Gene expression profiles predict benefit of neoadjuvant immune checkpoint therapy in triple-negative breast cancer

RNA expression levels in peripheral immune cells from patients with triple-negative breast cancer enabled differentiation between patients who might benefit from neoadjuvant immune checkpoint therapy compared with standard therapy in a substudy of the GeparNuevo trial.

Recently, the randomised, phase 2 GeparNuevo trial (NCT02685059) demonstrated that the addition of durvalumab to anthracycline/taxane-based neoadjuvant chemotherapy improved pathologic complete response (pCR) rate and survival in patients with triple-negative breast cancer [1,2]. In a subproject, Dr Hanna Huebner (Erlangen University Hospital, Germany) and colleagues collected blood samples from participants to explore biomarkers that predict who might benefit from neoadjuvant immune checkpoint therapy compared with standard neoadjuvant therapy [3].

At baseline, blood samples from 117 participants enrolled in the GeparNuevo trial were available for RNA testing (n=63 treated with durvalumab/chemotherapy; n=54 treated with placebo/chemotherapy). Based on the RNA expression, 16 different immune cell scores were defined, as well as 26 immune signalling scores. The correlation of these scores with treatment outcome parameters (i.e. pCR, distant disease-free survival [DDFS]) was analysed, as well as any correlation of expression of 31 individual genes with these outcome parameters.

Expression of 1 immune cell score (i.e. mast cells) and 5 individual genes (i.e. CCL3, DPP4, ITGA4, MYC, and TIMP1) were significantly associated with pCR. For example, participants with low CCL3 or high ITGA4 expression benefitted from durvalumab (i.e. higher pCR rate), whereas in participants with high expression of CCL3 or low expression of ITGA4 before neoadjuvant therapy, pCR was lower with durvalumab compared with placebo. On the other hand, high expression of DPP4 or low expression of TIMP1 was associated with a higher pCR regardless of the treatment arm (i.e. durvalumab or placebo added to the neoadjuvant treatment).

With respect to DDFS, 2 immune cell scores, 1 immune signalling score, and the expression of 31 individual genes appeared to be significantly associated with this treatment outcome parameter. For example, a high Treg cell score was associated with a longer DDFS, both for placebo- and durvalumab-treated participants. Participants with low AKT signalling scores benefitted from durvalumab, whereas durvalumab did not improve DDFS in participants with a high AKT signalling score. Likewise, low expression of CDK2, high expression of MYC, and high expression of TIMP1 were associated with a DDFS benefit of durvalumab.

Based on these results, Dr Huebner concluded that “in patients with triple-negative breast cancer, RNA expression levels from peripheral immune cells could enable differentiation between patients who might benefit from neoadjuvant immune checkpoint therapy compared with standard therapy. However, further research is necessary to validate and expand upon these initial results.”

1. Loibl S, et al. Ann Oncol. 2019;30:1279–1288.
2. Loibl S, et al. Ann Oncol. 2022;33:1149–1158.
3. Huebner H, et al. RNA expression levels from peripheral immune cells, a minimal-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. Abstract 1101, ASCO Annual Meeting 2023, 2–6 June, Chicago, USA.

 

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Posted on 2 August, 20232 August, 2023