PD10-04: Exploration of the Relationship between Loss of PTEN and BRCA1 Expression in Triple Negative Breast Carcinoma.

Abstract

Abstract Based on the mechanism of action of PARP inhibitors, BRCAness breast and ovarian cancers could be defined as the optimal group of tumours to target with such drugs. As the BRCAness phenotype is not fully defined at present, a surrogate phenotype of triple negative breast cancer (TNBC) has been proposed. Results of recent clinical trials involving PARP inhibitors in the context of TNBC do not demonstrate a significant improvement in overall survival or progression free survival, partly due to the inaccurate selection of certain tumours. Data from cell culture studies suggests that loss of PTEN expression could be a marker of PARP inhibitor sensitivity. Materials and Methods: A retrospective study of 160 TNBC resected at Institut Bergonie between 1989 and 2010 was undertaken. Inclusion criteria were: ER & PR immunohistochemcial (IHC) negativity (<10% tumour cells positive), non-amplification of HER2 (IHC score 0, 1, or 2 with negative FISH analysis) and an invasive ductal carcinoma resected before chemotherapy. For some familial cases, germline BRCA1 mutation screening had been performed in a diagnostic setting and was accompanied by genetic counselling. PTEN IHC, point mutation and gross rearrangement screening, along with BRCA1 expression and promoter methylation analysis (through real-time PCR and bisulfite treatment, respectively) and 53BP1 IHC were undertaken on this series of TNBC. Results: Twenty percent of sporadic and familial TNBC demonstrated reduced BRCA1 expression with a greater than 7 fold reduction in expression. Almost half of tumours demonstrated a complete loss of PTEN expression as assessed by IHC, with a deleterious PTEN point mutation identified in 5% of cases. Although a slight correlation is observed between the complete loss of PTEN and a reduction in BRCA1 expression, a complete overlap of these two alterations was not observed; tumours with reduced BRCA1 expression do not always demonstrate complete negativity on PTEN IHC and certain tumours displaying complete negativity on PTEN IHC do not show a reduction in BRCA1 expression. Full immunohistochemical characterization of the tumour series (ER, PR, HER2, AR, CK5/6 & EGFR) together with the results of PTEN, BRCA1 and 53BP1 analyses will be presented. Conclusion These results suggest that at present, loss of PTEN expression is not a suitable surrogate marker for tumours with reduced BRCA1 expression. This should be borne in mind for ancillary studies of clinical trials involving PARP inhibitors in the treatment of breast tumours and further investigation is warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD10-04.