Abstract
Trastuzumab-based chemotherapy has shown remarkable clinical benefits for patients with HER2-positive breast cancer. 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 coactivator, to be coamplified 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. The coexpression of WBP2 and HER2 in breast tumors was validated using IHC. 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 multicenter retrospective study involving 143 patients given neoadjuvant trastuzumab-based chemotherapy was conducted to determine whether WBP2 expression correlates with pathologic complete response (pCR). Elevated expression of WBP2 significantly enhanced breast cancer's response to trastuzumab by augmenting trastuzumab-induced HER2 downregulation and cell-cycle arrest via inhibition of cyclin D expression. High level of WBP2 correlated with better pCR (67.19%) compared with low WBP2 level (26.58%). The highest response was observed in subgroups of patients with high WBP2-expressing tumors also aged below 50 years (77.78%) or were premenopausal 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. WBP2 expression correlates with the response of HER2-positive breast cancer to trastuzumab-based neoadjuvant chemotherapy.
Highlights
Breast cancer is the second leading cause of cancer-related deaths in women, especially among women aged 40–59 years [1]
The highest response was observed in subgroups of patients with high WW-binding protein 2 (WBP2)–expressing tumors aged below 50 years (77.78%) or were premenopausal in status (73.33%)
WBP2 expression correlates with the response of human epidermal growth factor receptor 2 (HER2)-positive breast cancer to trastuzumab-based neoadjuvant chemotherapy
Summary
Breast cancer is the second leading cause of cancer-related deaths in women, especially among women aged 40–59 years [1]. Breast cancer can be molecularly subclassified into four groups depending on the estrogen (ER)/progesterone (PR) and human epidermal growth factor receptor 2 (HER2) status: luminal A (ER and/or PR positive with low Ki67), luminal B (ER and/or PR positive and either HER2 positive or HER2 negative with high Ki67), HER2 (HER2 positive), and basal-like HER2 ( known as ErbB2/neu) is amplified and overexpressed in 15%– 20% of breast cancer. Trastuzumab humanized mAb is the first HER2-targeted therapy that was approved by the United States Food and Drug Administration (US FDA) for metastatic HER2-overexpressing breast cancer as the first-line therapy often in combination with chemotherapy [5,6,7]. HER2 or EGFR2 is one of the 4 members of the EGF receptor (EGFR) family of tyrosine kinases.
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