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Open Access Research article

Cell Line Derived Multi-Gene Predictor of Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer: A Validation Study on US Oncology 02-103 Clinical Trial

Kui Shen1, Yuan Qi2, Nan Song1*, Chunqiao Tian1, Shara D Rice1, Michael J Gabrin1, Stacey L Brower1, William Fraser Symmans3, Joyce A O’Shaughnessy4, Frankie A Holmes5, Lina Asmar6 and Lajos Pusztai7

Author Affiliations

1 Department of Product Development, Precision Therapeutics, Inc, 2516 Jane Street, Pittsburgh, PA 15203, USA

2 Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA

3 Department of Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0085, Houston, TX 77030, USA

4 Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Baylor-Sammons Cancer Center, 3535 Worth St., Collins 5, Dallas, TX 75246, USA

5 Texas Oncology, US Oncology, 925 Gessner St #550, Houston, TX 77024, USA

6 Biostatistics and Medical Writing, US Oncology Research, US Oncology, The Woodlands, Woodlands, TX 77380, USA

7 Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230, USA

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BMC Medical Genomics 2012, 5:51  doi:10.1186/1755-8794-5-51

Published: 16 November 2012

Abstract

Background

The purpose of this study is to assess the predictive accuracy of a multi-gene predictor of response to docetaxel, 5-fluorouracil, epirubicin and cyclophosphamide combination chemotherapy on gene expression data from patients who received these drugs as neoadjuvant treatment.

Methods

Tumor samples were obtained from patients with stage II-III breast cancer before starting neoadjuvant chemotherapy with four cycles of 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by four cycles of docetaxel/capecitabine (TX) on US Oncology clinical trial 02-103. Most patients with HER-2-positive cancer also received trastuzumab (H). The chemotherapy predictor (TFEC-MGP) was developed from publicly available gene expression data of 42 breast cancer cell-lines with corresponding in vitro chemotherapy sensitivity results for the four chemotherapy drugs. No predictor was developed for treatment with trastuzumab. The predictive performance of TFEC-MGP in distinguishing cases with pathologic complete response from those with residual disease was evaluated for the FEC/TX and FEC/TX plus H group separately. The area under the receiver-operating characteristic curve (AU-ROC) was used as the metric of predictive performance. Genomic predictions were performed blinded to clinical outcome.

Results

The AU-ROC was 0.70 (95% CI: 0.57-0.82) for the FEC/TX group (n=66) and 0.43 (95% CI: 0.20-0.66) for the FEC/TX plus H group (n=25). Among the patients treated with FEC/TX, the AU-ROC was 0.69 (95% CI: 0.52-0.86) for estrogen receptor (ER)-negative (n=28) and it was 0.59 (95% CI: 0.36-0.82) for ER-positive cancers (n=37). ER status was not reported for one patient.

Conclusions

Our results indicate that the cell line derived 291-probeset genomic predictor of response to FEC/TX combination chemotherapy shows good performance in a blinded validation study, particularly in ER-negative patients.

Keywords:
Multi-gene predictor of chemosensitivity; Breast cancer; Cell lines