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HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant

Whitfield B Growdon1, Jolijn Groeneweg2, Virginia Byron2

  • 1Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Harvard Medical School, Boston, MA 02115, United States.

Gynecologic Oncology
|January 21, 2015
PubMed
Abstract

Insights

High-grade endometrial cancer (EnCa) shows elevated levels of the p95HER2 variant compared to breast cancer (BrCa). This finding may explain why trastuzumab is ineffective against EnCa, despite HER2 overexpression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • High-grade endometrial cancer (EnCa) overexpresses HER2 (ERBB2).
  • Trastuzumab, a HER2-targeted therapy, has shown limited efficacy in EnCa clinical trials.
  • A truncated p95HER2 variant may contribute to trastuzumab resistance.

Purpose of the Study:

  • To investigate the expression of the p95HER2 truncated variant in high-grade endometrial cancer.
  • To compare p95HER2 levels in EnCa with those in HER2-expressing breast cancer (BrCa).

Main Methods:

  • Analysis of 86 high-grade EnCa tumor specimens (2000-2011).
  • Tumor genotyping, HER2 immunohistochemistry (IHC), HER2 FISH, and assessment of total HER2 (H2T) and p95HER2.
  • Comparison with a cohort of 107 breast tumors matched for HER2 protein expression.

Main Results:

  • High HER2 expression (2+ or 3+) observed in 59% of EnCa tumors.
  • HER2 gene amplification detected in 16% of EnCa tumors (12 USC, 4 endometrioid).
  • Elevated p95HER2 expression (>2.8RF/mm²) found in 53% of EnCa cases, correlating with H2T levels.
  • High-grade EnCa exhibited significantly higher p95HER2 levels compared to matched breast tumors (p<0.001).

Conclusions:

  • High-grade endometrial cancer expresses higher levels of the p95HER2 variant than breast cancer.
  • Elevated p95HER2 may be a key factor contributing to trastuzumab resistance in EnCa.
  • Further investigation into HER2-targeted therapies accounting for p95HER2 in EnCa is warranted.
Keywords:
HER2 over-expressionHigh grade endometrial carcinomaTrastuzumab resistancep95HER2

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