The use of antibody-drug conjugates targeting human epidermal growth factor receptor-2 (HER2), such as trastuzumab-deruxtecan, has increased the need for accurate methods to characterize human epidermal growth factor receptor-2 status, particularly in human epidermal growth factor receptor-2-low breast cancers. In a study published in The American Journal of Surgical Pathology, researchers evaluated whether HER2 messenger RNA (mRNA) scores from an approved genomic assay could provide a quantitative measure of expression and how these scores compared with immunohistochemistry (IHC).
Data from 1,524 patients with estrogen receptor–positive, HER2-negative breast cancer who underwent tumor genomic profiling between 2011 and 2023 were analyzed. HER2 mRNA scores were compared across IHC subgroups, including HER2-0, ultralow, 1+, and 2+ with negative in situ hybridization. Median mRNA scores increased progressively with higher IHC categories, and HER2-low tumors demonstrated significantly higher scores than HER2-0 tumors. Receiver operating characteristic analyses showed that HER2 mRNA scores had an area under the curve of 0.76 when distinguishing HER2-0 from HER2-low tumors and 0.81 when distinguishing HER2-null from ultralow or higher tumors. An mRNA score of 8.9 was identified as a cutoff value, although an overlap between groups was observed.
Clinicopathologic analyses indicated that tumors with Ki-67 labeling index less than 20 percent and recurrence scores of 25 or lower were more likely to have HER2 mRNA scores above 8.9. Low Ki-67 (less than 20 percent) and recurrence scores of 25 or lower were associated with higher HER2 mRNA scores, while progesterone receptor negativity, high Ki-67, high nuclear grade, age older than 50 years, and low HER2 mRNA score were independently associated with recurrence scores greater than 25.
Twenty-eight percent of cases showed discordance between IHC and HER2 mRNA score; most discordant cases were HER2-ultralow/low with low mRNA scores. Multivariate analysis identified high nuclear grade and high Ki-67 expression as independent predictors of discordance.
The results support the use of the tumor genomic profiling test for identifying HER2-ultralow or HER2-low BC in conjunction with IHC.
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