Integrative proteomic and gene expression analysis identify potential biomarkers for adjuvant trastuzumab resistance: analysis from the Fin-her phase III randomized trial

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.