Volume 204, January 2026, Pages 17-22Author links open overlay panelRachel L. Furuya a 1, Whitney Grither a 1, Mark G. Evans b, Sharon Wu b, Jaclyn F. Hechtman b, Harris B. Krause b, Andrew Elliott b, Cara Mathews c, Matthew T. Oliver c, Katherine Miller c, Shuanzeng Wei d, Rouba Ali-Fehmi e, David A. Bryant b, Matthew J. Oberley b, Matthew A. Powell a, Premal H. Thaker aShow moreHighlights•

Gastric and breast HER2 IHC criteria show high concordance for positive and negative overexpression in endometrial tumors.

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Discordant staining occurred most in equivocal tumors, more often classified as equivocal with gastric scoring.

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RNA expression levels appear to stratify between discordant vs. negative and equivocal vs negative tumors.

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HER2-positivity was associated with worse survival in EEA, improved in SEC, and no difference in UCS.

AbstractBackground

Immunohistochemistry (IHC) testing is the primary method to determine HER2 status at many institutions, often with reflex to in situ hybridization (ISH). DNA- and RNA- based platforms are emerging for HER-2 assessment. While approved IHC algorithms exist for HER2 scoring in breast and gastric carcinomas, neither has been validated in endometrial cancer. This study seeks to compare them and evaluate patterns of DNA and RNA expression.

Methods

263 endometrioid endometrial adenocarcinoma (EEA), 275 serous endometrial carcinoma (SEC), and 214 uterine carcinosarcoma (UCS) specimens were randomly selected. Previously stained HER2 IHC slides underwent blinded review by two board-certified pathologists and were scored utilizing gastric and breast criteria. Tumors were analyzed for ERBB2 copy number amplification by DNA sequencing and ERBB2 RNA expression by RNA sequencing. Statistical significance was determined using unpaired t-test.

Results

Concordance between scoring algorithms was high for HER2-positive (95 %) and HER2-negative (88 %) cases. Of discordant tumors, the majority (89.7 % of EEA, 68.8 % of SEC, and 81.8 % of UCS) were negative by breast but equivocal by gastric criteria. RNA expression levels were significantly different between discordant cases and negative cases and between negative and equivocal cases. HER2-positivity was associated with worse survival in EEC, improved in SEC, and no difference in UCS.

Conclusions

Breast and gastric scoring criteria show high concordance in endometrial carcinoma, with discordance primarily in equivocal tumors. RNA expression may help stratify equivocal from negative cases. Further study is needed to determine whether HER2 alterations at the DNA, RNA, or protein level predict response to newer generation HER2-targeted therapies.

Previous article in issueNext article in issueKeywords

Endometrial cancer

HER2

Immunohistochemistry

Gastric

Breast

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1

Both Rachel Furuya and Whitney Grither contributed equally as co-first authors for this manuscript.

Published by Elsevier Inc.