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Since the U.S. Food and Drug Administration (FDA) approval of trastuzumab deruxtecan (T-DXd) for advanced HER2-low breast cancer, researchers and clinicians have raised an important question of whether HER2-low should be considered as a separate clinical entity with distinct molecular and clinicopathological features, or solely a biomarker for a HER2-directed antibody–drug conjugate. |
If HER2-low is considered as a separate clinical subtype, this may require updating the clinical guidelines on human epidermal growth factor receptor 2 (HER2) scoring and testing in breast cancer along with its therapeutic indication. |
This editorial provides current available data on characteristics of HER2-low breast cancer, and most importantly, addresses the recent timely updates from the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines on reporting terminology for HER2-low versus HER2-negative breast cancer. |
Human epidermal growth factor receptor 2 (HER2) expression has historically been scored on a continuous scale from very low/absent to very high (0 to 3+) using an immunohistochemistry (IHC) staining assay. A HER2 IHC score of 0 represents a staining pattern where there is no staining or incomplete membrane staining that is faint or barely perceptible in less than 10% of tumor cells. A score of 1+ is defined as faint or barely perceptible incomplete membrane staining in more than 10% of tumor cells. Tumors with weak–moderate complete membrane staining in more than 10% of tumor cells are scored as 2+. Lastly, tumors with complete, intense membrane staining involving more than 10% of tumor cells receive a 3+ expression score. Historically, breast cancer has been classified as HER2-positive when the expression is scored as 3+ or 2+ by IHC—if gene amplification is further confirmed in the latter by in situ hybridization (ISH), which is defined by a HER2/CEP17 ratio of less than 2.0, with an average HER2 copy number of 4.0 to 5.9 per cell [1]. HER2-directed therapies, including naked antibodies such as trastuzumab [2] and pertuzumab [3] and small-molecule inhibitors such as lapatinib [4], were indicated for patients with HER2-positive breast cancer. However, this paradigm shifted in 2022 when the results of the DESTINY-Breast04 clinical trial [5] not only unlocked a new unique treatment option of a HER2-directed antibody–drug conjugate (ADC) but also supported a newly described category called HER2-low, tumors with HER2 IHC scores of 1+ or 2+ with negative ISH [6, 7]. This trial found that targeting low levels of HER2 expression with trastuzumab deruxtecan (T-DXd) in patients with metastatic breast cancer resulted in better outcomes than those treated with chemotherapy. The risk of disease progression or death was about 50% lower and the risk of death was 36% lower with T-DXd than with chemotherapy, regardless of hormone receptor status [5]. These results led to the U.S. Food and Drug Administration (FDA) approval of T-DXd for the treatment of advanced HER2-low breast cancer. As a result, clinical guidelines have been updated to recommend this new standard-of-care therapy in advanced HER2-low breast cancer [8].
While the results of DESTINY-Breast04 are practice-changing, this newly identified category of HER2-low breast cancer has raised several questions and challenges among researchers and clinicians. One of the questions is whether HER2-low breast cancer should be classified as a separate clinical entity [9]. To be considered as an independent breast cancer subtype, a few key questions need to be addressed: (1) Do HER2-low tumors display molecular and clinical characteristics distinct from other subtypes of breast cancer? (2) How does HER2-low status affect prognosis and survival outcomes in breast cancer? Understanding whether HER2-low tumors exhibit different behaviors that translate into better survival outcomes as compared to HER2-negative will be necessary before classifying it as a new category of breast cancer. However, these questions remain under investigation.
Experts continued to debate whether HER2-low should be considered a separate clinical entity or solely a biomarker for targeted therapy at the 2022 San Antonio Breast Cancer Symposium [10]. Several studies have also shown contradictory results in addressing this question [11]. A few studies have shown that there were differences in gene expression profiles between HER2-low and HER2-negative breast cancer; however, this was largely driven by the hormone receptor (HR) status [12, 13]. A pooled analysis of four prospective neoadjuvant clinical trials showed that patients with HER2-low tumors had significantly longer survival but lower pathological complete response (pCR) rates than HER2-negative tumors, suggesting that HER2-low breast cancer should be considered a different subtype [14].
On the contrary, a more recent large-scale retrospective cohort study demonstrated that there were minimal prognostic differences between HER2-low and HER2-negative breast cancer. In a multivariable analysis, the investigators found that HER2-low status was associated with small improvements in overall survival (OS) and lower rates of pCR [15]. However, these differences were small in magnitude and were likely attributable to other factors such as HR-positive luminal versus triple-negative basal-like biology rather than the low level of HER2 expression on the cell surface. These studies concluded that there were no statistically significant differences in survival outcomes between HER2-low and HER2-negative breast cancer, and therefore, HER2-low should not be considered a separate clinical entity.
