Over the last 30 years, HER2 testing has evolved from a prognostic tool to a predictive biomarker. In the early 1990s, HER2 testing was used to identify breast cancer patients with aggressive clinical behavior and poor prognosis through immunohistochemistry (IHC) or gene amplification by in situ hybridization (ISH) techniques.
However, with the development of HER2-targeted therapies, such as trastuzumab, HER2 testing became a predictive tool as well, indicating patients who are likely to respond to targeted anti-HER2 therapies. Recently, the emergence of therapeutic indications for patients with HER2-low breast cancer has significantly expanded the number of those who may benefit from HER2-targeted therapies.
Evolution of guidelines for HER2 testing
In response to concerns regarding discrepancies between local and central laboratories in the initial HER2-targeted clinical trials, particularly in cases where local laboratories reported positive IHC results that could not be replicated, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) collaborated to produce the first iteration of the ASCO/CAP HER2 testing guidelines in 2007. These guidelines have since been updated in 2013 and 2018, to better categorize results based on evolving data on less common scenarios. In parallel, the HER2 guidelines developed in the United Kingdom (UK) were created to standardize the methodology and reporting of HER2 testing in the UK.
The definition of HER2 positive result by IHC has been adjusted with each update. In the most recent 2018 version, the definition of an IHC 2+ equivocal result was also refined from the 2013 version to "weak to moderate complete membrane staining observed in >10 percent of tumor cells" since the terms "circumferential" and "incomplete" in the 2013 version were deemed contradictory. The UK HER2 IHC guidelines have also undergone fine-tuning of the HER2-positive (3+) cutoff point in updates from 2004 to 2008, with the latest update in 2015 being essentially identical to the ASCO/CAP 2018 version in this regard.
Evolution of breast cancer treatment
Traditionally, pathologists aimed to distinguish between HER2-positive and HER2-negative breast carcinomas. This approach was strengthened by the 2018 ASCO/CAP guideline update, which was based on clinical data demonstrating that only tumors driven by HER2 overexpression benefit from the addition of anti-HER2 therapy to standard chemotherapy. Historically, this binary treatment decision-making process was used when considering HER2-targeted therapies, assuming that only HER2-positive patients (i.e., those defined by HER2 overexpression and/or amplification) should receive anti-HER2 agents.
However, as new therapeutic compounds like antibody drug conjugates (ADCs) have emerged, the range of available treatment options has greatly expanded for patients with breast cancer. ADCs target and deliver chemotherapy inside cancer cells, reducing systemic exposure to cytotoxic agents. Studies have shown that these therapies have produced encouraging response rates not only in patients with HER2-positive tumors but also in patients with so-called "HER2-low" breast cancer.
Trastuzumab deruxtecan is the first FDA-approved ADC of this type. Another emerging ADC targeting HER2-low breast cancer is trastuzumab duocarmazine (SYD-985). In clinical trials, treatment with trastuzumab duocarmazine led to a partial response in 28 percent and 40 percent of patients with HER2-low ER-positive and ER-negative breast cancer, respectively.
The availability of anti-HER2 ADC treatment presents new and exciting possibilities for treating HER2-low breast cancer. This is due to the retention of the antitumor properties of cytotoxic agents and an improved tumor-specific HER2-targeting homing effect. These anti-HER2 agents enable the treatment of patients who were traditionally ineligible for treatment.
The importance of the multidisciplinary team in HER2-low breast cancer
To fully understand the clinical characteristics and prognosis of these patients, a collaborative multidisciplinary approach between pathologists and oncologists is imperative. With the introduction of targeted therapies for HER2-low breast cancer, pathologists must be able to more accurately assess HER2 protein expression at the lower end of the spectrum.
“While reflex testing based on IHC results or first-line ISH may be common practice,” says Aysegul A. Sahin, MD, FASCP, an internationally recognized breast pathology expert and Professor in the Department of Pathology at MD Anderson Cancer Center in Houston, Texas. “This approach may deny potentially beneficial therapy to patients with HER2-low breast cancer,” Dr. Sahin explains. “Therefore, routinely performing IHC and ISH assays in all breast cancer cases may become necessary since some breast cancers show discordance between IHC and ISH. These advancements may lead to further updates in the ASCO/CAP HER2 guidelines to create a new HER2-low breast cancer category.”
Dr. Sahin serves as faculty for one of ASCP’s CME/CMLE-accredited online courses designed to help pathologists, laboratory professionals, and other members of the cancer care team apply the latest scientific evidence when evaluating HER2 status and be comfortable having an open dialogue surrounding challenging HER2 cases and how treatment is informed by HER2 status.
Because breast cancer is such a complex disease, it is crucial for the laboratory team to be able to appropriately identify HER2-low breast cancer to optimize treatment and patient outcomes. To improve your skills and stay on top of emerging information in this area, visit ASCP’s
HER2-low Breast Cancer resource page.
