Correlation of HER2 Protein Level With mRNA Level Quantified by RNAscope in Breast Cancer

Xiaoxian Li, Ji Hoon Lee, Yuan Gao, Jilun Zhang, Katherine M. Bates, David L. Rimm, Huina Zhang, Geoffrey Hughes Smith, Diane Lawson, Jane Meisel, Jenny Chang, Lei Huo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Trastuzumab deruxtecan (T-DXd) has been approved by the US Food and Drug Administration (FDA) to treat patients with metastatic HER2-positive and HER2-low breast cancer, and clinical trials are examining its efficacy against early-stage breast cancer. Current HER2 immunohistochemical (IHC) assays are suboptimal in evaluating HER2-low breast cancers and identifying which patients would benefit from T-DXd. HER2 expression in 526 breast cancer tissue microarray (TMA) cores was measured using the FDA-approved PATHWAY and HercepTest IHC assays, and the corresponding RNA levels were evaluated by RNAscope. HER2 protein levels by regression analysis using a quantitative immunofluorescence score against cell line arrays with known HER2 protein levels determined by mass spectrometry were available in 48 of the cores. RNAscope was also performed in 32 metastatic biopsies from 23 patients who were subsequently treated with T-DXd, and the results were correlated with response rate. HER2 RNA levels by RNAscope strongly correlated with HER2 protein levels (P < .0001) and with HER2 IHC H-scores from the PATHWAY and HercepTest assays (P < .0001). However, neither protein levels nor RNA levels significantly differed between cases scored 0, ultralow, and 1+ by PATHWAY and HercepTest. The RNA levels were significantly higher (P = .030) in responders (6.4 ± 8.2 dots/cell, n = 12) than those in nonresponders (2.6 ± 2.2, n = 20) to T-DXd. RNAscope is a simple assay that can be objectively quantified and is a promising alternative to current IHC assays in evaluating HER2 expression in breast cancers, especially HER2-low cases, and may identify patients who would benefit from T-DXd.

Original languageEnglish (US)
Article number100408
JournalModern Pathology
Volume37
Issue number2
DOIs
StatePublished - Feb 2024

Keywords

  • Biomarker
  • HER2
  • Predictive
  • RNAscope
  • T-DXd
  • quantification

ASJC Scopus subject areas

  • Medicine(all)

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