The validation of a unique gene signature for triple negative breast cancer (TNBC) prognosis and predicting benefit for immunotherapy

Breast cancer (BC) is the most diagnosed cancer worldwide and the leading cause of cancer-related deaths in women. In Qatar, although the age standardized rate (ASR) of BC (70.1) in 2020 is slightly lower than the global ASR (85.0), the percentage of BC within all cancers diagnosed in the 35-54 age group (50%) was higher than the global percentage (35%). Younger age of diagnosis is often a characteristic of triple negative breast cancer (TNBC) which accounts for 15-20% of diagnosed BCs. TNBC is highly aggressive, associated with a higher risk of recurrence and lacks effective therapies, imposing a burden on the healthcare system. Our in-silico analysis based on the TCGA BC dataset identified a unique 30-gene signature in TNBC consisting of genes that are targets of the histone methyltransferase EZH2. Higher expression of the 30-gene signature is significantly associated with improved survival in TNBC and in inversely associated with immune signatures such as downregulation of the expression of the PD-1 and CTLA4, MHC and lymphocyte infiltration score. We hypothesize that the 30-gene signature may contribute to immune evasion and thus resistance to immunotherapy and that it can be a potential predictive and prognostic biomarker for cancer immunotherapy in TNBC. To this end, this project aims to initially investigate the association of the 30-gene signature with more established biomarkers (TMB, PD-L1 and immune signatures) through in silico analysis on the TCGA BC dataset. Furthermore, the proposal aims to investigate the significance of the 30-gene signature in contributing to immune evasion and resistance to immunotherapy through in vitro studies on BC cell line and in mouse models. Finally, the potential of the 30-gene signature as a prognostic and predictive biomarker, alone side other well-established biomarkers such as TMB, PD-L1, TILs and immune signatures, will be validated on a retrospective BC cohort from Qatar. Importantly, it is expected that this project will generate clinical data and identify the cancer-specific immune landscape of BC tumors in Qatar facilitating unique biomarker discovery and supporting a business case for routine practice of immune and molecular profiling for precision oncology.

Hamad Bin Khalifa University (HBKU)