Disclosures: The Breast Cancer Research Foundation and NCI provided funding for this study. Rimm reports honoraria, grants and/or instrument support from Akoya, Amgen, AstraZeneca, Bristol Myers Squibb, Cell Signaling Technology, Cepheid, Danaher, Eli Lilly and Co., Konica/Minolta, Merck, NanoString, Navigate Biopharma, NextCure, Odonate, Paige, Roche, Sanofi and Ventana. Please see the study for all other authors' relevant financial disclosures.
April 15, 2022
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New HER2 assay may be needed to guide breast cancer treatment with trastuzumab deruxtecan

Disclosures: The Breast Cancer Research Foundation and NCI provided funding for this study. Rimm reports honoraria, grants and/or instrument support from Akoya, Amgen, AstraZeneca, Bristol Myers Squibb, Cell Signaling Technology, Cepheid, Danaher, Eli Lilly and Co., Konica/Minolta, Merck, NanoString, Navigate Biopharma, NextCure, Odonate, Paige, Roche, Sanofi and Ventana. Please see the study for all other authors' relevant financial disclosures.
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The use of current standard HER2 assays as diagnostic tests may result in misassignment of patients for treatment of breast cancer with trastuzumab deruxtecan, according to a study published in JAMA Oncology.

"To accurately determine which patients will benefit from trastuzumab deruxtecan, clinicians should insist that their pathology partners use a new, more sensitive assay. The legacy protein assay and the fluorescent in situ hybridization (FISH) assays are not appropriate for trastuzumab deruxtecan and similar drugs in the pipeline," study co-author David L. Rimm, MD, PhD, Anthony N. Brady professor of pathology and director of pathology tissue services at Yale Cancer Center, told Healio.

Quote from Aileen I. Fernandez, PhD.

Background

Rimm and colleagues pursued the study because of the success of trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) in treating women with nonamplified ERBB2 (HER2) breast cancer. “About 15% of breast cancer shows amplification of the ERBB2 gene,” Rimm said. "Gene amplification leads to more than 1 million copies of the HER2 protein in breast cancer cells.”

Rimm said treatment with trastuzumab (Herceptin, Genentech) has been successful among such patients for more than 25 years.

David L. Rimm, MD, PhD
David L. Rimm

“The new drug, trastuzumab deruxtecan, works on patients with many fewer copies of the HER2 protein — maybe as few as 10,000 to 20,000,” Rimm said. “So now, instead of 15% of breast cancer cases, as many as 60% to 70% of breast cancers may respond. The problem is that the assay designed to pick out the 15% of cases with more than 1 million copies of the protein does not work well to distinguish patient tumors with no copies of the protein from patient tumors with 20,000.”

Methodology

Rimm and colleagues evaluated College of American Pathologists’ proficiency surveys for HER2 expression in breast cancer from 2019 and 2020. Their analysis included scores from 1,391 to 1,452 laboratories of 40 HER2 cores from each laboratory — 20 cores twice a year, for a total of 80.

The researchers used the HER2 assay as they would in their own laboratory and scored the two-tissue microarray. They summarized the relative frequency and distribution of each score given to every HER2 core.

Additionally, they collected a second, independent analytic data set of breast biopsies done in 2018 from the archives of the department of pathology at Yale. Eighteen board-certified pathologists read the set, which was enriched in cases with HER2 scores of 2+ and 3+.

Determining the suitability of the current standard HER2 immunohistochemistry assays to select patients with low HER2 positivity for trastuzumab deruxtecan served as the study's primary objective.

Key findings

Results from the College of American Pathologists surveys showed 19% of the cases read by 1,400 labs generated results with less than 70% agreement between a HER2 score of 0 vs. 1+.

The 18 pathologists in the second part of the research read the same slides from a selected set of breast cancer biopsies, resulting in only 26% agreement among them on scores of 0 and 1+, compared with the 58% concordance between 2+ and 3+, because of the poor quality of the current test in the critical range for trastuzumab deruxtecan, researchers reported.

“This paper is among (or the) first to identify this issue, and hopefully we will soon see commercially available assays designed for these new drugs,” Rimm told Healio. “Note that current FDA approval for trastuzumab deruxtecan is only for the ERBB2-amplified cases, but recent data suggest that soon the FDA will approve the drug for unamplified cases.”

Implications

Because of trastuzumab deruxtecan’s efficacy, Rimm and colleagues believe patients may be misassigned for treatment or for no treatment if the decision depends on performance of the current standard HER2 assays widely used globally. The problem could be fixed with new assays that stratify cases with lower HER2 expression, combined with standardization of the assays with calibration slides, they wrote.

“I would reemphasize the need to develop a new, more specific and sensitive assay that can better identify patients,” Aileen I. Fernandez, PhD, postdoctoral fellow at Yale Cancer Center and lead author of the study, told Healio. “I also would like to see further work focusing on preanalytical techniques used. This will help in further understanding if standardizations can be implemented to further improve this assay.”

References:

Fernandez AI, et al. JAMA Oncol. 2022;doi:10.1001/jamaoncol.2021.7239.
Yale Cancer Center study suggests improved diagnostic testing needed to guide HER2 breast cancer treatment (press release). https://medicine.yale.edu/news-article/yale-cancer-center-study-suggests-improved-diagnostic-testing-needed-to-guide-her2-breast-cancer-treatment/. Published Feb. 3, 2022. Accessed Feb. 7, 2022.

For more information:

David L. Rimm, MD, PhD, and Aileen I. Fernandez, PhD, can be reached at Department of Pathology, BML 116, Yale University School of Medicine, 310 Cedar St., P.O. Box 208023, New Haven, CT 06520-8023; email Rimm at david.rimm@yale.edu; email Fernandez at aileen.fernandez@yale.edu.