Breast Cancer Research and Treatment

, Volume 123, Issue 1, pp 189–196 | Cite as

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

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)

References

  1. 1.
    Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334CrossRefPubMedGoogle Scholar
  2. 2.
    von Minckwitz G KM, Kümmel S, Fasching P, Eiermann W, Blohmer J-U, Costa SD, Sibylle L, Dietmar V, Untch M (2008) Integrated meta-analysis on 6402 patients with early breast cancer receiving neoadjuvant anthracycline-taxane ± trastuzumab containing chemotherapy. SABCS Abstract 792008Google Scholar
  3. 3.
    Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423CrossRefPubMedGoogle Scholar
  4. 4.
    Bernstein C, Bernstein H, Payne CM, Garewal H (2002) DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res 511(2):145–178CrossRefPubMedGoogle Scholar
  5. 5.
    Tassone P, Di Martino MT, Ventura M, Pietragalla A, Cucinotto I, Calimeri T et al (2009) Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo. Cancer Biol Ther 8(7):648–653CrossRefPubMedGoogle Scholar
  6. 6.
    Murray MM, Mullan PB, Harkin DP (2007) Role played by BRCA1 in transcriptional regulation in response to therapy. Biochem Soc Trans 35(5):1342–1346CrossRefPubMedGoogle Scholar
  7. 7.
    Kennedy RD, Quinn JE, Mullan PB, Johnston PG, Harkin DP (2004) The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96(22):1659–1668CrossRefPubMedGoogle Scholar
  8. 8.
    Tassone P, Tagliaferri P, Perricelli A, Blotta S, Quaresima B, Martelli ML et al (2003) BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer 88(8):1285–1291CrossRefPubMedGoogle Scholar
  9. 9.
    Delaloge S, Bidard F, El Masmoudi Y, Bressac de Paillerets B, Caron O, Bourgier C, Garbay J, Spielmann M, André F. BRCA1 germ-line mutation: Predictive of sensitivity to anthracyclin alkylating agents regimens but not to taxanes? J Clin Oncol. Abstract 5742008 May 20, 26Google Scholar
  10. 10.
    Chappuis PO, Goffin J, Wong N, Perret C, Ghadirian P, Tonin PN et al (2002) A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 39(8):608–610CrossRefPubMedGoogle Scholar
  11. 11.
    Hubert A, Mali B, Hamburger T, Rottenberg Y, Uziely B, Peretz T et al (2009) Response to neo-adjuvant chemotherapy in BRCA1 and BRCA2 related stage III breast cancer. Fam Cancer 8:173–177CrossRefPubMedGoogle Scholar
  12. 12.
    Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C et al (2009) Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 115:359–363CrossRefPubMedGoogle Scholar
  13. 13.
    Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M et al (2008) Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat 108(2):289–296CrossRefPubMedGoogle Scholar
  14. 14.
    Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D et al (2007) BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26(14):2126–2132CrossRefPubMedGoogle Scholar
  15. 15.
    James CR, Quinn JE, Mullan PB, Johnston PG, Harkin DP (2007) BRCA1, a potential predictive biomarker in the treatment of breast cancer. Oncologist 12(2):142–150CrossRefPubMedGoogle Scholar
  16. 16.
    Turner NC, Reis-Filho JS (2006) Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25(43):5846–5853CrossRefPubMedGoogle Scholar
  17. 17.
    Brody LC (2005) Treating cancer by targeting a weakness. N Engl J Med 353(9):949–950CrossRefPubMedGoogle Scholar
  18. 18.
    Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4(10):814–819CrossRefPubMedGoogle Scholar
  19. 19.
    Mueller CR, Roskelley CD (2003) Regulation of BRCA1 expression and its relationship to sporadic breast cancer. Breast Cancer Res 5(1):45–52CrossRefPubMedGoogle Scholar
  20. 20.
    van de Vijver MJ, He YD, van’ t Veer LJ, Dai H, Hart AA, Voskuil DW et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009CrossRefPubMedGoogle Scholar
  21. 21.
    Mohsin SK, Weiss HL, Gutierrez MC, Chamness GC, Schiff R, Digiovanna MP et al (2005) Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J Clin Oncol 23(11):2460–2468CrossRefPubMedGoogle Scholar
