Predicting response/resistance to endocrine therapy for breast cancer

Background

Endocrine therapy for breast cancer is a major modality for the treatment of breast cancer, producing response rates between 30% and 40% of unselected patients with the minimum of toxicity. However, the majority of patients receive no benefits and, after successful treatment, tumour regrowth may occur. Optimal management therefore requires accurate predictors of response and early identification of resistance. The present article reviews results from neoadjuvant studies in which endocrine therapy was given to patients whose primary breast cancer was still within the breast so that changes in tumour volume could be used to assess clinical response and so that sequential biopsies could be taken for molecular analyses designed to identify predictive markers.

Methods

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.

Results

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 expression in 125 genes were detected between non-responders and responders. A combination of gene changes produced increased discrimination. The identity of the genes and their relevance to the prediction of response and mechanisms of resistance will be discussed.

Conclusions

Early changes in gene expression profiles may define tumour groups with differing sensitivity to endocrine therapy and permit early recognition of response and resistance. However, clinical utility at the level of individual patients has yet to be validated and explored.