Breast Cancer Research and Treatment

, Volume 123, Issue 1, pp 189–196

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
Clinical trial
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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.

Keywords

Breast cancer DNA repair BRCA1 Gene expression signatures Anthracycline sensitivity 

Supplementary material

10549_2010_983_MOESM1_ESM.ppt (706 kb)
Supplementary material 1 (PPT 706 kb)
10549_2010_983_MOESM2_ESM.xls (748 kb)
Supplementary material 2 (XLS 747 kb)
10549_2010_983_MOESM3_ESM.xls (921 kb)
Supplementary material 3 (XLS 921 kb)

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • A. A. Rodriguez
    • 1
  • A. Makris
    • 2
  • M. F. Wu
    • 1
  • M. Rimawi
    • 1
  • A. Froehlich
    • 1
  • B. Dave
    • 1
  • S. G. Hilsenbeck
    • 1
  • G. C. Chamness
    • 1
  • M. T. Lewis
    • 1
  • L. E. Dobrolecki
    • 1
  • D. Jain
    • 3
  • S. Sahoo
    • 3
  • C. K. Osborne
    • 1
  • J. C. Chang
    • 1
  1. 1.Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonUSA
  2. 2.Mount Vernon HospitalLondonUK
  3. 3.University of LouisvilleLouisvilleUSA

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