An immune infiltrate rich in Treg is associated with worse prognosis in breast cancer, although there is controversy regarding their role and clinical relevance among the different tumor subtypes. This project aims to analyze the expression of Treg-related genes and its relationship with pathological response to neoadjuvant docetaxel-carboplatin in a cohort of patients with early-stage TNBC.
Within a prospective multicenter study, we analyzed 221 pre-treatment FFPE tumor samples from patients with TNBC who had received neoadjuvant docetaxel-carboplatin. By RNA sequencing, we analyzed 23 genes related to Treg. By IHC, we analyzed the presence of tumor-infiltrating lymphocytes (TILs). We performed univariate logistic regressions of the correlation of the expression of these genes with the response and multivariate analysis of the genes whose expression showed a statistically significant correlation with response.
5 genes presented a higher expression in responders vs. non-responders in multivariable analysis: FOXP3 (p = 0.04), CTLA4 (p = 0.005), CD4 (p = 0.013), CD274 (p = 0.03), and FCRL1 (p = 0.019). The differences in CD8 expression (RNAseq) and the presence of TILs according to response were also studied. Responders had more TILs and higher CD8 expression. Ratios between FOXP3 with CD4, CD8, and TILs were calculated. In univariate analysis, responders had lower FOXP3/CD8A ratio (p = 0.102), FOXP3/CD8B ratio (p = 0.0352), and higher sTILs/FOXP3 ratio (p = 0.0104). These differences were not significant in the multivariate analysis.
In our cohort, the overexpression of genes related to Treg is associated with a better pathological response to treatment. This is observed in context of a greater immune infiltrate. A higher FOXP3/CD8 ratio is associated with a worse response in the univariate analysis, without reaching statistical significance in the multivariate analysis. Additional studies are needed to identify the mechanisms by which Treg modulate response in TNBC, whether their action is always immunosuppressive, or why they exert a different effect depending on the breast cancer subtype.
Fundación para la Investigación Biomédica del Hospital Gregorio Marañón.
This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects \"PI 15/00117\" and \"PI18/01775\" and co-funded by the European Union and by Centro de Investigación Biomédica en Red de Salud Carlos III CiberONC-ISCIII.
R. Martín Lozano: Financial Interests, Personal, Training: Sanofi, Vifor Pharma, Lilly. T. Massarrah: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Roche, GSK; Financial Interests, Personal, Training: Novartis, AstraZeneca. C. Bueno Muiño: Financial Interests, Personal, Invited Speaker: Roche, Novartis, Lilly, MSD, AstraZeneca, GSK; Financial Interests, Personal, Training: Roche, Novartis , Clovis, Pfizer. S. Lopez-Tarruella Cobo: Financial Interests, Personal, Advisory Board: Celgene, Novartis, Pierre Fabre, Pfizer, Roche, AstraZeneca, Daiichi Sankyo, MSD, Seagen, Gilead, Lilly; Financial Interests, Personal, Invited Speaker: Novartis, Roche, Lilly. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Personal, Invited Speaker: TRIO; Non-Financial Interests, Personal, Leadership Role: GEICAM. All other authors have declared no conflicts of interest.