Expression profile of residual breast cancer after primary chemotherapy based on doxorubicin

Abstract

Listen

Translate article

639 Background: Expression profile of the remaining malignant cells in breast cancer after the last cycle of primary chemotherapy (PCT) based on doxorubicin (AC) might help to identify a resistant phenotype. Methods: To analyse changes in gene expression in samples of primary breast tumors before and after systemic chemotherapy, ten pt (median age 46.5 years, 3 post-menopausal) clinically staged as II (n=2) or III (n=8) breast cancer were submitted to PCT, receiving at least 90% of the planned doxorubicin dose in a median interval of 66.5 days. Samples were obtained by tumor biopsy before PCT and after 4 courses of AC, upon surgical intervention. Surgery was performed at least 28 days after AC last course. All pts presented a tumor reduction according to RECIST. Samples were hand-dissected to eliminate non-tumoral tissue. RNA was extracted, amplified and gene expression analysed using a cDNA microarray plataform having 4608 genes. Results: One hundred and seven genes were found differentially expressed by both a permuted Student t test at a False Discovery Rate (FDR) level ≤ 0.001 and p≤0.05 by paired Student t test. Unsupervised hierarchical clustering employing 34 differentially expressed genes at FDR level < 0.001 and Bayesian Error Rate < 50% allowed a proper discrimination of 100% post treatment samples. The discriminators included genes up-regulated such as SEPT1, a member of GTPase family, a growth factor receptor (PDGFRL) implicated in transcapillary transport in tumors and Pumilio homolog1 (PUM-1), an essential protein for stem cell maintenance and self-renewal. Genes involved in proliferation were repressed including IRS1 (insulin receptor substrate-1), PTPRC (a regulator of citokyne receptor signaling), CORO1C (coronin) and CSE1L (CAS) which depletion leads to cell cycle arrest. Notably HMG2L1 (high-mobility group protein 2-like1) was also down regulated reflecting enhanced excision repair mechanism. Conclusion: Genes differentially expressed in residual breast cancer after PCT may potentially represent a signature profile for doxorubicin reistance. Supported by FAPESP. No significant financial relationships to disclose.