Q&A: Understanding HER2- Low Breast Cancer

It is estimated that nearly half of breast cancer cases previously classified as HER2-negative disease can now be redefined as HER2-low. In this interview, Dr Karl J. D’Silva discusses the emerging evidence surrounding this new breast cancer subtype and how it can lead to better patient care.
Could you provide a brief overview of the pathologic features that differentiate HER2-low breast cancer from other subtypes?
Breast cancer has traditionally been classified as HER2-positive or HER2-negative, based on immunohistochemistry (IHC) scoring or gene amplification. HER2-positive breast cancer is typically defined as IHC3+ or IHC2+ with positive in situ hybridization (ISH) results. These cases are routinely treated with HER2-targeted therapies such as trastuzumab- and pertuzumab-based regimens. HER2-negative breast cancer is characterized as IHC0, IHC1+, or IHC2+. Historically, these patients have not received HER2-targeted therapy.
Recently, a subset known as HER2-low breast cancer has emerged. This is defined as IHC1+ or IHC2+ with no ERBB2 amplification, distinguishing it from HER2-positive cancer. HER2-low tumors express lower levels of the HER2 protein and may not be eligible for traditional HER2-targeted therapies.
There was a trial called DESTINY-Breast04,[1] which demonstrated that the HER2/neu-targeted antibody drug conjugate trastuzumab deruxtecan improves survival in patients with previously treated advanced metastatic breast cancer. This trial led to the approval of trastuzumab deruxtecan, both in the United States as well as the European Union, after prior chemotherapy in the metastatic setting or disease recurrence within 6 months of adjuvant chemotherapy.
This was the first targeted therapy approved for this particular group of patients, which account for 45%-55% of all breast cancer,[2,3,4] and is important because understanding HER2-low status is critical for refining treatment strategies, exploring new therapeutic options, and achieving better oncologic outcomes, especially in postmenopausal patents. This trial represented a big change in the clinical landscape, but we find it’s also presenting a new challenge, including finding patients with HER2/neu-low breast cancer.
Can you discuss the European Society for Medical Oncology (ESMO) clinical consensus for the emergence of HER2-low breast cancer, specifically regarding its biology and clinical management? How might this consensus inform the design of future of clinical trials?
The ESMO consensus[5] acknowledges that HER2-low breast cancer represents a distinct category that impacts both its biological characterization and clinical management. Recent real-world studies suggest that HER2/neu-low tumors are significantly associated with higher estrogen receptor (ER) and lower progesterone receptor (PR) expression in ER-positive cohorts. In ER-negative cohorts, HER2/neu-low tumors are associated with a lower tumor grade.
Additional research indicates that HER2/neu-low and ER-positive early-stage breast cancer was also associated with a lower tumor grade and lower Oncotype DX recurrence scores. The PR expression score was associated with an outcome which was found to be higher with the ER-positive cohort. However, there was no substantial molecular difference between the HER2/neu-low and the HER2/neu-0 tumors after correcting for the expression of the hormone receptors.
Therefore, HER2-low should not be considered as a distinct molecular entity, but rather a heterogeneous group of tumors with the biology primarily driven by the presence or absence of hormone receptor expression. Thus, the current consensus is that we have to better differentiate between HER2-low and HER2-zero patients to tailor treatment strategies more effectively.
The National Comprehensive Cancer Network (NCCN) has updated its breast cancer guidelines to address treatment of patients with HER2-low disease. Could you please discuss this update and the impact it could have on patient care?
The 2024 NCCN Guidelines’ expansion of treatment options for HER2-low metastatic breast cancer is a significant advancement, especially considering that many of these patients were previously classified as HER2-negative and had limited treatment options.[6] Most notably, we have found that the second-generation antibody drug conjugates (ADCs) represent the only class of HER2/neu-targeted therapy that has shown clinically meaningful activity in these patients. This is primarily related to the delivery of the cytotoxic molecule rather than the blockade of the HER2/neu pathway. The effectiveness of these therapies depends on the ability to transport the drug right into the nucleus of the cell. This targeted delivery mechanism allows the drug to enter cancer cells and release its cytotoxic agent, even when HER2 expression is low. The key difference from first-generation therapies is that the therapeutic activity of these ADCs is less dependent on high HER2 expression levels and more on the efficient intracellular delivery of cytotoxic drugs.
This approach sets forth a new strategy in the management of patients with HER2-low breast cancer, and evidence shows this in the phase 2 DAISY trial, which evaluated treatment options for patients not eligible for traditional HER2-targeted therapies, as well as in the phase 3 DESTINY-04 trial.[1,7]
At this year’s American Society of Clinical Oncology (ASCO) annual meeting, the efficacy of neoadjuvant endocrine therapy for HER2-low breast cancer was a large focus. Could you please discuss these findings?
Neoadjuvant endocrine therapies are crucial for treating hormone receptor–positive patients. There has been ongoing debate about whether HER2-low tumors represent a distinct category that requires a unique treatment approach, particularly regarding ADCs targeting HER2-low tumors.
Recent findings, presented at ASCO 2024, highlight the importance of adopting strategies effective in metastatic disease to early-stage treatments, noting favorable outcomes.[8] The study adhered to ASCO Clinical Trials Network guidelines for HER2-low tumors and analyzed data from the National Cancer Database, focusing on patients with stage I-III ER-positive breast cancer who received neoadjuvant endocrine therapy for at least 90 days, up to a maximum of 270 days. Patients who had prior neoadjuvant chemotherapy or other malignancies were excluded.
The results indicated that HER2/neu-low tumors had greater significant clinical response to neoadjuvant endocrine therapy when compared with HER2/neu-negative disease. This suggests that HER2-low tumors might benefit from tailored treatment approaches in the neoadjuvant setting.
Which characteristics of HER2-low breast cancer affect the risk for disease recurrence and prognosis, and how might these insights guide patient management strategies?
HER2-low breast cancer is characterized by higher likelihood of hormone receptor positivity, grade 2 tumors, and ductal histology. These features make HER2-low disease a distinct clinical entity with unique molecular, genetic, and histologic traits.
While initial studies suggested that HER2-low breast cancer might have a more favorable prognosis compared with HER2-positive tumors, ongoing research is providing a clearer understanding of its clinical significance. Emerging data indicate that HER2-low breast cancer can have a better outcome than initially expected, although its prognosis can vary, based on molecular markers like hormone receptor status and tumor microenvironment.
This evolving knowledge is laying the foundation for improved classification systems and more tailored therapeutic strategies, ultimately enhancing patient management. As we continue to learn more about the biology of HER2-low disease, we’ll be able to better shape patient management by identifying subgroups that could benefit from novel treatments, including ADCs, while also guiding decisions about endocrine therapy and chemotherapy for early-stage and metastatic disease.