DNA repair signature is associated with anthracycline response in triple negative breast cancer patients

A. A. Rodriguez, A. Makris, M. F. Wu, M. Rimawi, A. Froehlich, B. Dave, S. G. Hilsenbeck, G. C. Chamness, M. T. Lewis, L. E. Dobrolecki, D. Jain, S. Sahoo, C. K. Osborne, J. C. Chang

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

We hypothesized that a subset of sporadic triple negative (TN) breast cancer patients whose tumors have defective DNA repair similar to BRCA1-associated tumors are more likely to exhibit up-regulation of DNA repair-related genes, anthracycline-sensitivity, and taxane-resistance. We derived a defective DNA repair gene expression signature of 334 genes by applying a previously published BRCA1-associated expression pattern to three datasets of sporadic TN breast cancers. We confirmed a subset of 69 of the most differentially expressed genes by quantitative RT-PCR, using a low density custom array (LDA). Next, we tested the association of this DNA repair microarray signature expression with pathologic response in neoadjuvant anthracycline trials of FEC (n = 50) and AC (n = 16), or taxane-based TET chemotherapy (n = 39). Finally, we collected paraffin-fixed, formalin-embedded biopsies from TN patients who had received neoadjuvant AC (n = 28), and tested the utility of the LDA to discriminate response. Correlation between RNA expression measured by the microarrays and 69-gene LDA was ascertained. This defective DNA repair microarray gene expression pattern was significantly associated with anthracycline response and taxane resistance, with the area under the ordinary receiver operating characteristic curve (AUC) of 0.61 (95% CI = 0.45-0.77), and 0.65 (95% CI = 0.46-0.85), respectively. From the FFPE samples, the 69-gene LDA could discriminate AC responders, with AUC of 0.79 (95% CI = 0.59-0.98). In conclusion, a promising defective DNA repair gene expression signature appears to differentiate TN breast cancers that are sensitive to anthracyclines and resistant to taxane-based chemotherapy, and should be tested in clinical trials with other DNA-damaging agents and PARP-1 inhibitors.

Original languageEnglish (US)
Pages (from-to)189-196
Number of pages8
JournalBreast Cancer Research and Treatment
Volume123
Issue number1
DOIs
StatePublished - Aug 2010

Fingerprint

Triple Negative Breast Neoplasms
Anthracyclines
DNA Repair
Genes
Oligonucleotide Array Sequence Analysis
Transcriptome
Area Under Curve
Drug Therapy
ROC Curve
Paraffin
Formaldehyde
Neoplasms
Up-Regulation
Clinical Trials
RNA
Biopsy
Gene Expression
Polymerase Chain Reaction
taxane
DNA

Keywords

  • Anthracycline sensitivity
  • BRCA1
  • Breast cancer
  • DNA repair
  • Gene expression signatures

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

Rodriguez, A. A., Makris, A., Wu, M. F., Rimawi, M., Froehlich, A., Dave, B., ... Chang, J. C. (2010). DNA repair signature is associated with anthracycline response in triple negative breast cancer patients. Breast Cancer Research and Treatment, 123(1), 189-196. https://doi.org/10.1007/s10549-010-0983-z

DNA repair signature is associated with anthracycline response in triple negative breast cancer patients. / Rodriguez, A. A.; Makris, A.; Wu, M. F.; Rimawi, M.; Froehlich, A.; Dave, B.; Hilsenbeck, S. G.; Chamness, G. C.; Lewis, M. T.; Dobrolecki, L. E.; Jain, D.; Sahoo, S.; Osborne, C. K.; Chang, J. C.

In: Breast Cancer Research and Treatment, Vol. 123, No. 1, 08.2010, p. 189-196.

Research output: Contribution to journalArticle

Rodriguez, AA, Makris, A, Wu, MF, Rimawi, M, Froehlich, A, Dave, B, Hilsenbeck, SG, Chamness, GC, Lewis, MT, Dobrolecki, LE, Jain, D, Sahoo, S, Osborne, CK & Chang, JC 2010, 'DNA repair signature is associated with anthracycline response in triple negative breast cancer patients', Breast Cancer Research and Treatment, vol. 123, no. 1, pp. 189-196. https://doi.org/10.1007/s10549-010-0983-z
Rodriguez, A. A. ; Makris, A. ; Wu, M. F. ; Rimawi, M. ; Froehlich, A. ; Dave, B. ; Hilsenbeck, S. G. ; Chamness, G. C. ; Lewis, M. T. ; Dobrolecki, L. E. ; Jain, D. ; Sahoo, S. ; Osborne, C. K. ; Chang, J. C. / DNA repair signature is associated with anthracycline response in triple negative breast cancer patients. In: Breast Cancer Research and Treatment. 2010 ; Vol. 123, No. 1. pp. 189-196.
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