Integrative proteomic and gene expression analysis identify potential biomarkers for adjuvant trastuzumab resistance:
Amir Sonnenblick1, Sylvain Brohée1, Debora Fumagalli1
1Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Abstract:
Trastuzumab is a remarkably effective therapy for patients with human epidermal growth factor receptor 2 (HER2)--positive breast cancer (BC). However, not all women with high levels of HER2 benefit from trastuzumab. By integrating mRNA and protein expression data from Reverse-Phase Protein Array Analysis (RPPA) in HER2-positive BC, we developed gene expression metagenes that reflect pathway activation levels. Next we assessed the ability of these metagenes to predict resistance to adjuvant trastuzumab using gene expression data from two independent datasets.10 metagenes passed external validation (false discovery rate [fdr] < 0.05) and showed biological relevance with their pathway of origin. These metagenes were further screened for their association with trastuzumab resistance. An association with trastuzumab resistance was observed and validated only for the AnnexinA1 metagene (ANXA1). In the randomised phase III Fin-her study, tumours with low levels of the ANXA1 metagene showed a benefit from trastuzumab (multivariate: hazard ratio [HR] for distant recurrence = 0.16[95%CI 0.05-0.5]; p = 0.002; fdr = 0.03), while high expression levels of the ANXA1 metagene were associated with a lack of benefit to trastuzmab (HR = 1.29[95%CI 0.55-3.02]; p = 0.56). The association of ANXA1 with trastuzumab resistance was successfully validated in an independent series of subjects who had received trastuzumab with chemotherapy (Log Rank; p = 0.01).In conclusion, in HER2-positive BC, some proteins are associated with distinct gene expression profiles. Our findings identify the ANXA1metagene as a novel biomarker for trastuzumab resistance.
Insights
A novel biomarker, the AnnexinA1 metagene (ANXA1), predicts resistance to trastuzumab therapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Low ANXA1 levels indicate benefit, while high levels suggest lack of response.
Area of Science:
- Oncology
- Genomics
- Biomarker Discovery
Background:
- Trastuzumab is effective for HER2-positive breast cancer, but not all patients benefit.
- Predicting response to trastuzumab remains a clinical challenge.
Purpose of the Study:
- To identify gene expression biomarkers predicting trastuzumab resistance in HER2-positive breast cancer.
- To validate the predictive ability of identified biomarkers.
Main Methods:
- Integrated mRNA and protein expression data using Reverse-Phase Protein Array Analysis (RPPA).
- Developed gene expression metagenes to reflect pathway activation.
- Assessed metagene ability to predict trastuzumab resistance in independent datasets.
Main Results:
- Ten metagenes passed validation, showing biological relevance.
- The AnnexinA1 metagene (ANXA1) was uniquely associated with trastuzumab resistance.
- Low ANXA1 levels predicted trastuzumab benefit (HR=0.16, p=0.002), while high levels indicated lack of benefit (HR=1.29, p=0.56).
- ANXA1's association with resistance was validated in an independent cohort (p=0.01).
Conclusions:
- Distinct gene expression profiles correlate with protein expression in HER2-positive breast cancer.
- The ANXA1 metagene is a novel predictive biomarker for trastuzumab resistance.
- This finding may guide personalized treatment strategies for HER2-positive breast cancer patients.
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