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Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer

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Abstract

Taxanes and anthracyclines improve the outcome of early breast cancer, although the benefit is limited to a small proportion of patients and are toxic. We prospectively looked for predictors of response to these drugs. Experimental design: Four cycles of doxorubicin (75 mg/m2) or docetaxel (100 mg/m2) were compared as presurgical chemotherapy for breast cancer. Biomarkers were determined by immunohistochemistry and fluorescent in situ hybridization using prechemotherapy core biopsies. Tumors were also classified into one of the molecular intrinsic subtypes using an immunohistochemical panel of five biomarkers and genomic profiles. Single genes and intrinsic subtypes were correlated with response to doxorubicin versus docetaxel. Among the 204 evaluable patients, significant predictors of sensitivity in multivariate analysis were low topo2a expression and ER-negative status for doxorubicin and small tumor size and ER-negative status for docetaxel. Predictors of resistance in multivariate analysis were triple-negative status (ER/PgR/HER2 negative by IHC/FISH) for doxorubicin, and high TNM stage for docetaxel. Triple-negative tumors were associated with topo2a overexpression more than the other subtypes. In 94 patients with gene expression profiles, docetaxel was superior to doxorubicin in the basal-like subtype (good pathological response rate − PCR + class I of 56 vs. 0%; P = 0.034); no significant differences were observed in the other subtypes when comparing these two drugs. Low topo2a expression and ER-negative status were predictors of response to doxorubicin, while small tumor size and ER-negative status predicted response to docetaxel. Docetaxel was superior to doxorubicin in triple-negative/basal-like tumors, while no significant differences were seen in the remaining intrinsic subtypes.

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References

  1. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998;352(9132):930–942

  2. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365(9472):1687–1717

    Google Scholar 

  3. Henderson IC, Berry DA, Demetri GD et al (2003) Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983

    Article  PubMed  CAS  Google Scholar 

  4. Mamounas EP, Bryant J, Lembersky BC et al (2005) Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for nodepositive breast cancer: results from NSABP-B 28. J Clin Oncol 23:3686–3696

    Article  PubMed  CAS  Google Scholar 

  5. Martin M, Pienkowski T, Mackey J et al (2005) Adjuvant docetaxel for node positive breast cancer. N Engl J Med 352:2302–2313

    Article  PubMed  CAS  Google Scholar 

  6. Roche H, Fumoleau P, Spielmann M et al (2006) Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PASC 01 Trial. J Clin Oncol 24:5664–5671

    Article  PubMed  CAS  Google Scholar 

  7. Jones S, Holmes FA, O’Shaughnessy JO et al (2009) Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 27:1177–1183

    Article  PubMed  CAS  Google Scholar 

  8. Martin M, Rodriguez-Lescure A, Ruiz A et al (2008) Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst 100:805–814

    Article  PubMed  CAS  Google Scholar 

  9. Francis P, Crown J, Di Leo A et al (2008) Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst 100(2):121–133

    Article  PubMed  CAS  Google Scholar 

  10. Gianni L, Baselga J, Eiermann W (2009) Phase III trial valuating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol 27:2474–2481

    Article  PubMed  CAS  Google Scholar 

  11. Goldstein LJ, O’Neill A, Sparano JA et al (2008) Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol 26:4078–4085

    Article  Google Scholar 

  12. Ellis P, Barrett-Lee P, Johnson L et al (2009) Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet 373:1681–1692

    Article  PubMed  CAS  Google Scholar 

  13. Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  PubMed  CAS  Google Scholar 

  14. Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

    Article  PubMed  CAS  Google Scholar 

  15. Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423

    Article  PubMed  CAS  Google Scholar 

  16. Cheang MA, Chia SK, Vodue D et al (2009) Ki67 index, HERT2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750

    Article  PubMed  CAS  Google Scholar 

  17. Carey L, Dees EC, Sawyer L et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329–2334

    Article  PubMed  CAS  Google Scholar 

  18. Rouzier R, Perou CM, Symmans WF et al (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–5685

    Article  PubMed  CAS  Google Scholar 

  19. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422

    Article  PubMed  Google Scholar 

  20. Parker JS, Mullins M, Cheang MC et al (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160–1167

    Article  PubMed  Google Scholar 

  21. Prat A, Parker J, Karginova O et al (2010) Phenotyphic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12:R68

    Article  PubMed  Google Scholar 

  22. Hugh J, Hanson J, Cheang MCU et al (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: Use of an immunohistochemical definition in the BCIRG 001 Trial. J Clin Oncol 27:1168–1176

    Article  PubMed  CAS  Google Scholar 

  23. Arriola E, Moreno A, Varela M et al (2006) Predictive value of HER-2 and topoisomerase IIα in response to primary doxorubicin in breast cancer. Eur J Cancer 42:2954–2960

    Article  PubMed  CAS  Google Scholar 

  24. Tham YL, Gomez LF, Mohsin S et al (2005) Clinical response to neoadjuvant docetaxel predicts improved outcome in patients with large locally advanced breast cancer. Breast Cancer Res Treat 94:279–284

    Article  PubMed  CAS  Google Scholar 

  25. Gradishar WJ, Wedam SB, Jahanzeb M et al (2005) Neoadjuvant docetaxel followed by adjuvant doxorubicin and cyclophosphamide in patients with stage III breast cancer. Ann Oncol 16:1297–1304

    Article  PubMed  CAS  Google Scholar 

  26. Slamon DJ, Press MF (2009) Alterations in the TOP2A and HER2 genes: association with adjuvant anthracycline sensitivity in human breast cancers. J Natl Cancer Inst 101:615–619

    Article  PubMed  CAS  Google Scholar 

  27. Pritchard KI, Shepherd LE, O’Malley FP et al (2006) HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354:2103–2111

    Article  PubMed  CAS  Google Scholar 

  28. Gennari A, Sormani MP, Pronzato P et al (2008) HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100:14–20

    Article  PubMed  CAS  Google Scholar 

  29. Zhang F, Yang Y, Smith T et al (2003) Correlation between HER-2 expression and response to neoadjuvant chemotherapy with 5-fluororuacil, doxorubicin, and cyclophosphamide in patients with breast carcinoma. Cancer 97:1758–1765

    Article  PubMed  CAS  Google Scholar 

  30. Penault-Llorca F, Cayre A, Bouchet Mishellany F et al (2003) Induction chemotherapy for breast carcinoma: predictive markers and relation with outcome. Int J Oncol 22:1319–1325

    PubMed  CAS  Google Scholar 

  31. Petit T, Wilt M, Velten M et al (2004) Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 40:205–211

    Article  PubMed  CAS  Google Scholar 

  32. Geisler S, Lǿnning PE, Aas T et al (2001) Influence of TP53 gene alterations and c-erbB2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res 61:2505–2512

    PubMed  CAS  Google Scholar 

  33. Di Leo A, Chan S, Paesmans M et al (2004) HE2/neu as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Breast Cancer Res Treat 86:197–206

    Article  PubMed  CAS  Google Scholar 

  34. Järvinen TAH, Holli K, Kuukasjärvi T, Isola JJ (1998) Predictive value of topoisomerase IIα and other prognostic factors for epirubicin chemotherapy in advanced breast cancer. Br J Cancer 77:2267–2273

    Article  PubMed  Google Scholar 

  35. Esteva F, Hortobagyi GN (2009) Topoisomerase IIα amplification and anthracycline-based chemotherapy: the jury is still out. J Clin Oncol 27:3416–3417

    Article  PubMed  CAS  Google Scholar 

  36. Pritchard KI (2009) Are HER2 and TOP2A useful as prognostic or predictive biomarkers for anthracycline-based adjuvant chemotherapy for breast cancer? J Clin Oncol 27:3875–3876

    Article  PubMed  Google Scholar 

  37. Gianni L, Valagussa P (2009) Anthracyclines and early breast cancer: the end of an era? J Clin Oncol 27:1155–1157

    Article  PubMed  CAS  Google Scholar 

  38. Buzdar AU (2006) Topoisomerase IIα gene amplification and response to anthracycline-containing adjuvant chemotherapy in breast cancer. J Clin Oncol 24:2409–2411

    Article  PubMed  Google Scholar 

  39. Coon JS, Marcus E, Gupta-Burt S et al (2002) Amplification and overexpression of topoisomerase IIα predict response to anthracycline-based therapy in locally advanced breast cancer. Clin Cancer Res 8:1061–1067

    PubMed  CAS  Google Scholar 

  40. Cardoso F, Durbecq V, Larsimont D et al (2004) Correlation between complete response to anthracycline-based chemotherapy and topoisomerase IIα gene amplification and protein expression in locally advanced breast cancer. Int J Oncol 24:201–209

    PubMed  CAS  Google Scholar 

  41. Knoop AS, Knudsen H, Basley E et al (2005) Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive marker in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 23:7483–7490

    Article  PubMed  CAS  Google Scholar 

  42. Tanner M, Isola J, Wiklund T et al (2006) Topoisomerase II-alpha gene amplification predicts favourable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 24:2428–2436

    Article  PubMed  CAS  Google Scholar 

  43. Di Leo A, Gancberg D, Larsimont D et al (2002) HER-2 amplification and topoisomerase IIα gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 8:1107–1116

    PubMed  CAS  Google Scholar 

  44. Park K, Kim J, Lim S, Han S (2003) Topoisomerase II-α (topoII) and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy. Eur J Cancer 39:631–634

