Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer
Michalina Janiszewska, … , Franziska Michor, Kornelia Polyak
Michalina Janiszewska, … , Franziska Michor, Kornelia Polyak
Published April 22, 2021
Citation Information: JCI Insight. 2021;6(11):e147617. https://doi.org/10.1172/jci.insight.147617.
View: Text | PDF
Research Article Oncology

The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer

  • Text
  • PDF
Abstract

Despite the availability of multiple human epidermal growth factor receptor 2–targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1–positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.

Authors

Michalina Janiszewska, Shayna Stein, Otto Metzger Filho, Jennifer Eng, Natalie L. Kingston, Nicholas W. Harper, Inga H. Rye, Maša Alečković, Anne Trinh, Katherine C. Murphy, Elisabetta Marangoni, Simona Cristea, Benjamin Oakes, Eric P. Winer, Ian E. Krop, Hege G. Russnes, Paul T. Spellman, Elmar Bucher, Zhi Hu, Koei Chin, Joe W. Gray, Franziska Michor, Kornelia Polyak

×

Figure 2

Phenotypic single-cell diversity measured by CycIF.

Options: View larger image (or click on image) Download as PowerPoint
Phenotypic single-cell diversity measured by CycIF.
(A) Representative C...
(A) Representative CycIF staining in HER2+ case 0016 (top) and ER+ case 0018 (bottom). Vim, Vimentin. Scale bars: 50 μm. (B) Hierarchical clustering of samples based on HER2 and ER positivity in tumor cells. pCR, pathological complete response; DN, double-negative (ER–HER2–). (C) Association between CycIF subtype identified in B and pCR. HER2+ and mixed tumors had significantly better response than DN or ER+ (χ2, P = 0.022). (D–F) Associations between tumor and immune measurements of composition (D), proximity (E), and heterogeneity (F) and pCR. Wilcoxon’s rank-sum test P values are shown. GZM, granzyme B.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts