor, and Ki67) as a method to identify patients with low HER2 expression..

。。

'There are methods of HER2 quantification that are going to happen, whether it's my method or some other method,' Rimm said. 'I agree that IHC is a lot easier, but if it doesn't work or if people ultimately prove that being quantitative is more important, then quantitative [testing] will happen. It probably won't happen at every lab, but rather it will occur in the big central labs that have the ability to take on expensive machinery and take on expensive validation processes in order to give a better result.'.

我同意IHC要容易得多，但如果它不起作用，或者如果人们最终证明定量更重要，那么定量（测试）就会发生。它可能不会发生在每个实验室，而是会发生在大型中央实验室，这些实验室有能力采用昂贵的机器和昂贵的验证过程，以产生更好的结果。”。

The future of the HER2 biomarker and HER2-targeted treatment will also be undoubtedly affected by the indications AstraZeneca and Daiichi Sankyo advance Enhertu into next. The firms have begun studying the drug in hormone receptor-positive, HER2-negative unresectable or metastatic breast cancer patients in the Phase III DESTINY-Breast15 trial, which has two cohorts of HER2-low and HER2-negative, or IHC 0, breast cancer patients.

毫无疑问，HER2生物标志物和HER2靶向治疗的未来也将受到阿斯利康和第一三共推进Enhertu进入next的适应症的影响。这些公司已经开始在III期DESTINY-Breast15试验中研究激素受体阳性，HER2阴性不可切除或转移性乳腺癌患者的药物，该试验有两组HER2低和HER2阴性或IHC 0乳腺癌患者。

.

.

Tarantino suggested that with the current data on Enhertu showing activity in each of these HER2 expression categories, it may be the case that almost all breast cancer patients could benefit from this drug. 'Probably you can see a benefit with this drug irrespective of HER2 expression,' he said. 'To some extent, the HER2 expression can further boost the activity of [Enhertu], but even in the absence of it, you can have activity.'.

塔伦蒂诺（Tarantino）建议，目前关于Enhertu的数据显示，这些HER2表达类别中的每一种都有活性，因此几乎所有乳腺癌患者都可能从这种药物中受益。”他说：“不管HER2的表达如何，你都可能看到这种药物的益处。”。

The companies have not disclosed when they expect to report the first data from DESTINY-Breast15 trial and the HER2 IHC 0 cohort, but the trial is recruiting patients worldwide and has an estimated completion date in 2027. 'We also know that even IHC 0 patients have minuscule levels of HER2 expression, so it truly is not binary, and that's the rationale of going after the IHC 0s,' Switzer explained.

这些公司尚未透露何时将报告DESTINY-Breast15试验和HER2 IHC 0队列的第一批数据，但该试验正在全球招募患者，预计完成日期为2027年。”我们还知道，即使是IHC 0患者的HER2表达水平也很低，因此它确实不是二元的，这就是追求IHC 0的理由，”斯威策解释道。

'Potentially, this drug is so sensitive to the HER2 protein that all it takes are these tiny amounts of HER2 for the drug to attack the cancer cells with its payload.'.

“潜在地，这种药物对HER2蛋白如此敏感，以至于药物只需要这些微量的HER2就可以用其有效载荷攻击癌细胞。”。

Tarantino was also part of research that aimed to characterize whether HER2-low was a distinct subtype of breast cancer with different clinical features from HER2-negative disease. After exploring clinical pathologic features, genomic profiles, and the prognosis of HER2-low versus HER2-negative breast cancer patients, his team found no major differences to define a new subtype.

塔伦蒂诺也是研究的一部分，旨在表征HER2-low是否是乳腺癌的一种独特亚型，具有与HER2阴性疾病不同的临床特征。在探索了HER2低与HER2阴性乳腺癌患者的临床病理特征，基因组特征和预后后，他的团队发现在定义新的亚型方面没有重大差异。

.

.

'As soon as there is a new drug for this new category called HER2-low breast cancer, everybody starts thinking that HER2 low is something distinct or a subtype of breast cancer, ' Tarantino said. 'What was apparent is that it's basically a continuum of HER2 expression and without striking differences among those that express low HER2 or zero HER2.

塔伦蒂诺说：“一旦有一种新的药物治疗这一新类别的HER2-low乳腺癌，每个人都会开始认为HER2-low是乳腺癌的一种独特或亚型。”显而易见的是，它基本上是HER2表达的连续统一体，并且在表达低HER2或零HER2的那些之间没有显着差异。

This is something that helps us to consider treatment with this drug in HER2 0 patients.'.

这有助于我们考虑在HER2 0患者中使用这种药物进行治疗。”。