Targetable ERBB2/HER2 Mutations in Gynecologic Malignancies: Clinicopathological, Immunohistochemical, and Molecular Correlations.
Journal
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists
ISSN: 1538-7151
Titre abrégé: Int J Gynecol Pathol
Pays: United States
ID NLM: 8214845
Informations de publication
Date de publication:
10 Jun 2024
10 Jun 2024
Historique:
medline:
24
6
2024
pubmed:
24
6
2024
entrez:
24
6
2024
Statut:
aheadofprint
Résumé
Targeted anti-HER2 therapy has been recently added to the standard treatment recommendations in endometrial serous carcinoma. Current eligibility requires testing for HER2 overexpression and/or gene amplification by immunohistochemistry and by fluorescence in situ hybridization. However, clinical trials have also demonstrated the efficacy of anti-HER2 drugs against activating ERBB2/HER2 mutations in a variety of solid tumor types, and fam-trastuzumab deruxtecan is now approved by the US Food and Drug Administration for HER2-mutant non-small cell lung cancer. This study aimed at evaluating the detailed clinical, histomorphological, immunohistochemical, and molecular characteristics of gynecologic malignancies with ERBB2/HER2 mutations. We identified 16 tumors with 19 ERBB2/HER2 mutations in our departmental archives: 11 endometrial primaries, 2 endocervical adenocarcinomas, 1 ovarian mucinous adenocarcinoma, 1 tubo-ovarian undifferentiated carcinoma, and 1 high-grade endometrioid adenocarcinoma of Mullerian origin. ERBB2/HER2 mutations most often involved the tyrosine kinase domain (52.6%), and the most frequent specific mutation was R678Q (31.6%), involving the juxtamembrane domain. More than half (54.5%) of endometrial carcinomas and half of all tumors were MMR-deficient, resulting from MSH6 loss in all but 2 tumors. None of the tumors (0%) were POLE-mutated, while 18.8% were TP53-mutated. HER2 IHC was negative (score 0 or 1+) in 12 tumors (67%) and equivocal (score 2+) in 4 tumors (33%), whereas none of the tumors were scored as HER2 3+. Score 2+ was associated with R678Q, L755S, I767M mutations, and ERBB2/HER2 rearrangement with a breakpoint in exon 23. Concurrent ERBB2/HER2 amplification was identified in 2 endometrial carcinomas, with HER2/CEP17 ratios of 3.1 and 3.5. We also queried the cBioportal database, which revealed 70 ERBB2/HER2-mutant gynecologic tumors with a total of 77 ERBB2/HER2 mutations, most often involving the active site of the tyrosine kinase domain (n=36; 46.8%), and the most common specific mutation was S310F (n=20; 26%), located in the extracellular domain. Our results provide important details regarding the clinicopathological and molecular associations of potentially actionable ERBB2/HER2 mutations in endometrial carcinoma and other gynecological cancer types and contribute to addressing clinical treatment needs and improving pathology testing recommendations in the future.
Identifiants
pubmed: 38914011
doi: 10.1097/PGP.0000000000001050
pii: 00004347-990000000-00169
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 by the International Society of Gynecological Pathologists.
Déclaration de conflit d'intérêts
D.I.L. and J.A.E. are employees of Foundation Medicine, Inc., and shareholders in Roche. The remaining authors declare no conflicts of interest.
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