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Reclassification of many HER2-negative breast cancers as HER2-low, combined with a new targeted treatment option for this subset, stands to benefit a wide swath of patients with metastatic or unresectable cases, but raises many clinical questions as well.

The FDA recently approved the first therapy targeted against HER2-low breast cancer -- trastuzumab deruxtecan (T-DXd, Enhertu), an antibody drug conjugate given as an IV infusion for patients with unresectable or metastatic HER2-low disease.

"The approval of trastuzumab deruxtecan has now allowed a new strategy for us to better target and treat breast cancer," said Erica Stringer-Reasor, MD, of the University of Alabama at Birmingham. "Previously we had a binary classification for HER2 breast cancer; tumors were positive or negative for the protein. Now, with this HER2-low category there is a spectrum of classifications."

Low-level expression of HER2 is defined immunohistochemically as 1+ or 2+ with lack of HER2 gene amplification measured by in situ hybridization. Some patients with HER2-low disease can have what was traditionally called triple-negative breast cancer (TNBC) or can have hormone-receptor positive disease.

HER2-positive disease is defined as 3+ on immunohistochemistry. That encompasses about 15% to 20% of patients diagnosed with breast cancer each year. The HER2-low category is expected to include up to an additional 55% of patients formerly categorized as having HER2-negative disease.

A New Option

"If a patient goes from the category of HER2-negative to HER2-low, that is a big change in what options they would have available to them now," said Melissa McShane, MD, of Fox Chase Cancer Center in Philadelphia.

Patients with HER2-low breast cancer are eligible for trastuzumab deruxtecan if they have received a prior chemotherapy in the metastatic setting or their cancer returned during adjuvant chemotherapy or within 6 months of completing it.

Patients treated with trastuzumab deruxtecan in the phase III saw significant improvements in progression-free survival and overall survival compared with physician's choice of chemotherapy. Among the 89% of participants who had hormone-receptor positive disease, the median progression-free survival was 10.1 months with trastuzumab deruxtecan compared with 5.4 months with physician's choice. Median overall survival was 23.9 versus 17.5 months, respectively.

Patients with hormone receptor positive and HER2-low disease will traditionally start on first-line endocrine therapy; usually this is an aromatase inhibitor or tamoxifen along with a CDK4/6 inhibitor. In DESTINY-Breast04, about 70% of patients with hormone-receptor positive disease had prior CDK4/6 therapy.

Subsequent treatment would depend on the tumor mutational status, McShane said. For example, a patient with PIK3CA-mutated disease might have second-line treatment with alpelisib (Piqray) plus fulvestrant.

Patients with TNBC typically receive upfront chemotherapy, plus or minus immunotherapy depending on the tumor's PD-L1 status. They may also receive treatment with the antibody drug conjugate sacituzumab govitecan (Trodelvy). McShane pointed out that although patients with TNBC were included in DESTINY-Breast04, it was a smaller number.

Among all patients in the study, median progression-free survival was 9.9 months for trastuzumab deruxtecan compared with 5.1 months for physician's choice; median overall survival was 23.4 versus 16.8 months, respectively.

"Mortality was reduced by 36%," Stringer-Reasor said. "Patients who received this targeted therapy were observed to live better and longer on this targeted therapy."

How to Incorporate

Stringer-Reasor and McShane have both already begun to incorporate this therapy into clinical practice.

"This is especially important right now for patients with HER2-low disease who have TNBC," McShane said. "I am currently looking to use this in patients who have progressed on one line of chemotherapy, plus or minus sacituzumab govitecan."

However, McShane said one must look at the data for TNBC with a grain of salt given that only about 10% of patients (63 total) in the DESTINY-Breast04 trial were in that category.

"There will be ongoing discussions regarding how we sequence this with sacituzumab govitecan for patients with HER2-low disease that are hormone receptor negative," McShane said.

For patients with hormone receptor-positive disease, trastuzumab deruxtecan was studied in those who had progressed through either two lines of endocrine therapy or one line of endocrine therapy and a line of chemotherapy.

"Whether or not we move it up is something we will need to reevaluate," McShane said. "We have to begin to figure out the nuances on how to incorporate this."

In the subgroup of patients with hormone receptor-positive disease, strong data support the use of CDK4/6 inhibitors with endocrine-based therapy, she noted, and there are also data showing overall and progression-free survival advantages with ribociclib (Kisqali) and patients tolerating treatment for an average of 2 years.

"We would definitely not be considering [trastuzumab deruxtecan] a first-line therapy for these patients," she said. "But for patients having rapid progression through hormone therapy, you might consider doing a more targeted therapy like trastuzumab deruxtecan sooner, because the tumor is proving to be endocrine resistant."

There will also be discussion about whether patients need to receive chemotherapy at all prior to trastuzumab deruxtecan.

Side Effects

The adverse effects familiar to clinicians from use of trastuzumab deruxtecan for its indication in treatment of HER2-positive disease are also seen in HER2-low disease: nausea, hair loss, vomiting, constipation, low blood counts, and a decrease in appetite, Stringer-Reasor noted.

The drug also carries a boxed warning for the risk of interstitial lung disease, for which patient education of the signs and symptoms and early detection is key, according to McShane.

"Being aware of the potential for interstitial lung disease and addressing it as soon as concern arises allows us to initiate corticosteroids and hopefully prevent a fatal event," she said. "Any signs of shortness of breath or hypoxia and the medication should be held until further investigation is done, and there should be a low threshold for starting high-dose steroids."

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