Neoadjuvant endocrine therapy in breast cancer up-regulates the cytotoxic drug pump ABCG2/BCRP, and may lead to resistance to subsequent chemotherapy


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Baek Kim1
1University of Leeds

Abstract

Background

Neoadjuvant systemic therapy for breast cancer is increasingly utilised to down-stage tumours, thereby enabling increase in rates of breast conserving surgery as opposed to mastectomy. However, little is known about how neoadjuvant systemic therapy impacts on response to subsequent adjuvant therapies that may be required. Neoadjuvant systemic therapy provides opportunities to consider this question, by studying therapy-induced expression changes between pre- and post-treatment samples. These data are relatively lacking in the context of neoadjuvant endocrine therapy (NAET), as opposed to neoadjuvant chemotherapy. Here, we investigate the relevance of expression of the xenobiotic transporter ABCG2/BCRP, a gene/protein associated with chemoresistance, in the context of neoadjuvant endocrine therapy and particularly with reference to subsequent chemotherapy treatment after NAET.

Method

ABCG2/BCRP expression was assessed by immunohistochemistry or by expression arrays in matched patient samples pre- and post-neoadjuvant endocrine therapy in three separate cohorts (Leeds, Edinburgh, and Houston). Cell culture was used to model the impact of endocrine therapy induced changes in ABCG2/BCRP on subsequent chemotherapy response, using Western blots, qPCR, survival assays and cell cycle analyses.

Results

ABCG2/BCRP was commonly and significantly up-regulated in breast cancer patients after treatment with NAET in all three cohorts encompassing a total of 200 patients (p<0.01). Treatment with the endocrine therapeutic tamoxifen similarly induced significant and dose-dependent ABCG2/BCRP up-regulation (p<0.05) in a relevant model cell line, the oestrogen receptor positive line T47D. Critically, this up-regulation was associated with significantly increased chemoresistance to subsequent treatment with epirubicin, an anthracycline chemotherapeutic known to be an ABCG2/BCRP substrate. Pre-treatment with tamoxifen resulted in increased T47D cell survival from subsequent epirubicin treatment with increased cell survival by more than 2-fold (p<0.05).

Conclusion

Our data suggest that NAET-induced up-regulation of ABCG2/BCRP could potentially reduce the efficacy of adjuvant chemotherapy treatment in breast cancer patients. Therefore, clinical outcomes following this treatment sequence warrant further study.