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.