Whole-transcriptome analysis links trastuzumab sensitivity of breast tumors to both HER2 dependence and immune cell
Tiziana Triulzi1, Loris De Cecco2, Marco Sandri1
1Department of Experimental Oncology and Molecular Medicine, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Abstract:
While results thus far demonstrate the clinical benefit of trastuzumab, some patients do not respond to this therapy. To identify a molecular predictor of trastuzumab benefit, we conducted whole-transcriptome analysis of primary HER2+ breast carcinomas obtained from patients treated with trastuzumab-containing therapies and correlated the molecular portrait with treatment benefit. The estimated association between gene expression and relapse-free survival allowed development of a trastuzumab risk model (TRAR), with ERBB2 and ESR1 expression as core elements, able to identify patients with high and low risk of relapse. Application of the TRAR model to 24 HER2+ core biopsies from patients treated with neo-adjuvant trastuzumab indicated that it is predictive of trastuzumab response. Examination of TRAR in available whole-transcriptome datasets indicated that this model stratifies patients according to response to trastuzumab-based neo-adjuvant treatment but not to chemotherapy alone. Pathway analysis revealed that TRAR-low tumors expressed genes of the immune response, with higher numbers of CD8-positive cells detected immunohistochemically compared to TRAR-high tumors. The TRAR model identifies tumors that benefit from trastuzumab-based treatment as those most enriched in CD8-positive immune infiltrating cells and with high ERBB2 and low ESR1 mRNA levels, indicating the requirement for both features in achieving trastuzumab response.
Insights
A new Trastuzumab Risk (TRAR) model predicts patient response to trastuzumab therapy in HER2+ breast cancer. TRAR identifies patients likely to benefit based on ERBB2, ESR1, and CD8+ immune cell levels.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Trastuzumab is a key therapy for HER2-positive breast cancer, but not all patients respond.
- Identifying predictors of trastuzumab benefit is crucial for personalized treatment strategies.
Purpose of the Study:
- To develop and validate a molecular predictor of trastuzumab benefit in HER2-positive breast cancer.
- To correlate gene expression profiles with relapse-free survival in patients treated with trastuzumab.
Main Methods:
- Whole-transcriptome analysis of primary HER2+ breast carcinomas.
- Development of the Trastuzumab Risk (TRAR) model using ERBB2 and ESR1 expression.
- Validation of the TRAR model in independent patient cohorts and datasets.
Main Results:
- The TRAR model, incorporating ERBB2 and ESR1 expression, accurately predicts trastuzumab response in HER2+ breast cancer.
- TRAR stratifies patients for trastuzumab-based neoadjuvant treatment response, but not chemotherapy alone.
- TRAR-low tumors show enrichment in immune response genes and higher CD8-positive cell infiltration.
Conclusions:
- The TRAR model is a predictive tool for trastuzumab benefit in HER2+ breast cancer.
- Tumor immune microenvironment, particularly CD8+ cell infiltration, alongside ERBB2 and ESR1 expression, is critical for trastuzumab response.
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