Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer.

INTRODUCTION: Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. METHODS: Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n=84), gene expression profiling (n=47), matched pre- and post-AI aCGH (n=19 pairs) and Ki67-based AI-response analysis (n=39). RESULTS: Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). CONCLUSIONS: These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response.

Relationship between oestrogen receptor status and proliferation in predicting response and long-term outcome to neoadjuvant chemotherapy for breast cancer.

Oestrogen receptor (ER) negative breast cancers are more likely to achieve a pathological complete response (pCR) to neoadjuvant chemotherapy compared to those with ER positive tumours. ER positive tumours exhibit low proliferation and ER negative cancers high proliferation. The aim of this study was to determine to what extent the better response of ER negative cancers correlates with proliferation rate. A retrospective analysis of a prospectively maintained database identified 175 neoadjuvant chemotherapy patients with tissue available for Ki67 analysis. On univariate analysis, pre-therapy Ki67 (P = 0.04), ER status (P = 0.002), HER2 status (P = 0.004) and grade (P = 0.0009) were associated with a pCR. In a multivariate model, HER2 was the only significant predictor of pCR. No significant relationship between pre-therapy Ki67 and relapse-free and overall survival was demonstrated. Ki67 is not an independent predictor of clinical CR or pCR. Aspects of ER status beyond its inverse relationship with proliferation may contribute to its predictive value for pCR.

The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer.

PURPOSE: To compare the prognostic significance of proliferation, as assessed by Ki67 expression, in breast cancer before and after neoadjuvant chemotherapy. METHODS: A retrospective search of a prospectively maintained clinical database was performed to identify patients treated with neoadjuvant chemotherapy at the Royal Marsden Hospital. The expression of Ki67 was assessed using immunohistochemistry in pre-therapy core-needle biopsy and post-therapy surgical excision specimens. The following factors were considered pre- and post-chemotherapy for their relationship with relapse-free and overall survival: age, menstrual status, T and N stage, pre-therapy operability, Ki67, ER, PgR, HER2, grade, histological subtype, vascular invasion, clinical response, chemotherapy regimen, type of surgery performed, adjuvant therapy, pathological tumour size and nodal involvement. RESULTS: In a matched cohort of 103 patients, on multivariate analysis of relapse-free survival, post-therapy Ki67 was the only significant independent prognostic factor. On multivariate analysis for overall survival, both pre- and excision Ki67 were significant independent predictors but the latter showed a stronger prognostic impact. The highest and lowest tertiles of excision Ki67 had different prognosis for both 5-year relapse-free (27% vs. 77%) and overall (39% and 93%) survival. In a cohort of 284 patients with only excision samples, post-therapy Ki67 was a significant independent prognostic factor on multivariate analysis. CONCLUSION: Post-chemotherapy Ki67 is a strong predictor of outcome for patients not achieving a pathological complete response.