A recent study is aiming to understand and classify the HER2 protein levels in breast cancer, particularly those with early-stage, estrogen receptor-positive (ER-positive) breast cancer.
The trial, which was a part of the 2025 American Society of Oncology (ASCO) Annual Meeting, suggests that by re-examining existing ways of interpreting HER2 levels, more patients may benefit from the efficacy seen with antibody-drug conjugates (ADCs) for the treatment of HER2-low breast cancer.
“There appears to be a potential need for re-examination of existing HER2 interpretations to define candidates for Enhertu (trastuzumab deruxtecan; TDXd) treatment,” the researchers wrote in their abstract.
Providers know that ADCs can be very effective for breast cancers that have low levels of a protein called HER2; however, there has been debate around how to classify HER2-low breast cancers, and whether they are truly different from cancers with no HER2 or very, very low, or ultra-low HER2.
What did the researchers do?
In the study, the researchers looked back at information from 849 patients who had early-stage breast cancer that was ER-positive and initially classified as HER2-negative, who also underwent Oncotype DX testing after surgery.
They then re-examined the tissue samples from these patients to specifically evaluate their HER2 levels using a method called immunohistochemistry (IHC). Under re-evaluation, the researchers used a more detailed classification system that included ultra-low HER2 expression. They then compared these new HER2 classifications to other important information about the patients’ cancers, like how aggressive the cancer was, and how well patients did over time.
Key findings: A closer look at HER2 levels
When the researchers re-evaluated the HER2 levels, they found that 15.2% were reclassified as “HER2-null” (meaning no HER2), 28.4% were reclassified as HER2-ultralow, and 45.5% and 11%, respectively, were reclassified as HER2-1+ and HER2-2+ (which fall under the HER2-low category). Moreover, among the cases that were originally thought to have no HER2, nearly half (45.5%) were actually reclassified as HER2-ultralow when a more detailed look was taken.
When looking at the Oncotype DX test results, which predict the risk of cancer returning, the study found that a lower percentage of HER2-low patients were in the high-risk group compared to HER2-null patients. Using an Oncotype Dx score of 26, 20.9% with HER2-null, 13.3% with HER2-ultralow, and 12.7% with HER2-low were considered high risk.
After 44 months of follow-up, patients identified as HER2-low demonstrated improved disease-free survival (meaning their cancer was less likely to come back), reducing the risk for disease recurrence by 67%, compared with those classified as HER2-null. Those with HER2-ultralow disease showed no significant difference in disease-free survival. However, according to a multivariable analysis, neither HER2-low nor ultralow had significant differences in Oncotype Dx high-risk proportions or survival outcomes.
One of the key findings was that patients whose cancers were reclassified as HER2-low showed some important differences compared to those classified as HER2-null. HER2-low cancers were more likely to have stronger levels of ER expression (which means they respond well to hormone therapy), a healthy version of a gene called p53 (which helps control cell growth), and lower levels of a protein called Ki-67 (which indicates slower cancer growth).
“This difference is attributable to variations in clinicopathological features observed in HER2-low cases, and neither HER2 ultra-low nor HER2-low demonstrated independent prognostic significance when compared to HER2-null,” the researchers wrote.
In addition, these differences suggest that HER2-low cancers might behave differently than HER2-null cancers.
What does this mean for patients?
While the initial survival findings for HER2-low were promising, when the researchers took into account other factors that can influence survival, they found that neither HER2-low nor HER2-ultralow independently predicted a better outcome compared to HER2-null. This means that while HER2-low cancers have some different features that are linked to a better outlook, these differences seem to be due to other characteristics of the tumor, rather than HER2-low status itself being a direct predictor of survival when other factors are considered.
Despite this, the researchers believe that these findings highlight a “potential need for re-examination of existing HER2 interpretations.” They suggested that a more careful and detailed classification of HER2 levels could help doctors better identify which patients might benefit from new treatments like Enhertu, a type of antibody-drug conjugate, leading to more personalized and effective treatment plans for patients.
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