Abstract P4-05-05: Molecular effects of initial core biopsies in neoadjuvant window studies

Abstract

Abstract Background A growing number of studies are assessing the effects of drugs on breast cancers by investigating the molecular changes in tumours between the initial core biopsy taken at diagnosis and the excision specimen removed at surgery 2-3 weeks later. It is imperative to know if molecular profiles of tumours change over time without treatment and to assess whether the core biopsy itself influences the molecular profile. This study aimed to investigate changes in molecular profiles of breast cancer between the initial core biopsy and the excision specimen in patients who had no intervening treatment. Methods 83 patients with paired fresh frozen tissue specimens from an initial diagnostic core biopsy and the later surgical excision biopsy have been studied. Following RNA extraction and processing, Illumina HT-12 BeadArrays were used for gene expression profiling. Samples were analysed for significant changes in gene expression and compared with a large dataset of patients treated with neoadjuvant letrozole. Results Analysis is on-going and results from all patients will be available by December 2013. Pairwise Rank Product analysis (false discovery rate 0.01) of the first 12 patients representing all subtypes of breast cancer (6 ER+, 4 HER2+, 2 triple negative) with a mean interval of 22.9 days (range 15 - 33 days) between specimens, identified 346 down regulated genes. Functional processes represented by these genes were; ribosomes, regulation of cell death and apoptosis, and protein complex biogenesis. Up-regulated processes (236 genes) included functions relating to regulation of transcription, mRNA processing/splicing and ECM remodelling. No consistent changes in a 60 gene immune signature were seen across these 12 patients. Integration of this dataset with a large letrozole-treated dataset, demonstrated that less than 1% of genes that changed on-treatment with letrozole, changed without treatment. Conclusions This is the largest study investigating molecular profiles of the same breast cancer sampled at different times. It has shown: · No consistent changes in expression of genes associated with wound healing and immune response 15-33 days after core biopsy · Stability of the genetic profile of individual tumours despite multiple biopsies · Stability in the genes that are changed by two weeks of treatment with daily letrozole. This study provides definitive evidence of the validity of preoperative or window of opportunity molecular studies and has major implications for investigating the effects of new therapeutic drugs. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-05.