Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.

Use of an RNA-based assay for evaluating HER2 status

March 2024—Human epidermal growth factor receptor 2 is a critical biomarker in breast cancer, gastrointestinal malignancies, and other cancers. HER2 protein expression can be evaluated using IHC, and the DNA copy number of its encoding gene, ERBB2, can be evaluated using FISH. In most clinical settings, IHC evaluation is categorized as positive (3+), equivocal (2+), or negative (0 to 1+), with equivocal cases being reflexed to FISH. Patients with HER2-positive tumors, defined as either 3+ or 2+/FISH positive, have been eligible to receive HER2-targeted therapy for many years. More recently, the FDA approved the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) to treat patients with HER2-low breast cancer, defined as tumors with IHC 1+ or 2+/FISH negative. This promising treatment has allowed many more patients to receive molecular-targeted therapy. Yet it can be difficult to distinguish IHC 0 from IHC 1+ cases because such categorization relies on subjective scoring by pathologists. While HER2 status is traditionally evaluated at the DNA level with FISH and at the protein level with IHC, one can also evaluate HER2 status at the mRNA expression level. RNA­scope (Advanced Cell Diagnostics, Newark, Calif.) is an in situ hybridization assay that quantitatively assesses HER2 messenger RNA levels by whole slide imaging of a single formalin-fixed, paraffin-embedded tissue section. The authors compared RNA­scope with IHC and demonstrated a strong correlation between RNA and protein levels, especially in clinical samples. They also evaluated the correlation between RNA­scope results and patients’ response to T-DXd treatment. The authors found that HER2 RNA levels were significantly higher in patients who responded to T-DXd treatment than in nonresponders. Furthermore, RNA­scope scores better classified patients’ T-DXd response rates than did IHC scores. While these findings are promising, additional validation with larger cohorts in prospective clinical trials will be necessary. Nonetheless, RNA­scope is a promising alternative to IHC assays for evaluating HER2 expression in breast cancer.

Li X, Lee JH, Gao Y, et al. Correlation of HER2 protein level with mRNA level quantified by RNA­scope in breast cancer. Mod Pathol. 2024. https://doi.org/10.1016/j.modpat.2023.100408

Correspondence: Dr. Xiaoxian Li at xli40@emory.edu