The HER2-low and HER2-ultralow breast cancer subtype designations have led to a changed landscape in HER2-directed therapies, as well as a desire for more sensitive assays that may better quantify HER2 expression.
The HER2-low subcategory has particular relevance, since more than 50% of breast cancers are defined as HER2-low.
From Binary to Multiple Tiers
A HER2-positive status reflects breast cancer cells with extra copies of the HER2 gene, or higher expression of HER2 proteins on the surface of these cells, which may lead to a more aggressive cancer biology. Conversely, a HER2-negative status reflects cells with typical amounts of HER2 proteins.
"Until recently, the results of HER2 testing were binary: classified as either positive or negative. Over the years, efforts have increased to refine and create greater precision around determination of HER2 status," said Erica Mayer, MD, MPH, of Dana-Farber Cancer Institute in Boston.
The HER2-low and -ultralow breast tumor classifications were previously considered to be HER2 negative. HER2 classification relies on immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), which examines the number of copies of the HER2 gene inside a cancer cell. "On FISH, HER2 positive is defined as at least two times the number of copies of HER2 genes compared to a control gene," explained Mayer.
IHC uses a scoring system of 0 to 3 to designate HER2 status, in which a score of 0 represents no detectable amount of HER2 protein, and a score of 3 represents excessive amounts. For patients with an IHC score of 2+, a FISH test can delineate between HER2-positive and HER2-low status.
- An IHC score of 3+ is considered HER2 positive
- An IHC score of 2+ is considered HER2 positive with a positive FISH test and HER2 low with a negative FISH test
- An IHC score of 1+ is considered HER2 low
- An IHC score of >0 but <1 is considered HER2 ultralow
- An IHC score of 0 is considered HER2 negative
Underestimating HER2 Expression
Current pathologic methods may underestimate the proportion of breast cancers that express low levels of HER2. "Assessment of HER2 expression by IHC has a lot of subjectivity and is semiquantitative," said Rachel Layman, MD, of the University of Texas MD Anderson Cancer Center in Houston.
The distinction between IHC 1+ and IHC 0 is particularly prone to subjectivity. In a , the researchers noted that manual annotation, the standard practice for evaluating and quantifying HER2 IHC in routine practice, is observer dependent and liable to subjective error.
"The problem is particularly acute in relation to the distinction between IHC 1+ (incomplete membrane staining that is faint or barely perceptible and within >10% of the invasive tumor cells) and IHC 0 (no staining or membrane staining that is incomplete and is faint or barely perceptible and within ≤10% of the invasive tumor cells)," they wrote.
Available IHC assays may be suboptimal for detecting low levels of HER2 protein expression, "and could result in false-negative and false-positive test determinations around the IHC 0/IHC 1+ threshold that would incorrectly influence treatment recommendations and potentially impact data from ongoing clinical trials that still rely on them," noted authors of a in breast cancer from the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP).
The guidelines were informed by findings from the DESTINY-Breast04 trial involving 494 patients with HER2-low (defined as a score of 1+ on IHC analysis or as an IHC score of 2+ and negative results on FISH) metastatic breast cancer who had received at least one previous line of chemotherapy and were randomized to the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd; Enhertu) or physician's choice of chemotherapy.
Patients in the T-DXd group had a median progression-free survival (PFS) of 9.9 months compared with 5.1 months among those receiving physician's choice of chemotherapy (P<0.001) and a median overall survival of 23.4 versus 16.8 months, respectively (P=0.001).
"The patients enrolled into DESTINY-Breast04 were technically HER2 negative [by old criteria]," said Mayer. "They were not thought of as having HER2-driven disease, so they were not receiving other HER2-directed therapies."
HER2 Heterogeneity
HER2 heterogeneity within a tumor cell can also affect IHC scoring accuracy. HER2 heterogeneity is defined as the presence of at least two distinct clones of cells with different levels of HER2 amplification within a tumor. Due to heterogeneity in HER2 levels, medical oncologists are encouraged to consider HER2-low results from any biopsy, not only the most recent, in treatment decisions.
No Standard for HER2 Ultralow
HER2 ultralow is somewhat controversial, and implementation of the HER2 ultralow classification in clinical practice has been difficult, said Layman.
Ultralow is considered to be any hint of HER2 staining visible in a patient who is technically HER2 negative. "This is not an automated type of finding ... this is not an AI [artificial intelligence] finding. It's really more the pathologist who believes that they can see some element of HER2 staining in the cancer cell or the membrane of the cancer cell," said Mayer.
Layman noted that "the problem is that there is no such thing as ultralow in pathology guidelines, and therefore pathologists across the country do not have a standard for ultralow. Given that, some academic medical centers may report something similar to ultralow but may not call it ultralow because it's not an official pathology designation."
The majority of patients are not treated at academic medical centers, she added. "They are treated at community centers, where a pathologist might be reading breast cancer cases and other cancer cases and even noncancer cases. So, they may not have the expertise to designate between 0 and 1+," she said.
Alternate methods of pathologic assessment and interpretation of HER2 testing are being assessed in an effort to improve accuracy. "Some newer tests are assessing quantification of the protein expression, even using artificial intelligence as a complement to traditional pathologic assessment," Layman noted.
Expanding ADC Treatment
The ASCO/CAP panel noted that a result of IHC 0 may not mean that a cancer has no targetable HER2 protein present because HER2 assays are semiquantitative and were optimized to detect HER2 overexpression. Furthermore, some data suggest that IHC 0 cancers respond similarly to T-DXd as HER2-low cancers.
The panel acknowledged a new indication for T-DXd when HER2 is not overexpressed or amplified but is IHC 1+ or 2+ without amplification by FISH.
"Once the data from DESTINY-Breast04 emerged, it dramatically changed our consideration of HER2 status and unlocked a large population of patients for whom T-DXd was now a potent treatment option," Mayer said.
More recently, the phase III randomized DESTINY-Breast06 trial found a significant improvement in PFS with T-DXd compared with chemotherapy in patients with hormone receptor-positive and either HER2-low or HER2-ultralow metastatic breast cancer following at least one line of endocrine therapy and no prior chemotherapy. Of the study participants, about 18% were considered to have HER2-ultralow disease.
Therefore, it appears that any amount of HER2 expression may be sufficient to elicit an antitumor response by a potent ADC targeting HER2. These data lend further support for the bystander effect, in which the chemotherapy portion of ADCs enters and kills nearby tumor cells -- even those that have little or no HER2 expression.
HER2 low and ultralow may have less relevance in the future as studies with T-DXd and similar agents are ongoing to assess activity in true HER2 0 cases, said Mayer. "It may end up that if activity can be confirmed in the true HER2 0 population, the concept of HER2 low may no longer be necessary and we would be able to offer T-DXd regardless of HER2 status. But until we have more data, we still now are considering the concept of HER2 low and ultralow."
Disclosures
Mayer reported consulting/advisory roles for Lilly, Novartis, and AstraZeneca.
Layman reported consulting/advisory roles for Novartis, Eli Lilly, Pfizer, and Celcuity, and research/grant funding from Pfizer, Novartis, Eli Lilly, Zentalis, Puma, Celcuity, Accutar Biotechnology, and Arvinas.