Abstract P1-03-07: Investigation of combination treatment an aromatase inhibitor and anti-inflammatory treatment in a model of oestrogen receptor positive breast cancer

Abstract

Abstract Background: Previous analysis has revealed that high pre-treatment expression of an inflammatory gene expression signature and lymphocytic infiltration are correlated with poor response to neoadjuvant aromatase inhibitor (AI) treatment1. Upon treatment with AIs, inflammatory gene expression also increases1. These changes are also seen in vitro where an increase in chemokine secretion has been observed upon oestrogen deprivation, suggesting that treatment with anti-oestrogen therapy may modulate the immune response. In addition, non-steroidal anti-inflammatory drug (NSAID) intake is associated with a significantly decreased risk of disease recurrence and breast cancer related death. In this study we set out to investigate the immunological response to AI treatment alone and in combination with NSAID treatment in an animal model of estrogen receptor positive (ER+ve) breast cancer. Methods: A syngeneic immunocompetent murine ER+ breast tumour model was used in which SSM3 ER+ BrCa cells were injected into the mammary pad of wild-type 129SvEv mice. Once tumours reached a size of 49 mm2, mice were ovariectomised and treated with combinations of letrozole, celecoxib, aspirin and vehicle control. Tumours were measured for 25 days following treatment and tumours were analysed using flow cytometry and immunohistochemistry. Results: Treatment with letrozole alone and letrozole + celecoxib resulted in a significant reduction tumour size after 25 days of treatment (p<0.001). Examination of the immune cell infiltrate of these tumours using flow cytometry determined that combination letrozole and celecoxib resulted in decreased numbers of CD11b+ cells compared to vehicle treated tumours (p = 0.02), and to celecoxib only treated tumours (p = 0.008). Working within recommended guidelines for assessing stromal TILs in H&E sections in a larger cohort (n=51), we determined that the percentage of stromal TILs increased in all treatment groups compared to the pre-treatment biopsy, and that the combination treatment had lower levels of TILs compared to vehicle treated tumours (p = 0.02). Conclusions: We conclude that treatment of ER+ BrCa with letrozole induces an immune response in the tumour microenvironment which can be modulated by the addition of an NSAID. Our findings suggest that modulation of the immune response to endocrine therapy may have the potential to enhance response to treatment.