Hormone Therapy Enhances Anti-PD1 Efficacy in Premenopausal Estrogen Receptor-Positive and HER2-Negative Advanced Breast Cancer

Hormone Therapy Enhances Anti-PD-1 Efficacy: A Breakthrough Study Targeting Estrogen Receptor-Positive/HER2-Negative Metastatic Breast Cancer

Background: Why Conduct This Study?

In recent years, cancer immunotherapies have achieved transformative success, with notable efficacy in “hot tumors,” such as triple-negative breast cancer (TNBC), which have high levels of immune infiltration. However, for estrogen receptor-positive/human epidermal growth factor receptor-2 negative (ER+/HER2−) metastatic breast cancer (MBC), the overall response rate to immunotherapy remains low. This is primarily due to characteristics such as low tumor mutational burden (TMB), sparse tumor-infiltrating lymphocytes (TILs), and low PD-L1 (programmed death-ligand 1) expression. Consequently, the ER+/HER2− subtype is often classified as a “cold tumor,” with limited immune responsiveness.

Given these traits, a natural question arises: Can hormonal therapy enhance the effects of immunotherapy for such “cold tumors”? Estrogen’s dual role in both breast cancer cells and the tumor microenvironment suggests that anti-estrogen treatments might reduce immune suppression and activate immune-related mechanisms within the tumor microenvironment. The research team hypothesized that combining anti-PD-1 antibodies with hormonal therapy could improve therapeutic responses in ER+/HER2− metastatic breast cancer. This study was initiated to explore this hypothesis.

Study Source and Publication Information

This groundbreaking research was conducted by I-Chun Chen, Ching-Hung Lin, and their team, primarily from the National Taiwan University Cancer Center and National Taiwan University Hospital departments. The study was published in Cell Reports Medicine on January 21, 2025, Volume 6, with the DOI: 10.1016/j.xcrm.2024.101879.

Study Design and Methodology: Clinical Trial of Hormone Therapy Combined with Immunotherapy

The study was an open-label, single-center, phase I/II clinical trial designed to evaluate the efficacy of combining the anti-PD-1 antibody pembrolizumab with the nonsteroidal aromatase inhibitor exemestane and the gonadotropin-releasing hormone agonist leuprolide. Below is a detailed breakdown of the study design.

(a) Study Workflow and Experimental Details

  1. Patient Screening and Enrollment

    • A total of 39 candidate patients were screened, with 16 successfully enrolled and 15 receiving at least one dose of the study treatment. The enrolled patients were all premenopausal women with ER+/HER2− metastatic breast cancer who had failed one or two lines of hormone therapy.
    • Reasons for exclusion included hepatitis B surface antigen positivity, non-measurable lesions, or having undergone more than two prior lines of therapy.
  2. Treatment Protocol

    • Over a 28-day treatment cycle, pembrolizumab was administered intravenously at 100–150 mg on days 1 and 15. Exemestane was taken orally at 25 mg daily, while leuprolide was administered subcutaneously at 3.75 mg monthly.
    • Treatment continued until disease progression, unacceptable adverse events, or voluntary patient withdrawal.
  3. Tumor Sample Collection and Analysis

    • Tumor samples were collected at baseline, during cycle 3, and at the end of the study. Multiple analytical methods were employed, including immunohistochemistry (IHC), RNA sequencing, and Nanostring-based platforms.
  4. RNA Sequencing and Bioinformatics Analysis

    • RNA was extracted and prepared for next-generation sequencing with the TruSeq Stranded mRNA kit on the Novaseq 6000 platform, using deep sequencing with a 150 bp paired-end format.
    • Raw reads were aligned to the reference genome using STAR software, differential gene expression analysis was conducted, and pathway enrichment was identified using Gene Set Enrichment Analysis (GSEA).
  5. Study Objectives and Data Processing

    • Tumor mutational burden, TIL percentage, and PD-L1 expression levels were analyzed. Immune-related gene signatures were quantified using the Nanostring platform.

(b) Key Findings

  1. Clinical Efficacy

    • Among the 14 evaluable patients, the 8-month progression-free survival (PFS) rate was 64.3%, with a median PFS of 10.1 months.
    • The overall objective response rate (ORR) was 35.7%, and the clinical benefit rate reached an impressive 85.7%, including cases of partial responses and stable disease.
  2. Changes in Immune Microenvironment

    • Nanostring analysis revealed a significant post-treatment increase in immune cells, such as CD56dim natural killer (NK) cells and Th1 cells, as well as upregulated expression of immune-related genes (e.g., MHC class I-related genes and T-cell receptor-associated genes).
    • Differentially expressed gene (DEG) analysis identified that treatment response was strongly correlated with upregulated genes such as CCDC74A and VSTM2A.
  3. Immune Suppression Markers

    • Even patients with low PD-L1 expression (%) demonstrated favorable responses, suggesting that PD-L1 alone may not be sufficient to predict therapeutic efficacy.
    • Similarly, low TMB levels did not preclude the success of this combination therapy.

© Conclusion and Significance

This study demonstrated that combining anti-PD-1 antibodies with hormonal therapy significantly enhances immune therapy efficacy for ER+/HER2− breast cancer. This approach not only overcomes the limitations of standalone hormone or immunotherapy but also improves immune microenvironment activation, transitioning the tumor to an “immunoactive” state and fostering higher responsiveness to immunotherapy.

The findings lay the groundwork for future randomized clinical trials with larger sample sizes and provide a solid basis for optimizing combination treatment strategies.

(d) Research Highlights

  1. Novel Combination Therapy: The study was the first to evaluate the efficacy of hormonal therapy combined with immunotherapy for ER+/HER2− breast cancer.
  2. Significant Therapeutic Outcomes: The observed clinical response rates and progression-free survival notably surpassed historical benchmarks.
  3. Activation of the Immune Microenvironment: Post-treatment upregulation of TILs and immune-related gene expression highlighted the synergistic potential of the combined approach.

(e) Additional Insights

The study utilized innovative data analysis methodologies, including RNA sequencing and GSEA, to uncover potential mechanisms underlying therapeutic responses. Additionally, it integrated immune microenvironment features with expression profile data related to patient heterogeneity, offering insightful strategies for addressing “cold tumors.”

Summary

This study provides a major contribution to the ER+/HER2− breast cancer field by combining the immune-regulating potential of hormonal therapy with the direct checkpoint inhibition of immunotherapy. This approach addresses key treatment limitations and enhances the understanding of the complex immune microenvironment within these tumors. The proposed combination therapy represents a pivotal advancement in clinical cancer research and offers new hope for patients with a historically difficult-to-treat cancer subtype.