Activated Hippo Pathway is Associated with a Worse Response to Trastuzumab and Worse Survival in HER2-Positive Breast Cancer.

Background: The Hippo signaling pathway is an evolutionarily conserved network that regulates cell proliferation, apoptosis, and stemness. It also plays an important role in tumorigenesis and cancer progression, and previous studies have indicated that Hippo signaling promotes trastuzumab resistance in breast cancer (BC). However, its clinical relevance in patients with BC remains unclear.

Patients and methods: Clinical and transcriptomics data from two large cohorts, METABRIC and TCGA, were analyzed. A Hippo pathway score was calculated by applying Gene Set Variation Analysis to the curated Kyoto Encyclopedia of Genes and Genomes (KEGG) Hippo pathway gene set (43 genes). Patients were stratified into high and low groups based on the top tertile of Hippo pathway scores in each cohort.

Results: High Hippo pathway scores were significantly associated with worse disease-specific survival (DSS) in HER2-positive BC. In both cohorts, the Hippo pathway score showed the largest hazard ratio (HR) for DSS in HER2-positive BC compared with YAP1 or TAZ, transcription co-activators that are key components in the Hippo pathway (HR = 2.47, p = 0.04, and HR = 41.8, p = 0.03). Breast cancers with high Hippo pathway activity were associated with enrichment of cell proliferation and metastasis-related gene sets, including epithelial-mesenchymal transition, Notch, Hedgehog, and TGF-β signaling. Moreover, high Hippo pathway scores correlated with lower infiltration of anti-cancer immune cells (Th1 cells, dendritic cells, and M1-macrophages). Notably, low Hippo pathway scores were linked to a higher pathological complete response following trastuzumab-based neoadjuvant chemotherapy (p = 0.035).

Conclusions: Enhanced Hippo pathway activity in HER2-positive BC is associated with worse prognoses, metastasis-related gene enrichment, and reduced anti-cancer immune cell infiltration, potentially contributing to trastuzumab resistance.