Dr. Debu Tripathy is a professor and chairman of the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in Houston.

Dr. Debu Tripathy

Dr. Debu Tripathy discussed the importance of understanding the distinctions between HER2-low and HER2-ultralow breast cancer.

Understanding the Distinction Between HER2-Low and HER2-Ultralow Breast Cancer 

All patients with breast cancer who may be candidates for antibody-drug conjugate therapy should undergo HER2 testing to determine eligibility for Enhertu (fam-trastuzumab deruxtecan-nxki) — an agent that was 

, according to Dr. Debu Tripathy, who says that the agent has shown durable responses and superiority over standard chemotherapy, though its efficacy compared with targeted therapies remains unclear.

In an interview with CURE®, Tripathy discussed the importance of understanding the distinctions between HER2-low and HER2-ultralow, as well as highlighted how patients can discuss testing with their oncologists. Tripathy is currently a professor and chairman of the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in Houston, and the editor-in-chief of CURE®.

The first thing is to make sure that their tumor is being tested for HER2 content, everybody's tumor who may be a candidate for antibody-drug conjugate therapy should be tested because it leaves open the possibility of using Enhertu. We know that, in general, the data has shown that patients can get durable responses to this agent, and it is better than the standard-of-care chemotherapy. [However], we don't know how it may stand up against targeted therapies; this is an area that needs further study.

We do use certain targeted therapies, like PI3K targeted therapy in patients that have alterations in that pathway and so on. But when it comes to shifting over to chemotherapy, we do know from the DESTINY-Breast series of trials that this really remains a viable and strong possibility to use this antibody-drug conjugate. That's why it's important that we know that we at least need to do HER2 testing.

Secondly, it's important that the pathologists that are doing the testing are equipped, knowledgeable and able to report to you the level of HER2-positive versus -negative. Within the negative groups, which ones are HER2-low, that would be 1+ and 2+ — the 2+, of course, being FISH negative — those would be the HER2-low that we are more familiar with, but now the HER2-ultralow category is being added. This really does require … that the pathologist is familiar with the ultralow concept, [consisting of] this very faint, partial membrane staining, and is something that they should be able to report out. That is an important distinction, because those patients are also going to be eligible for treatment with the Enhertu [agent].

Transcript has been edited for clarity and conciseness.

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Videos

Dr. Debu Tripathy discusses the FDA approval of Enhertu in unresectable or metastatic hormone receptor HR+, HER2-low or -ultralow breast cancer.

An Expert Explains the Enhertu Approval in HER2-Low and -Ultralow Breast Cancer

On Jan. 27, the Food and Drug Administration (FDA) 

granted approval to treatment with Enhertu

 (fam-trastuzumab deruxtecan-nxki) for patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low or -ultralow breast cancer that has progressed following at least one endocrine therapy in the metastatic setting.

This approval was supported by findings from the 

 which were shared in June 2024. In the study, Enhertu reduced the risk of disease progression or death by 36% compared with chemotherapy in 866 patients with chemotherapy-naïve, HR-positive, HER2-low or -ultralow metastatic breast cancer. The median progression-free survival was 13.2 months with Enhertu versus 8.1 months with chemotherapy. The objective response rate in the overall population was 62.6% for Enhertu versus 34.4% for chemotherapy, with complete responses occurring in 2.5% and 0% of patients, respectively.

Progression-free survival: the time during and after treatment that a patient with cancer lives without the disease worsening.

Objective response rate: the percentage of patients whose cancer disappears or shrinks from treatment.

Complete response: when there are no detectable signs of cancer in the body after treatment.

In an interview with CURE®, Dr. Debu Tripathy discussed the regulatory approval and what it could mean for eligible patients within the landscape. Tripathy is a professor and chairman of the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in Houston, and the editor-in-chief of CURE®.

The recent approval for Enhertu in patients that have HR-positive, and HER2-low or -ultralow breast cancers expands the number of patients that can benefit from treatment. We've [seen] from some of the earlier trials, like the DAISY trial — which was a small phase 2 trial that enrolled some patients with totally HER2-negative breast cancers — that some responses [have been] seen. It's difficult to quantify very low HER2 since most assays are based on declaring patients to be truly HER2-positive by the conventional [criteria], where you have either amplification of the gene or overexpression. The very low levels of detection are ultimately, I think, going to require special techniques. However, those who are experts at reading it can do this with a normal, generally approved assay for HER2 determination.

In some of the early observations, this was formally studied in a large phase 3 randomized trial, the DESTINEY-Breast06 trial, which enrolled HER2-low patients, but it also enrolled a cohort of patients that were HER2-ultralow. This is defined as very weak staining in less than 10% of cells, and anything more than that is considered HER2-low. Ultralow states that there has to be some epithelial staining. It can even be partial staining of a part of the cell, but the ones that are truly totally negative are true zeros. That is the distinction to be made; we're now expanding it to this ultralow group.

The DESTINEY-Breast06 trial was a randomized trial comparing standard of care treatment versus Enhertu in patients who had progressed on endocrine therapies and had low or ultralow [disease]. That study was overall positive, including a subset of patients with ultralow, although that subset was small and didn't have the statistical power on its own to show that, but as time goes on, there may be more power as we get more events in that overall cohort.

Dr. Debu Tripathy

Understanding the Distinction Between HER2-Low and HER2-Ultralow Breast Cancer

An Expert Explains the Enhertu Approval in HER2-Low and -Ultralow Breast Cancer

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