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A stroma-related gene signature predicts sensitivity to epirubicin-containing neoadjuvant chemotherapy in breast cancer

ABSTRACT: The goal of the study was to identify a gene expression signature capable of predicting a pathological complete response following neoadjuvant anthracycline-based chemotherapy of breast cancer. The samples were taken from the FEC arm (5-fluorouracil, epirubicin, cyclophosphamide) of the EORTC 10994 trial. EORTC 10994 is a phase III clinical trial comparing FEC with ET (epirubicin, docetaxel) in patients with large operable, locally advanced or inflammatory breast cancer (www.eortc.be). Frozen biopsies were taken at randomisation. RNA was extracted from 100um thickness of 14G core needle biopsies. Adjacent sections were tested by H&E to confirm >20% tumour cell content. 200 ng total RNA per chip was amplified using the Affymetrix small sample protocol (IVT then Enzo). 102 tumours were tested on Affymetrix X3P chips. Single biopsies were tested per tumour. The CEL files were quantile normalised using rma. The clinical response measure was pathological complete response (pCR, disappearance of the tumour after chemotherapy with at most scattered invasive cells detected by histology). 102 tumors

ORGANISM(S): Homo sapiens

SUBMITTER: Farmer P

PROVIDER: S-ECPF-GEOD-4779 | biostudies-other | 2009 Jan

REPOSITORIES: biostudies-other

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Project description:BackgroundNeoadjuvant chemotherapy is a key component of breast cancer treatment regimens and pathologic complete response to this therapy varies among patients. This is presumably due to differences in the molecular mechanisms that underlie each tumor's disease pathology. Developing genomic clinical assays that accurately categorize responders from non-responders can provide patients with the most effective therapy for their individual disease.MethodsWe applied our previously developed E2F4 genomic signature to predict neoadjuvant chemotherapy response in breast cancer. E2F4 individual regulatory activity scores were calculated for 1129 patient samples across 5 independent breast cancer neoadjuvant chemotherapy datasets. Accuracy of the E2F4 signature in predicting neoadjuvant chemotherapy response was compared to that of the Oncotype DX and MammaPrint predictive signatures.ResultsIn all datasets, E2F4 activity level was an accurate predictor of neoadjuvant chemotherapy response, with high E2F4 scores predictive of achieving pathologic complete response and low scores predictive of residual disease. These results remained significant even after stratifying patients by estrogen receptor (ER) status, tumor stage, and breast cancer molecular subtypes. Compared to the Oncotype DX and MammaPrint signatures, our E2F4 signature achieved similar performance in predicting neoadjuvant chemotherapy response, though all signatures performed better in ER+ tumors compared to ER- ones. The accuracy of our signature was reproducible across datasets and was maintained when refined from a 199-gene signature down to a clinic-friendly 33-gene panel.ConclusionOverall, we show that our E2F4 signature is accurate in predicting patient response to neoadjuvant chemotherapy. As this signature is more refined and comparable in performance to other clinically available gene expression assays in the prediction of neoadjuvant chemotherapy response, it should be considered when evaluating potential treatment options.

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A stroma-related gene signature predicts sensitivity to epirubicin-containing neoadjuvant chemotherapy in breast cancer

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