477P Do ESR1-related mutations generate neoantigens in hormone-receptor-positive HER2-negative metastatic breast cancer?
Annals of Oncology(2023)
摘要
Breast Cancer (BC) is the most common type of cancer in women and 80% of cases are hormone-receptor positive. In 20 % a key mechanism of endocrine resistance to the standard first line is mutation of the ligand-binding domain of Estrogen Receptor 1 (ESR1) encoding estrogen receptor a. These mutations are clustered in a “hotspot” within the LBD. Four mutations are known in positions 537 and 538 (D538G, Y537C, Y537N, and Y537S), and lead to cell proliferation and potentially enhanced metastatic capacity. This project aims to identify if ESR1 receptor mutations are neoantigens in patients with HR+ HER2- metastatic BC, and thus resistant to endocrine therapy. We identified candidate ESR1-derived-peptides, to evaluate the immunogenicity of these peptides we conducted a vaccination assay on a humanized mouse model. We administered 100 μg of each peptides and 50 μg of CpG on day 0 (D0). We achieved three boosts with 50 μg of each peptides and 30 μg of CpG on D7, D14 and D21. Spleen and lymph nodes were isolated on D23 and immunogenicity tests were conducted. We also evaluated the immunogenicity of ESR1-derived peptides in PBMC on 30 healthy donors (HD) and 25 patients with mBC HR+ BC by ELISpot assay. Furthermore, we cloned T-cells with 2 stimulations in 30 days, to demonstrate that T-cells can lyse tumour cells. Preliminary results validated the HLA-A2 ESR1 peptide immunogenicity in humanized mice. In the same way, we demonstrated the ESR1 peptide immunogenicity in HD and patients with BC. Our results showed that 40% of patients had specific immune responses. and these patients presented secondary hormone-resistance. These data allow the selection of the most relevant peptides which are either weakly or not observed at all with HD. These results support that the ESR1 mutation generates neoantigens in hormone-receptor-positive metastatic breast cancer. From the perspective of those results, we will try to demonstrate the natural ESR1-specificity T cell clones to recognize and kill transduced ESR1 tumour cells. Additionally, we will analyze HLA Class I expression in mutated/non-mutated ESR1 patients by bioinformatics in order to understand if tumour resistance may be linked to the loss of HLA expression.
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关键词
metastatic breast cancer,breast cancer,mutations,hormone-receptor-positive
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