There are clinical and pathological considerations that need to be considered for widespread implementation of therapeutic recommendations in advanced HER2-low breast cancer [9]. Clinicians need to be better informed of the clinical significance and complex characteristics of HER2-low breast cancers as our current understanding of HER2-low expression evolves. HER2-low expression status may be subject to temporal fluctuations, and its expression status may change during the course of a patient’s therapy and/or disease progression. Thus, a tumor that expresses low levels of HER2 initially may lose all HER2 expression, or vice versa. This appears to be in direct contrast to HER2-overexpressing tumors, which tend to be more stable in their genomic aberration over time [16,17,18]. As a result, one could argue that HER2 expression itself is not consistent enough to define HER2-low as an independent subtype of breast cancer.
A major pathological challenge to accommodating the new treatment paradigm in advanced HER2-low breast cancer will be the accurate staining of HER2 samples and subsequent interpretation of the test results. The distinction between 0 and 1+ IHC scores has held no clinical significance up to now when testing for canonically defined HER2-positive tumors. The interpretation of the 1+ IHC score may be viewed as subjective, as some laboratories may interpret it as 1+ while others may interpret it as 0 or negative. Surveys from the College of American Pathologists showed that the concordance rate between 0 and 1+ interpretation among laboratories was only 26%, compared to 58% concordance between 2+ and 3+ scoring [19]. Standardizing techniques and laboratory parameters may reduce interobserver variability and improve the reliability of HER2-low assessment. In addition, strict protocol recommendations for HER2-low identification should be considered from vendors of FDA-approved HER2 companion diagnostics such as Roche/Venta and Agilent/Dako.
Current data are conflicting and insufficient to support a new classification of HER2 IHC 0 versus 1+ as prognostic or predictive threshold for therapy. Clinical trial data regarding HER2-directed ADC on HER2-negative tumors are limited. Patients with tumors with IHC scores of 0 were excluded from the DESTINY-Breast04 trial, and evidence is lacking that these tumors have distinct biology or that they respond differently to HER2-directed ADCs. The phase II DAISY trial demonstrated that the objective response rates (ORR) of HER2-low and HER2-negative breast cancers were similar when treated with T-DXd (37.5% vs. 29.7%, respectively), suggesting that HER2 expression may not be the sole determinant of T-DXd efficacy [20]. This may be due to the notion that HER2 expression varies on a continuous scale, and some tumors with HER2 IHC 0 (between 0 and 1) could have a degree of HER2 expression and may not be entirely HER2-negative. The DESTINY-Breast06 trial (NCT04494425), which is currently enrolling patients with tumors of IHC > 0 but < 1+, will provide more information [21]. Nevertheless, HER2-low is a clinically relevant biomarker for the treatment with T-DXd given the remarkable survival benefits seen with T-DXd over chemotherapy in patients with HER2 IHC 1+ or 2+/ISH-negative tumors. Pathologists and clinicians, therefore, should be aware that an IHC 0 versus IHC 1+ result has a new treatment implication in the metastatic setting.
Due to these aforementioned challenges, recent updates from American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines do not recommend changing the reporting terminology or designating a new classification for patients with a HER2 IHC score of 0 or 1+ at this time. HER2 IHC 0 or 1+ results should still be interpreted as HER2-negative using the previously recommended scoring algorithm; however, a quantitative IHC score (e.g., 1+ staining present) should be included on the report to identify those patients who may benefit from T-DXd [22].
The story is not over yet. We await the results from future studies to discern whether HER2-low tumors have distinct molecular and phenotypic features or whether HER2-low status remains a biomarker for HER2-directed ADCs.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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Kamal S. Saini is the guest editor of this topical collection. Kamal S. Saini played no part in the peer review or decision-making of this article at the editorial level and contributed solely as an author.
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Kamal S. Saini and Heidi Ko conceptualized the manuscript, Heidi Ko wrote the first draft of the manuscript. All authors (Heidi Ko, Rebecca A. Previs, Kyle C. Strickland, Jonathan Klein, Brian Caveney, Chiara Chiruzzi, Marcia Eisenberg, Eric A. Severson, Shakti Ramkissoon, and Kamal S. Saini) provided significant intellectual input and reviewed, edited, and approved the final manuscript. All authors have reviewed the final version of this manuscript and provided their consent to publish.
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Kamal S. Saini reports consulting fees from the European Commission, and stock and/or other ownership interests in Fortrea Inc. and Quantum Health Analytics (UK) Ltd., outside the submitted work. Heidi Ko, Rebecca A. Previs, Kyle C. Strickland, Jonathan Klein, Brian Caveney, Marcia Eisenberg, Eric A. Severson, and Shakti Ramkissoon are all employees of Labcorp, and Chiara Chiruzzi is an employee of Fortrea Inc.
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Ko, H., Previs, R.A., Strickland, K.C. et al. Is HER2-Low a New Clinical Entity or Merely a Biomarker for an Antibody Drug Conjugate?. Oncol Ther 12, 13–17 (2024). https://doi.org/10.1007/s40487-023-00249-0
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DOI: https://doi.org/10.1007/s40487-023-00249-0