Elevated WBP2 expression in HER2-positive breast cancers correlates with sensitivity to trastuzumab-based neo-adjuvant therapy:A Retrospective and Multicentric Study

Purpose: Trastuzumab-based chemotherapy has shown remarkable clinical benefits for HER2-positive breast cancer patients. However, treatment regimens involving trastuzumab had little or no effect for a subset of patients. Preliminary studies revealed WW-binding protein 2 (WBP2), an oncogenic transcription co-activator, to be co-amplified with HER2 in 36% of HER2-positive breast cancers. We hypothesize that WBP2 regulates and correlates with the response of HER2-positive breast cancer to trastuzumab. Experimental Design: The co-expression of WBP2 and HER2 in breast tumors was validated using immunohistochemistry. The role and mechanism of WBP2 in regulating breast cancer response to trastuzumab was elucidated using in vitro, patient-derived xenograft and murine xenograft models. A multi-center retrospective study involving 143 patients given neoadjuvant trastuzumab-based chemotherapy was conducted to determine if WBP2 expression correlates with pathologic complete response. Results: Elevated expression of WBP2 significantly enhanced breast cancer's response to trastuzumab by augmenting trastuzumab-induced downregulation of HER2 and arrest of cell cycle via inhibition of cyclin D expression. High level of WBP2 correlated with better pathologic complete response (67.19%) compared to low WBP2 level (26.58%). The highest response was observed in subgroups of patients with high WBP2-expressing tumors and also aged below 50 years (77.78%) or were pre-menopausal in status (73.33%). Retrospectively, WBP2 demonstrated sensitivity of 80 to 81% and specificity of 76.5 to 80% in discriminating between patients showing pCR and non-pCR. Conclusions: WBP2 expression correlates with the response of HER2-positive breast cancer to trastuzumab-based neoadjuvant chemotherapy.

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