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New HER2-Low Category Spurring Efforts to Understand Breast Cancer Biology, Develop Better Tests


SAN ANTONIO – The US approval of AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) for metastatic HER2-low breast cancer is spurring oncologists and pathologists to reconsider testing paradigms.

Since that approval in August, healthcare providers, pathologists, and researchers have had to quickly shift from a simpler HER2-positive/negative paradigm to a more complex and uncertain testing framework that includes a new HER2-low category. At the San Antonio Breast Cancer Symposium this week, experts considered what this paradigm shift means for past, present, and future drug trials and their ability to accurately identify patients who will benefit from Enhertu and next-generation targeted treatments.

According to the last updated 2018 guidelines from the American Society of Clinical Oncology and the College of American Pathologists, patients with a HER2 expression score by immunohistochemistry of 1+ or 0 are considered to have HER2-negative tumors and are ineligible for HER2-targeted treatment, such as Genentech's Herceptin (trastuzumab). Patients who have IHC 3+ scores or have IHC 2+ scores and also HER2 gene amplification by in situ hybridization (ISH) are eligible for HER2-targeted therapy.

But this was the dichotomous world before the DESTINY-Breast04 trial showed that Enhertu could cut the risk of disease progression or death by nearly 50 percent compared to physician's choice of chemotherapy in previously treated, hormone receptor (HR)-positive, advanced breast cancer patients with low HER2-expressing tumors, defined as IHC 1+ or IHC 2+ without gene amplification by ISH. The study showed similar efficacy for Enhertu in patients with triple-negative breast cancer, demonstrating that some patients categorized as estrogen receptor (ER), progesterone receptor (PR), and HER2-negative according to present testing criteria do have low HER2 expression and therefore can benefit from targeted treatment.

"We now have a HER2-low category that we have to figure out how to work with," said David Rimm, director of pathology tissue services at Yale School of Medicine.

The existence of this additional category has raised many new questions and introduced challenges for the field. Experts must define how much HER2 expression is needed in order for patients to be considered HER2-low or HER2 0 and better understand the treatment outcomes associated with different cutoffs. There must be efforts to standardize and reduce inter-lab and pathologist variability in HER2-low scoring. Furthermore, the field needs to achieve consensus around whether HER2-low tumors are distinct enough to be considered their own breast cancer subtype alongside hormone receptor-positive, HER2-positive, and triple-negative tumors.

Researchers debated and presented research on these issues at SABCS. For example, in one study involving pathologists from labs in the US, EU, Japan, Australia, and Brazil, Josef Rüschoff, a pathologist at the University of Regensburg, reported more than 80 percent overall rater concordance in scoring HER2-low slides tested on Roche's Ventana Pathway Anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody test or Agilent's Dako HercepTest. The Roche test was used in the DESTINY-Breast04 trial, and in October, the FDA approved it as a companion diagnostic for identifying HER2-low metastatic breast cancer patients eligible for Enhertu.

While Rüschoff and colleagues deemed this to be "an acceptable level of accuracy" for identifying HER2-low patients, Rimm disagreed and cited data his group published earlier this year showing far less pathologist agreement. When 18 pathologists were asked to read slides of selected breast cancer biopsies, there was a discordance of 41 percent in distinguishing tumors that were IHC 0 from IHC 1+ or higher and only a 10 percent discordance in distinguishing whether a tumor was IHC 3+ or not.

"If we look at the data more closely, the most liberal pathologist calls 40 percent [of slides] HER2 0 and the most conservative pathologist calls 20 percent [of slides] HER2 0," Rimm said, noting that given there are 21,000 pathologists in the US and 100,000 pathologists in the world, the field needs to figure out how many observers are needed to improve concordance in reading IHC 0 and 1+ cases. His group has done this calculation and will be publishing it soon in Modern Pathology.

The field is also not of one mind as to whether HER2-low tumors are distinct enough in biology and outcomes to be considered a separate breast cancer subset. By Rimm's estimate, at SABCS, researchers presented seven abstracts, analyzing data from more than 8,700 patients, suggesting that HER2 low is a separate subset. In four abstracts comprising data from more than 17,600 patients, researchers concluded that HER2 is not a distinct subset.

Giuseppe Curigliano, head of the division of early drug development at the European Institute of Oncology in Italy, and Sara Tolaney, chief of the division of breast oncology at the Dana-Farber Cancer Institute in Boston, debated this point at the meeting. Curigliano cited several features — for example, that HR-positive breast tumors tend to have HER2-low expression and that HER2-low tumors can switch between HER2 signaling and ER signaling based on therapy exposure — to argue that these types of tumors warrant different clinical categorization.

Meanwhile, Tolaney pointed out that most studies have not found an overall survival difference in HR-positive HER2-low and HER2 0 breast cancer and cited analysis presented at this meeting by Duke Health's Rani Bansal and colleagues, which showed that the genomic features of HER2-low tumors were similar to HR-positive or triple-negative disease, with few exceptions. Moreover, HER2-low status isn't stable and can increase with ER levels. Based on these factors, Tolaney argued that HER2-low is not a distinct subset but rather a biomarker for predicting which patients should receive antibody-drug conjugates like Enhertu.

Rimm reflected that since the IHC assays that are currently widely used to gauge HER2 status are not reproducible between pathologists and were not designed to gauge dynamic HER2-low expression, they make it hard to determine if these tumors are unique enough in terms of outcomes and prognosis to be a distinct breast cancer subgroup. If the field continues to use these broadly marketed IHC tests, a similar adjudication strategy should be applied for HER2 IHC 0 cases, Rimm suggested, just like pathologists adjudicate HER2 IHC 2+ scores, which are considered equivocal, with additional ISH testing.

AstraZeneca is currently developing such an orthogonal method using image analysis to quantify HER2 expression in each tumor cell. "This is a good first step, [but] it's not quantitative enough," Rimm said. "I would argue that we need to actually give you digital information or actual numbers." He noted that his lab at Yale and others are already running analytic assays using commonly available tools to measure HER2 protein on slides and report out results in attomole/mm2.

New assays specifically developed to quantify low levels of HER2 expression will be critical if researchers and oncologists want to more accurately determine the HER2-low or ultra-low cutoffs at which breast cancer patients will derive meaningful benefit from HER2-targeted antibody-drug conjugates.

Because of the historical HER2-positive/negative categorization, studies have excluded patients that were deemed HER2 0 but had some HER2 expression. However, the Phase II DAISY trial, data from which was reported last year at SABCS, showed that metastatic breast cancer patients with HER2-low and HER2 0 cancers derived benefit from Enhertu. "We have an obligation to our patients to make these valuable clinically annotated specimens available for high-priority secondary correlative studies with assays that are analytically and clinically validated and that could help us better define who are the patients most likely to benefit from these exciting treatments," Curigliano said, noting that the DESTINY-Breast06 trial comparing Enhertu against chemotherapy will also include patients with HER2 0 metastatic breast cancers.

Steven Vogl, a medical oncologist in private practice in the Bronx, New York, similarly urged researchers to get access to patient samples from the pivotal study that led to Enhertu's approval in HER2-low metastatic breast cancer and independently establish the biomarker cutoffs associated with response. "You probably should adjudicate the responses separately from the drug company because the drug company wants to make responses in everybody, if they can get away with it," Vogl said. "We need somebody to very carefully decide how much response is a response that the doctor would like to know about."

Rimm agreed that this type of independent validation is needed and said he hoped to stimulate a cooperative group to "try such a thing."