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Understanding HER2-Low Breast Cancer
Understanding HER2-Low Breast Cancer: Current Challenges and Emerging Opportunities for Treatment

Released: March 24, 2022

Expiration: March 23, 2023

Sara Hurvitz
Sara Hurvitz, MD
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The History of HER2 As A Biomarker In Breast Cancer
In the 1980s, Dr Dennis Slamon and colleagues identified that roughly 25% to 30% of breast cancers were characterized by amplification of the gene for HER2, leading to overexpression of the HER2 protein on cell surfaces. This overexpression was associated with a much more aggressive disease biology and worse outcomes for patients diagnosed with breast cancer regardless of disease stage.

With the understanding that HER2 amplification and overexpression can occur came numerous assays to detect whether a tumor has too much HER2 protein expressed on the cell’s surface. Cancers that are identified as being “HER2 positive” by way of amplification or overexpression were shown to benefit particularly well from HER2‑targeted antibody therapy such as trastuzumab. However, when patients’ tumors did not have overexpression of HER2, they didn’t appear to benefit from trastuzumab. 

Measurement of HER2 expression has traditionally been done by an immunohistochemistry (IHC) assay, which is simply a stain of tumor sections to identify the HER2 protein on the cell’s surface. A scoring system was developed whereby tumors were identified as having HER2 overexpression if they were scored as 3+. Tumor samples with a score of 2+ by IHC are considered indeterminate and are reflexively tested by in situ hybridization (ISH). If the ISH testing is positive, it is considered to be HER2 positive. If a sample is HER2 2+ and ISH testing is negative, or if the IHC is 0 or 1+, the tumor is considered HER2 negative. Historically, HER2‑directed therapies were not recommended for a tumor that was not HER2 overexpressing or amplified.

In recent years, the development of HER2‑directed antibody–drug conjugates such as trastuzumab deruxtecan has changed the treatment landscape for HER2-positive breast cancer. These agents target HER2 on the cell surface and deliver a cytotoxic payload to cancer cells that overexpress HER2, but they also can have effects in tumor cells with lower levels of HER2 expression. In other words, HER2 overexpression is not necessarily needed to exert the antitumor effects with HER2-directed antibody–drug conjugates.

With early data suggesting that trastuzumab deruxtecan may be effective not only in HER2‑overexpressing tumors, but also in tumors that have low levels of HER2 expression (1+ or 2+) came this distinction of tumors based on their level of expression of HER2. Currently, no therapy is specifically approved for what is now being called “HER2‑low breast cancer,” nor do we have any clear evidence that HER2‑low breast cancers behave differently from those that are HER2 negative (IHC 0). So, there is no strong evidence that HER2-low breast cancer is a distinct disease subtype in terms of its biology; it is simply that HER2, even if expressed at a low level, might be able to be used to deliver chemotherapy to the tumor cells via antibody–drug conjugates such as trastuzumab deruxtecan.

Antibody–Drug Conjugates for HER2-Low Breast Cancer
Phase I data with trastuzumab deruxtecan showed a promising level of activity in patients with HER2‑low advanced or metastatic breast cancer. In this trial, HER2 low was defined as IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested. Patients in this trial were heavily pretreated, but 37% of patients with HER2‑low breast cancer achieved an objective response to this antibody–drug conjugate, and these data provided proof of concept that trastuzumab deruxtecan may be effective even with low levels of HER2 expression.

Recently, a press release described data from the randomized phase III DESTINY‑Breast04 trial comparing trastuzumab deruxtecan with standard chemotherapy of physician’s choice in patients with HR-positive or HR-negative, HER2-low, unresectable or metastatic breast cancer after previous therapy with 1 or 2 lines of chemotherapy. These data suggested that there is a progression-free survival (PFS) and overall survival (OS) benefit with trastuzumab deruxtecan in this patient population. I am excited to see these data in a presentation or publication soon because this would be level 1 evidence if, indeed, the PFS and OS differences are significant. I think the DESTINY-Breast04 data hold promise for being practice changing.

I also am interested in seeing whether trastuzumab deruxtecan provides benefits in patients with HER2 IHC 0. We know that no breast tumors are entirely without expression of HER2, and there is some early evidence that trastuzumab deruxtecan may be beneficial even in tumors that are IHC 0. So, the biomarker data from this trial will be an important component to focus on once it is presented.

Controversies in HER2 Testing: Considerations for HER2-Low Breast Cancer
HER2 testing remains an area of controversy. Many studies have shown that IHC assays are fraught with interlaboratory variability and interpreter variations due to fixation techniques, length of fixation, etc. In clinical practice, one laboratory may call a tumor IHC 0, and another laboratory may call the same sample IHC 2+. If a particular therapy, such as trastuzumab deruxtecan, is proven beneficial for HER2‑low patients, resulting in an approved therapy based on IHC HER2‑low designation, we also will need to standardize the IHC testing technique so that we can ensure accurate identification of patients who are most likely to benefit from this therapy.

I think including measures to improve standardization of testing for HER2 expression is important moving forward. It also is imperative that oncologists are able to request appropriate IHC and ISH testing for HER2 and other biomarkers for their patients with breast cancer from pathologists they work with and understand the pathology reports they receive.

Your Thoughts?
Do you want to learn more about biomarker testing for HER2-low breast cancer? Go the American Society for Clinical Pathology website to access various educational materials, including online modules, podcasts, and downloadable slides on HER2 testing, at: www.ascp.org/content/learning/breast-cancer

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