Enhertu Before Surgery Falls Short in HER2-Low Early Breast Cancer

Giving Enhertu (trastuzumab deruxtecan) before surgery did not lead to enough patients having no remaining cancer at the time of surgery to change treatment for HER2-low, hormone receptor (HR)-positive early breast cancer, according to findings from the TALENT trial presented at the 2026 ESMO Congress.

In the trial, patients received Enhertu alone, Enhertu with Arimidex (anastrozole) or Enhertu followed by docetaxel and cyclophosphamide chemotherapy before surgery. Fewer than 10% of patients in any group had a pathologic complete response, meaning no invasive cancer was found at surgery. Those rates were 7% with Enhertu alone, 3% with Enhertu plus Arimidex and 9% with Enhertu followed by chemotherapy.

In an interview with CURE, Dr. Sara Hurvitz, professor and senior vice president of the Clinical Research Division at Fred Hutch Cancer Center and the University of Washington in Seattle, explained what HER2-low means, what the findings mean for patients and which side effects to watch for.

This interview has been edited for length and clarity.

CURE: What does HER2-low mean, and how can patients find out if their breast cancer falls into this group?

Hurvitz: HER2-low is simply describing whether or not a patient’s tumor has some expression of a protein on it called HER2. We’ve known for maybe 40 years or so that about 15% to 20% of patients with breast cancer have way too much HER2 expressed on the cancer cell, and that’s called HER2-positive breast cancer.

But in more recent years, drugs that target low levels of HER2 — one in particular called T-DXd [Enhertu] — have been developed that use even small amounts of HER2 on the breast cancer cell to target chemotherapy to the cancer cell, and that’s called HER2-low. It’s not overexpressing, but there’s just enough of it on the cancer cell to direct a targeted therapy to it.

What could these results mean for patients who get treatment before surgery?

At this point, these results do not change standard practice for patients with HER2-low, hormone receptor-positive early breast cancer. We were hoping that T-DXd given before surgery would significantly improve the percentage of patients who had all the disease respond and go away by the time of surgery. But in fact, fewer than 10% of patients experienced a pathologic complete response.

We did learn a lot from a biomarker standpoint that may help us in the future select patients who could have a de-escalated approach like this. But it’s not ready for prime time now.

Did adding hormone therapy to Enhertu help?

The objective response rates were fairly similar for patients treated with T-DXd or T-DXd plus anastrozole: 62% with T-DXd and 66% when you added anastrozole. That doesn’t demonstrate a significant improvement.

And when you look at pathologic complete response rates, the lowest were in the patients who received T-DXd with anastrozole. Only 3% of patients had a pathologic complete response, compared with 7% of patients with single-agent T-DXd. So there actually may be some antagonism between [T-DXd] and endocrine therapy, which has been seen in other studies, and so I personally am not in favor of using endocrine therapy with T-DXd based on these results.

Could Enhertu one day replace or shorten chemotherapy for some patients?

The sequencing of T-DXd followed by docetaxel and cyclophosphamide yielded a pathologic complete response rate of 9% and an overall response rate by imaging of 72%. While those were numerically higher than T-DXd alone or with anastrozole, they didn’t lead to a clinically meaningful change in pathologic complete response rate to the point where this would become a standard regimen.

We did do some biomarker analyses, though, and showed that baseline HER2 protein levels may correlate with pathologic complete response. So in the future, if these data are validated, we might be able to select patients who would benefit most from T-DXd-based therapy, and that could be very promising in terms of a de-escalation strategy. But they have to be validated.

What side effects should patients know about with Enhertu, and when should they call their care team?

T-DXd is currently only used in the metastatic setting for HER2-low breast cancer. The most common side effect is nausea, so patients should be receiving multiple anti-nausea medications up front. It can also cause fatigue and low blood counts.

Around 10% of patients can experience what’s called interstitial lung disease, which is inflammation of the lungs. Any patients who experience cough, shortness of breath or fever should immediately notify their physician, because the therapy should be stopped at least until it’s investigated and interstitial lung disease is ruled out.

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