Related Experiment Video
Updated: Oct 19, 2025
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
Integrated Molecular and Immune Phenotype of HER2-Positive Breast Cancer and Response to Neoadjuvant Therapy: A
Sara Pizzamiglio1, Chiara Maura Ciniselli1, Tiziana Triulzi2
1Unit of Bioinformatics and Biostatistics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Purpose:
Little is known about the efficacy of HER2-targeted therapy in patients with breast cancer showing different HER2-pathway dependence and immune phenotypes. Herein, we report a NeoALTTO exploratory analysis evaluating the clinical value of 22 types of tumor-infiltrating immune cells by CIBERSORT and 5 immune-related metagenes in the overall patient population, and in subgroups defined by the TRAR classifier as HER2-addicted (TRAR-low) or not (TRAR-high).
Patients And Methods:
Association of baseline TRAR, immune-related metagenes, and CIBERSORT data with pathologic complete response (pCR) and event-free survival (EFS) were assessed using logistic and Cox regression models. Corrections for multiple testing were performed by the Bonferroni method.
Results:
A total of 226 patients were analyzed: 80 (35%) achieved a pCR, and 64 (28%) experienced a relapse with a median follow-up of 6.7 (interquartile range 6.1-6.8) years; 108 cases were classified as TRAR-low, and 118 TRAR-high. Overall, γδ T-cell fraction [OR = 2.69; 95% confidence interval (CI), 1.40-5.18], and no immune-related metagenes were predictive of pCR. Notably, lymphocyte-specific kinase (LCK) predicted pCR to combination (OR = 2.53; 95% CI, 1.12-5.69), but not to single-agent trastuzumab or lapatinib [OR = 0.74; 95% CI, 0.45-1.22 (P interaction = 0.01)]. Integrating LCK with γδ T cells in a multivariate model added to the discriminatory capability of clinical and molecular variables with a shift in AUC from 0.80 (95% CI, 0.74-0.86) to 0.83 (95% CI, 0.78-0.89). In TRAR-low cases, activated mast cells, IFN and MHCII were reduced, and STAT1, HCK1, and γδ T cells were associated with pCR. STAT1 was broadly associated with improved EFS regardless of pCR, and nodal status in overall (HR = 0.68; 95% CI, 0.49-0.94) and in TRAR-low cases (HR = 0.50; 95% CI, 0.30-0.86).
Conclusions:
Immuno-phenotyping holds the promise to complement current predictive models in HER2-positive breast cancer and to assist in new therapeutic development.
Insights
Immune cell profiling, including gamma delta T cells and lymphocyte-specific kinase (LCK), predicts treatment response in HER2-positive breast cancer. This analysis enhances predictive models for better therapeutic development.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Efficacy of HER2-targeted therapy varies based on HER2-pathway dependence and immune phenotypes in breast cancer.
- Understanding these variations is crucial for optimizing treatment strategies.
Purpose of the Study:
- To evaluate the clinical utility of tumor-infiltrating immune cells and immune-related metagenes in predicting treatment response.
- To analyze subgroups based on HER2-pathway dependence (TRAR classifier).
Main Methods:
- Exploratory analysis of the NeoALTTO trial data.
- Utilized CIBERSORT for immune cell profiling (22 types) and identified 5 immune-related metagenes.
- Assessed associations with pathologic complete response (pCR) and event-free survival (EFS) using logistic and Cox regression models.
Main Results:
- Gamma delta T-cell fraction and lymphocyte-specific kinase (LCK) predicted pCR, with LCK showing specific efficacy in combination therapy.
- Immune markers like STAT1 were broadly associated with improved EFS.
- TRAR-low subgroup showed associations between specific immune cells (e.g., activated mast cells, γδ T cells) and pCR.
Conclusions:
- Immune phenotyping can enhance current predictive models for HER2-positive breast cancer.
- This approach holds promise for guiding new therapeutic development and personalizing treatment.
