ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Anti-HER2 therapy targets ERBB2-amplified/overexpressing endometrial carcinoma (EC).
• ERBB2 mutations are an alternative activation mechanism, but are rarely reported in EC.
• Characterizing ERBB2-mutated EC is crucial for understanding its distinct biology and therapeutic implications.

Purpose of the Study:

• To investigate the clinicopathologic and genetic features of ERBB2-mutated endometrial carcinoma.
• To compare ERBB2-mutated EC with ERBB2-wildtype and ERBB2-amplified EC.
• To assess the prognostic significance of ERBB2 mutations and amplification in EC.

Main Methods:

• Analysis of a cohort of 2638 ECs using clinical tumor-normal panel sequencing.
• Identification of pathogenic ERBB2 mutations and co-occurring ERBB2 amplification.
• Immunohistochemistry to assess HER2 protein expression.
• Comparison of molecular subtypes, tumor mutational burden, and chromosomal instability between groups.

Main Results:

• Found 69 (2.6%) ECs with pathogenic ERBB2 mutations; 11 also had ERBB2 amplification.
• V842I (38%) and R678Q (25%) were the most common ERBB2 mutations.
• ERBB2-mutated/non-amplified ECs were enriched for MSI-H and POLE subtypes, with high tumor mutational burden and low chromosomal instability.
• Low HER2 protein expression was observed in most ERBB2-mutated ECs.
• ERBB2 amplification, but not mutation alone, was associated with worse prognosis on univariate analysis.

Conclusions:

• ERBB2 mutation defines a rare, pathogenically distinct subgroup of endometrial carcinoma.
• This subgroup differs significantly from ERBB2-wildtype and ERBB2-amplified ECs.
• Findings highlight the importance of genetic profiling for understanding EC heterogeneity and guiding targeted therapies.