A phenocopy signature of TP53 loss predicts response to chemotherapy

In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53 -loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53 -loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53 -loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53 -loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial ( N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53 -loss phenocopy tumors compared to non- TP53 -loss phenocopy tumors (64% vs. 28%). The TP53- loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.