  22. 22.
    Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V et al (2009) A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 15(1):68–74CrossRefPubMedGoogle Scholar
  23. 23.
    Bonnefoi H, Potti A, Delorenzi M, Mauriac L, Campone M, Tubiana-Hulin M et al (2007) Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00–01 clinical trial. Lancet Oncol 8(12):1071–1078CrossRefPubMedGoogle Scholar
  24. 24.
    Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Elledge R et al (2003) Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 362(9381):362–369CrossRefPubMedGoogle Scholar
  25. 25.
    Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Tham YL et al (2005) Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. J Clin Oncol 23(6):1169–1177CrossRefPubMedGoogle Scholar
  26. 26.
    Martin RW, Orelli BJ, Yamazoe M, Minn AJ, Takeda S, Bishop DK (2007) RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors. Cancer Res 67(20):9658–9665CrossRefPubMedGoogle Scholar
  27. 27.
    Cronin M, Pho M, Dutta D, Stephans JC, Shak S, Kiefer MC et al (2004) Measurement of gene expression in archival paraffin-embedded tissues: development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay. Am J Pathol 164(1):35–42PubMedGoogle Scholar
  28. 28.
    Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034Google Scholar
  29. 29.
    Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA et al (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281CrossRefPubMedGoogle Scholar
  30. 30.
    Wysocki PJ, Korski K, Lamperska K, Zaluski J, Mackiewicz A (2008) Primary resistance to docetaxel-based chemotherapy in metastatic breast cancer patients correlates with a high frequency of BRCA1 mutations. Med Sci Monit 14(7):SC7–SC10PubMedGoogle Scholar
  31. 31.
    Tassone P, Blotta S, Palmieri C, Masciari S, Quaresima B, Montagna M et al (2005) Differential sensitivity of BRCA1-mutated HCC1937 human breast cancer cells to microtubule-interfering agents. Int J Oncol 26(5):1257–1263PubMedGoogle Scholar
  32. 32.
    Gilmore PM, McCabe N, Quinn JE, Kennedy RD, Gorski JJ, Andrews HN et al (2004) BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3. Cancer Res 64(12):4148–4154CrossRefPubMedGoogle Scholar
  33. 33.
    Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C (2007) An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol 8(8):R157CrossRefPubMedGoogle Scholar
  34. 34.
    Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H et al (2007) Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 9(5):R65CrossRefPubMedGoogle Scholar
  35. 35.
    Schneider BP, Winer EP, Foulkes WD, Garber J, Perou CM, Richardson A et al (2008) Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res 14(24):8010–8018CrossRefPubMedGoogle Scholar
  36. 36.
    Sgagias MK, Wagner KU, Hamik B, Stoeger S, Spieker R, Huber LJ et al (2004) Brca1-deficient murine mammary epithelial cells have increased sensitivity to CDDP and MMS. Cell Cycle 3(11):1451–1456PubMedGoogle Scholar
  37. 37.
    Ashworth A (2008) A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26(22):3785–3790CrossRefPubMedGoogle Scholar
  38. 38.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921CrossRefPubMedGoogle Scholar
  39. 39.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134CrossRefPubMedGoogle Scholar
  40. 40.
    O’Shaughnessy J, Osborne C, Pippen J, Yoffe M, Patt D, Monaghan G, Rocha C, Ossovskaya V, Sherman B, Bradley C (2009) Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol. Abstract 32009; 27Google Scholar
  41. 41.
    Abruzzo LV, Lee KY, Fuller A, Silverman A, Keating MJ, Medeiros LJ et al (2005) Validation of oligonucleotide microarray data using microfluidic low-density arrays: a new statistical method to normalize real-time RT-PCR data. Biotechniques 38(5):785–792CrossRefPubMedGoogle Scholar

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

Personalised recommendations