The Impact of the Hippo Pathway and Cell Metabolism on Pathological Complete Response in Locally Advanced Her2+ Breast Cancer: The TRISKELE Multicenter Prospective Study

SIMPLE SUMMARY: Pathological complete response (pCR) is a key outcome in locally advanced Her2+ breast cancer (BC) patients treated with anti-Her2−based neoadjuvant therapy. Several clinical and biological features may affect pCR rate, but reliable predictors are needed for clinical practice. The Hippo pathway and its main transducers, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), play a relevant role in treatment outcomes. We herein present evidence concerning the impact of the immunohistochemical expression of key Hippo transducers and their regulators, namely AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR), on the pCR rate of 65 Her2+ BC patients receiving neoadjuvant trastuzumab-based therapy. Low expression of TAZ, especially if concomitant with low expression of YAP and HMGCR and high expression of SCD1, was a negative predictor of pCR, although not confirmed in the multivariate analysis. However, our findings were concordant with overall survival data from the TCGA cohort. ABSTRACT: The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies.