Skip to main content

Advertisement

SpringerLink
Log in

A gene expression signature that predicts the therapeutic response of the basal-like breast cancer to neoadjuvant chemotherapy

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Several gene expression profiles have been reported to predict breast cancer response to neoadjuvant chemotherapy. These studies often consider breast cancer as a homogeneous entity, although higher rates of pathologic complete response (pCR) are known to occur within the basal-like subclass. We postulated that profiles with higher predictive accuracy could be derived from a subset analysis of basal-like tumors in isolation. Using a previously described “intrinsic” signature to differentiate breast tumor subclasses, we identified 50 basal-like tumors from two independent clinical trials associated with gene expression profile data. 24 tumor data sets were derived from a 119-patient neoadjuvant trial at our institution and an additional 26 tumor data sets were identified from a published data set (Hess et al. J Clin Oncol 24:4236–4244, 2006). The combined 50 basal-like tumors were partitioned to form a 37 sample training set with 13 sequestered for validation. Clinical surveillance occurred for a mean of 26 months. We identified a 23-gene profile which predicted pCR in basal-like breast cancers with 92% predictive accuracy in the sequestered validation data set. Furthermore, distinct cluster of patients with high rates of cancer recurrence was observed based on cluster analysis with the 23-gene signature. Disease-free survival analysis of these three clusters revealed significantly reduced survival in the patients of this high recurrence cluster. We identified a 23-gene signature which predicts response of basal-like breast cancer to neoadjuvant chemotherapy as well as disease-free survival. This signature is independent of tissue collection method and chemotherapeutic regimen.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bertucci F, Finetti P, Rougemont J, Charafe-Jauffret E, Nasser V, Loriod B, Camerlo J, Tagett R, Tarpin C, Houvenaeghel G et al (2004) Gene expression profiling for molecular characterization of inflammatory breast cancer and prediction of response to chemotherapy. Cancer Res 64(23):8558–8565

    Article  CAS  PubMed  Google Scholar 

  2. Hannemann J, Oosterkamp HM, Bosch CAJ, Velds A, Wessels LFA, Loo C, Rutgers EJ, Rodenhuis S, van de Vijver MJ (2005) Changes in gene expression associated with response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 23(15):3331–3342

    Article  CAS  PubMed  Google Scholar 

  3. Thuerigen O, Schneeweiss A, Toedt G, Warnat P, Hahn M, Kramer H, Brors B, Rudlowski C, Benner A, Schuetz F et al (2006) Gene expression signature predicting pathologic complete response with gemcitabine, epirubicin, and docetaxel in primary breast cancer. J Clin Oncol 24(12):1839–1845

    Article  CAS  PubMed  Google Scholar 

  4. Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA, Booser D, Theriault RL, Buzdar AU, Dempsey PJ et al (2006) Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol 24(26):4236–4244

    Article  CAS  PubMed  Google Scholar 

  5. Ayers M, Symmans WF, Stec J, Damokosh AI, Clark E, Hess K, Lecocke M, Metivier J, Booser D, Ibrahim N et al (2004) Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22(12):2284–2293

    Article  CAS  PubMed  Google Scholar 

  6. Iwao-Koizumi K, Matoba R, Ueno N, Kim SJ, Ando A, Miyoshi Y, Maeda E, Noguchi S, Kato K (2005) Prediction of docetaxel response in human breast cancer by gene expression profiling. J Clin Oncol 23(3):422–431

    Article  CAS  PubMed  Google Scholar 

  7. Koike Folgueira MAA, Carraro DM, Brentani H, da Costa Patrao DF, Barbosa EM, Netto MM, Caldeira JRF, Katayama MLH, Soares FA, Oliveira CT et al (2005) Gene expression profile associated with response to doxorubicin-based therapy in breast cancer. Clin Cancer Res 11(20):7434–7443

    Article  Google Scholar 

  8. Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Tham Y-L, Kalidas M, Elledge R, Mohsin S, Osborne CK et al (2005) Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. J Clin Oncol 23(6):1169–1177

    Article  CAS  PubMed  Google Scholar 

  9. Dressman HK, Hans C, Bild A, Olson JA, Rosen E, Marcom PK, Liotcheva VB, Jones EL, Vujaskovic Z, Marks J et al (2006) Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy. Clin Cancer Res 12(3):819–826

    Article  CAS  PubMed  Google Scholar 

  10. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci 100(14):8418–8423

    Article  CAS  PubMed  Google Scholar 

  11. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P et al (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11(16):5678–5685

    Article  CAS  PubMed  Google Scholar 

  12. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci 98(19):10869–10874

    Article  CAS  PubMed  Google Scholar 

  13. Banerjee S, Reis-Filho JS, Ashley S, Steele D, Ashworth A, Lakhani SR, Smith IE (2006) Basal-like breast carcinomas: clinical outcome and response to chemotherapy. J Clin Pathol 59(7):729–735

    Article  CAS  PubMed  Google Scholar 

  14. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334

    Article  CAS  PubMed  Google Scholar 

  15. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A et al (1998) Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16(8):2672–2685

    CAS  PubMed  Google Scholar 

  16. van der Hage JA, van de Velde CJH, Julien J-P, Tubiana-Hulin M, Vandervelden C, Duchateau L (2001) Preoperative chemotherapy in primary operable breast cancer: results from the european organization for research and treatment of cancer trial 10902. J Clin Oncol 19(22):4224–4237

    PubMed  Google Scholar 

  17. Wang J, Buchholz T, Middleton L, Allred D, Tucker SHK, Esteva F, Hortobagyi G, Sahin A (2002) Assessment of histologic features and expression of biomarkers in predicting pathologic response to anthracycline-based neoadjuvant chemotherapy in patients with breast carcinoma. Cancer 94(12):3107–3114

    Article  CAS  PubMed  Google Scholar 

  18. Mazouni C, Peintinger F, Wan-Kau S, Andre F, Gonzalez-Angulo AM, Symmans WF, Meric-Bernstam F, Valero V, Hortobagyi GN, Pusztai L (2007) Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol 25(19):2650–2655

    Article  CAS  PubMed  Google Scholar 

  19. Gentleman R, Carey V, Huber W, Irizarry R, Dudoit S (2005) Bioinformatics and computational biology solutions using R and bioconductor. Springer Science, New York

  20. Team RDC (2007) R: a language and environment for statistical computing. Vienna, Springer

    Google Scholar 

  21. Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Elledge R, Mohsin S, Osborne CK, Chamness GC, Allred DC et al (2003) Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 62(9381):362

    Article  Google Scholar 

  22. Cleator S, Tsimelzon A, Ashworth A, Dowsett M, Dexter T, Powles T, Hilsenbeck S, Wong H, Osborne CK, O’Connell P et al (2006) Gene expression patterns for doxorubicin (Adriamycin) and cyclophosphamide (cytoxan) (AC) response and resistance. Breast Cancer Res Treat 95(3):229–233

    Article  CAS  PubMed  Google Scholar 

  23. Symmans WF, Ayers M, Clark EA, Stec J, Hess KR, Sneige N, Buchholz TA, Krishnamurthy S, Ibrahim NK, Buzdar AU, Theriault RL, Rosales MF, Thomas ES, Gwyn KM, Green MC, Syed AR, Hortobagyi GN, Pusztai L (2003) Total RNA yield and microarray gene expression profiles from fine-needle aspiration biopsy and core-needle biopsy samples of breast carcinoma. Cancer 97(12):2960–2971

    Article  CAS  PubMed  Google Scholar 

  24. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24(36):5652–5657

    Article  PubMed  Google Scholar 

  25. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO (2007) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32

    Article  CAS  PubMed  Google Scholar 

  26. Fan C, Oh DS, Wessels L, Weigelt B, Nuyten DSA, Nobel AB, van’t Veer LJ, Perou CM (2006) Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 355(6):560–569

