MAGNOLIA

Triple negative breast cancer (TNBC) accounts for 15 to 20 percent of all breast cancers with over 200,000 cases each year. TNBC has the worst outcome with few treatments available. Despite important progress and recent approval of immunotherapy for TNBC, clinical benefits remain modest and restricted to a subset of patients. Notably, there is currently no reliable means to tell if a patient with TNBC will benefit or not from immunotherapy.

To address this, we will perform multiomics analysis of primary and metastatic TNBC lesions obtained from 2 randomized phase II clinical trials headed by our consortium: i) the GeparNuevo trial, investigating the addition of anti-PD-L1 to neoadjuvant chemotherapy in early TNBC; and ii) the SYNERGY trial, evaluating the combination of chemotherapy with anti-PD-L1 with or without an anti-CD73 mAb in previously untreated locally recurrent inoperable or metastatic TNBC.

Our objective is to define the adaptation of TNBC to immunotherapy with specific aims:
1) Identify features of TNBC tumors associated with response and resistance to immunotherapy by state-of-the-art profiling technologies (bulk tumor and single cell sequencing, spatial transcriptomics and proteomics);
2) Determine the impact of immunotherapy on the evolution of TNBC tumors through the profiling biopsies before and after treatment;
3) Evaluate the predictive value of the discovered biomarkers by testing their association with clinical response.
4) Develop preclinical TNBC models to functionally validate that targeting specific pathways discovered in aims 1) to 3), as well as identified putative targets by our consortium (i.e. CHI3L1, PAR-2, B7H4), synergize with anti-PD-1/L1.

Our project will allow clinicians to better identify TNBC patients with predicted benefit from immunotherapy, will validate therapeutic targets to enhance response to immunotherapy and will provide new strategies for next-generation immunotherapies of TNBC.