Therapeutic indications for antibody-drug conjugates estimated from HER2 and p53 expressions in endometrial carcinoma

Hum Pathol. 2024 Oct:152:105649. doi: 10.1016/j.humpath.2024.105649. Epub 2024 Aug 21.

Abstract

Objective: While human epidermal growth factor receptor 2 (HER2) is upregulated in endometrial carcinoma-especially in the p53 aberrant type- conventional anti-HER2 therapy is not typically used for this cancer type. Recently, HER2-targeted antibody-drug conjugates have shown antitumor effects against HER2 low-expressing cancers. Therefore, we analyzed the clinicopathological characteristics of HER2-positive endometrial carcinomas including those with low expression, as well as the prognostic significance of p53 and HER2 co-expression.

Methods: Immunohistochemistry for HER2 and p53 was performed in 530 patients with endometrial carcinoma; 124 cases (23%) were HER2-positive.

Results: Of the HER2-positive cases, >50% were 1+. A high prevalence of HER2 expression was observed in serous (64%), clear-cell (73%), and mixed (64%) carcinomas. Notably, 19% of endometrioid carcinomas were HER2-positive. HER2 positivity was significantly associated with age ≥60 years, high-grade histological subtype, deep myometrium invasion, stage III/IV, recurrence, and death. Univariate analysis showed that HER2-positive cases had reduced progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.012). However, after adjusting for stage, HER2 positivity was not associated with survival. In the early stage, co-expression of HER2-positive and p53 aberrant types was associated with shorter PFS (p < 0.001) and OS (p < 0.001) compared with at least one negative result. Multivariate analysis of PFS showed HER2 and p53 co-expression (hazard ratio, 1.891; 95% confidence interval, 1.183-5.971, p = 0.008) as an independent prognostic factor.

Conclusions: This study presents detailed clinicopathological characteristics and the prognostic impact of HER2-positivity in endometrial carcinomas. HER2-targeted antibody-drug conjugate therapy may be broadly applicable to endometrial carcinoma.

Keywords: Antibody-drug conjugate; Endometrial cancer; Human epidermal growth factor receptor 2; Immunohistochemistry; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological / therapeutic use
  • Biomarkers, Tumor* / analysis
  • Biomarkers, Tumor* / metabolism
  • Endometrial Neoplasms* / drug therapy
  • Endometrial Neoplasms* / metabolism
  • Endometrial Neoplasms* / pathology
  • Erb-b2 Receptor Tyrosine Kinases* / analysis
  • Erb-b2 Receptor Tyrosine Kinases* / metabolism
  • Female
  • Humans
  • Immunoconjugates* / therapeutic use
  • Immunohistochemistry
  • Middle Aged
  • Progression-Free Survival
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Erb-b2 Receptor Tyrosine Kinases
  • Tumor Suppressor Protein p53
  • Immunoconjugates
  • Biomarkers, Tumor
  • Antineoplastic Agents, Immunological
  • ERBB2 protein, human
  • TP53 protein, human