    Article  CAS  PubMed  Google Scholar 

  27. Keam B, Im SA, Kim HJ, Oh DY, Kim JH, Lee SH, Chie EK, Han W, Kim DW, Moon WK et al (2007) Prognostic impact of clinicopathologic parameters in stage II/III breast cancer treated with neoadjuvant docetaxel and doxorubicin chemotherapy: paradoxical features of the triple negative breast cancer. BMC Cancer 7:203

    Article  PubMed  Google Scholar 

  28. Estevez LG, Gradishar WJ (2004) Evidence-based use of neoadjuvant taxane in operable and inoperable breast cancer. Clin Cancer Res 10(10):3249–3261

    Article  CAS  PubMed  Google Scholar 

  29. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, Theriault RL, Singh G, Binkley SM, Sneige N et al (1999) Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17(2):460

    CAS  PubMed  Google Scholar 

  30. Chollet P, Amat S, Cure H, de Latour M, Le Bouedec G, Mouret-Reynier MA, Ferriere J, Achard J, Dauplat J, Penault-Llorca F (2002) Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer. Br J Cancer 8(86):1041–1046

    Article  Google Scholar 

  31. Gonzalez-Angulo AM, McGuire SE, Buchholz TA, Tucker SL, Kuerer HM, Rouzier R, Kau S-W, Huang EH, Morandi P, Ocana A et al (2005) Factors predictive of distant metastases in patients with breast cancer who have a pathologic complete response after neoadjuvant chemotherapy. J Clin Oncol 23(28):7098–7104

    Article  PubMed  Google Scholar 

  32. Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B (2001) Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 30:96–102

    Google Scholar 

  33. Dawood S, Broglio K, Kau S-W, Islam R, Symmans WF, Buchholz TA, McGuire SE, Meric-Bernstam F, Cristofanilli M, Hortobagyi GN et al (2008) Prognostic value of initial clinical disease stage after achieving pathological complete response. Oncologist 13(1):6–15

    Article  PubMed  Google Scholar 

  34. Guarneri V, Broglio K, Kau S-W, Cristofanilli M, Buzdar AU, Valero V, Buchholz T, Meric F, Middleton L, Hortobagyi GN et al (2006) Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 24(7):1037–1044

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Financial Support: NCI CA111530-01and the Barnes Jewish Hospital Foundation to RLA, NCI P30 CA91842 to MAW and Sanofi-Aventis US

Author information

Authors and Affiliations

  1. Department of Surgery, Washington University School of Medicine St. Louis, 660 South Euclid Avenue, Campus Box 8109, St. Louis, MO, 63110, USA

    Yiing Lin, Sacha Kuo, Timothy P. Fleming & Rebecca L. Aft

  2. Department of Pathology and Immunology, Washington University School of Medicine St. Louis, St. Louis, MO, USA

    Mark Watson

  3. Division of Biostatistics, Washington University School of Medicine St. Louis, St. Louis, MO, USA

    Kathryn M. Trinkaus

  4. Department of Medicine, Washington University School of Medicine St. Louis, St. Louis, MO, USA

    Michael J. Naughton & Katherine Weilbaecher

  5. John Cochran Veterans Administration Hospital, St. Louis, MO, USA

    Rebecca L. Aft

  6. University of Pennsylvania, Philadelphia, PA, USA

    Shin Lin

Authors
  1. Yiing Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark Watson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathryn M. Trinkaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sacha Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael J. Naughton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katherine Weilbaecher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Timothy P. Fleming
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rebecca L. Aft
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rebecca L. Aft.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, Y., Lin, S., Watson, M. et al. A gene expression signature that predicts the therapeutic response of the basal-like breast cancer to neoadjuvant chemotherapy. Breast Cancer Res Treat 123, 691–699 (2010). https://doi.org/10.1007/s10549-009-0664-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0664-y

Keywords

Search

Navigation