Predicting response/resistance to endocrine therapy for breast cancer

All patients had histologically confirmed breast cancer and were treated for 3–4 months with either tamoxifen or an aromatase inhibitor (anastrozole, exemestane or letrozole). Core or excisional tumour biopsies were taken before and at the end of treatment (and at 10–14 days in certain studies). Oestrogen receptors (ER), progestogen receptors and c-erbB1 and c-erbB2 were measured by immunohistochemistry. Microarray analysis was performed on tumour RNA extracted and amplified before hybridization on Affymetrix HG_U133A GeneChips for microarray analysis.Steroid hormone receptor status highly influences the response to all endocrine therapies, negative tumours failing to respond and response being more likely with increasing levels of ER and the concomitant presence of PgR. Conversely, tumour overexpression of c-erbB2 (and c-erbB1) is associated with resistance to tamoxifen but not aromatase inhibitors. While these receptors are helpful in identifying groups of tumours with differing sensitivity to endocrine therapy, they fail to predict accurately in individual cases. To address this deficiency, in Edinburgh we have looked for early genetic changes (at 10–14 days) that occur with treatment and might be associated with subsequent response to the aromatase inhibitor letrozole. Clinical response data were available for 43 cases, of which 33 (77%) were classified as responders (>50% reduction in tumour volume) and 30 (70%) displayed evidence of pathological response. No gene changed substantially with treatment in all cases; however, there was consistent upregulation of three genes and downregulation of 65 genes in 50 of the cases. Based on clustering techniques, it was possible to identify highly consistent changes in gene expression with treatment, which allowed tumours to be subdivided into groups showing distinct patterns of molecular changes. While the change in expression of any single gene failed to correlate with response, significant differences in change of expr