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Updated: Sep 9, 2025

Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
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Immune and Growth Factor Signaling Pathways Are Associated with Pathologic Complete Response to an Anti-Type I

Emmanuel F Petricoin1, Denise M Wolf2, Christina Yau3

  • 1Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 4, 2025
PubMed
Abstract

Insights

Biomarker analysis in breast cancer revealed that activated insulin-like growth factor 1 receptor (IGF-1R) and immune markers predict treatment response to neoadjuvant therapy, particularly in hormone receptor-positive tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Neoadjuvant breast cancer treatment aims to reduce tumor size before surgery.
  • Identifying predictive biomarkers is crucial for personalized therapy selection.
  • The I-SPY2 trial investigated novel neoadjuvant regimens including IGF-1R targeting agents.

Purpose of the Study:

  • To identify biomarkers predicting pathologic complete response (pCR) to paclitaxel, ganitumab (anti-IGF-1R antibody), and metformin (PGM) followed by AC chemotherapy.
  • To compare biomarker associations in the PGM arm versus a control chemotherapy arm.
  • To explore the role of IGF-1R pathway activation and immune markers in treatment response.

Main Methods:

  • Analysis of pretreatment tumor specimens from I-SPY2 trial participants.
  • Utilized laser capture microdissection and reverse-phase protein array.
  • Evaluated 32 prespecified biomarkers in the IGF-1R pathway and 109 exploratory markers.

Main Results:

  • Higher phosphorylated IGF-1R/insulin receptor (IR) levels correlated with increased pCR, especially in hormone receptor (HR)-positive breast cancer.
  • Immune response markers associated with pCR, with distinct patterns in HR+ and HR- tumors.
  • Specific markers (phospho-STAT1 Y701, low phospho-p27) linked to pCR in HR- tumors treated with PGM.

Conclusions:

  • Activated IGF-1R/IR signaling is associated with enhanced pCR to PGM in HR+ breast cancers.
  • Immune activation markers also predict response in both HR+ and HR- subgroups.
  • IGF-1R activation may directly influence tumor biology and immune response to neoadjuvant therapy.

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