PD-1-associated gene expression signature of neoadjuvant trastuzumab-treated tumors correlates with patient survival in HER2-positive breast cancer

William P.D. Hendricks, Natalia Briones, Rebecca F. Halperin, Salvatore Facista, Paul R. Heaton, Daruka Mahadevan, Suwon Kim

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive biomarkers for trastuzumab-elicited tumor immune responses. Immunohistochemistry showed that all tumors had an activated tumor immune microenvironment positive for nuclear NF-κB/p65RelA, CD4, and CD8 T cell markers, but only four out of eight tumors were positive for the PD-1 immune checkpoint molecule, which is indicative of an exhausted immune environment. Exome sequencing showed no specific driver mutations correlating with PD-1 positivity. Hierarchical clustering of the RNA sequencing data revealed two distinct groups, of which Group 2 represented the PD-1 positive tumors. A gene expression signature that was derived from this clustering composed of 89 genes stratified HER2+ breast cancer patients in the TCGA dataset and it was named PD-1-Associated Gene Expression Signature in HER2+ Breast Cancer (PAGES-HBC). Patients with the Group 2 PAGES-HBC composition had significantly more favorable survival outcomes with mortality reduced by 83% (hazard ratio 0.17; 95% CI, 0.05 to 0.60; p = 0.011). Analysis of three longitudinal samples from a single patient showed that PAGES-HBC might be transiently induced by trastuzumab, independent of clonal tumor expansion over time. We conclude that PAGES-HBC could be further developed as a prognostic predictor of trastuzumab response in HER2+ breast cancer patients and be potentially used as an alternative biomarker for anti-PD-1 therapy trials.

Original languageEnglish (US)
Article number1566
JournalCancers
Volume11
Issue number10
DOIs
StatePublished - Oct 2019

Keywords

  • Breast cancer
  • Gene signature
  • HER2
  • PD-1
  • Survival outcome
  • Trastuzumab
  • Tumor evolution

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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