RNA expression levels from peripheral immune cells, a minimally invasive liquid biopsy source to predict response to therapy, survival and immune-related adverse events in patients with triple negative breast cancer enrolled in the GeparNuevo trial

1011 Background: The impact of immune checkpoint therapy on the tumor microenvironment including tumor-infiltrating immune cells is well described. However, little is known about the circulating immune repertoire and its association with treatment outcome. Hence, we set out to investigate the RNA phenotype of peripheral immune cells before and during treatment of patients enrolled in the GeparNuevo trial (Loibl S et al. Annals Oncol 2022). Methods: The GeparNuevo trial investigated the outcome after neoadjuvant nabP-EC-chemotherapy in combination with the anti-PD-L1 immune checkpoint inhibitor durvalumab versus placebo in patients with non-metastatic triple negative breast cancer. Blood was collected before therapy (baseline), after window, before epirubicin/cyclophosphamide and at end of treatment. RNA from circulating leucocytes of 117 patients was extracted and analyzed using a custom NanoString nCounter CodeSet. Expression of 290 immune-related genes was quantified. The association of RNA expression and signatures with outcome parameters like pathologic complete response (pCR), distant disease-free survival (DDFS), invasive disease-free survival (iDFS), overall survival (OS), and immune-related adverse events (irAEs) were investigated. Results: Immune cell type scores representing macrophages and neutrophils significantly increased during treatment, while B cell, T and Th1 cell scores decreased (p < 0.0001, respectively) regardless of treatment arm. Multivariate logistic respectively multivariate Cox regression analysis revealed a significant association of each baseline DPP4 and MYC gene expression with pCR, DDFS, iDFS, and OS in patients. CDK2, F5 and HLA-DR mRNA expressions were associated with the presence of irAEs. The signature score for TNFR2 non-canonical NF-kB pathway, which is known for its protective capacity, was inversely associated with irAEs in the durvalumab arm (OR = 0.454, 95% CI 0.231-0.892, p = 0.0220). Multiple immune-related signatures at baseline were associated with tumor mutational burden. Conclusions: Our study indicates the importance of the peripheral immune phenotype for treatment response and survival. This association between RNA expression levels of circulating immune cells and outcome seems to be not only relevant for patients receiving immune checkpoint therapy, but also for those under standard chemotherapy alone. Clinical trial information: NCT02685059 .