    Article  PubMed  CAS  Google Scholar 

  45. Tubbs R, Barlow WE, Budd T et al (2009) Outcome of patients with early-stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status. J Clin Oncol 27:3881–3886

    Article  PubMed  CAS  Google Scholar 

  46. O′Malley FP, Chia S, Tu D et al (2009) Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101:644–650

    Article  PubMed  Google Scholar 

  47. Harris LN, Broadwater G, Abu-Khalaf M et al (2009) Topoisomerase IIα amplification does not predict benefit from dose-intense cyclophosphamide, doxorubicin, and fluorouracil therapy in HER-2amplified early breast cancer: results of CALGB 8541/150013. J Clin Oncol 27:3430–3436

    Article  PubMed  CAS  Google Scholar 

  48. Desmedt C, E. Azambuja E, Larsimont D et al (2009) Predicting the efficacy of anthracyclines in breast cancer (BC) patients: results of the neoadjuvant TOP trial. J Clin Oncol 27:15S (Abstr. 523)

  49. Durbecq V, Desmedt C, Paesmans M et al (2004) Correlation between topoisomerase IIα (Topo-II) gene amplification and protein expression in her-2 amplified breast cancer patients. Int J Oncol 25:1473–1479

    PubMed  CAS  Google Scholar 

  50. Mueller RE, Parkes RK, Androlis J (2004) O′Malley FP. Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples. Genes Chromosomes Cancer 39:288–297

    Article  PubMed  CAS  Google Scholar 

  51. Durbecq V, Paesmans M, Cardoso F et al (2004) Topoisomerase-IIα expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther 3:1207–1214

    PubMed  CAS  Google Scholar 

  52. Di Leo A, Larsimont D, Gancberg D et al (2001) HER-2 and topo-isomerase IIα as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide. Ann Oncol 12:1081–1089

    Article  PubMed  CAS  Google Scholar 

  53. Noguchi S (2006) Predictive factors for response to docetaxel in human breast cancer. Cancer Sci 97:813–820

    Article  PubMed  CAS  Google Scholar 

  54. Pustzai L (2007) Markers predicting clinical benefit in breast cancer from microtubule-targeting agents. Ann Oncol 18(Suppl 12):xii15–xii20

    Google Scholar 

  55. Gonzalez-Angulo A, Krishnamurthy S, Broglio KR et al (2004) Lack of association between amplification of her-2 and response to preoperative taxanes in patients with breast carcinoma. Cancer 101:258–263

    Article  PubMed  CAS  Google Scholar 

  56. Learn PA, Yeh IT, McNutt M et al (2005) HER2/neu expression as predictor of response to neoadjuvant docetaxel in patients with operable breast carcinoma. Cancer 103:2252–2260

    Article  PubMed  CAS  Google Scholar 

  57. Galmarini CM, Treilleux I, Cardoso F et al (2008) Class III β-tubulin isotype predicts response in adjuvant breast cancer patients randomly treated either with single-agent doxorubicin or docetaxel. Clin Cancer Res 14:4511–4516

    Article  PubMed  CAS  Google Scholar 

  58. Hasegawa S, Miyoshi Y, Egawa C et al (2003) Prediction of response to docetaxel by quantitative analysis of class I and III β-tubulin isotype mRNA expression in human breast cancers. Clin Cancer Res 9:2992–2997

    PubMed  CAS  Google Scholar 

  59. Bernard-Marty C, Treilleux I, Dumontet C et al (2002) Microtubule-associated parameters as predictive markers of docetaxel activity in advanced breast cancer patients: results of a pilot study. Clin Cancer Breast 3:341–345

    Article  CAS  Google Scholar 

  60. Pernault-Llorca F, André F, Sagan C et al (2009) Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2809–2815

    Article  Google Scholar 

  61. Miyoshi Y, Kurosumi M, Kurebayashi J et al (2008) Low nuclear grade but not cell proliferation predictive of pathological complete response to docetaxel in human breast cancer. J Cancer Res Clin Oncol 134:561–567

    Article  PubMed  CAS  Google Scholar 

  62. Minotti G, Menna P, Salvatorelli E et al (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229

    Article  PubMed  CAS  Google Scholar 

  63. Cheang M, Chia SK, Tu D et al (2009) Anthracyclines in basal breast cancer: the NCIC-CTG trial MA5 comparing adjuvant CMF to CEF. J Clin Oncol 27:15S (Abstr. 519)

    Google Scholar 

  64. Martín M, Rodríguez-Lescure A, Ruiz A et al (2010) Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer. Breast Cancer Res Treat 123:149–157

    Article  PubMed  Google Scholar 

  65. Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10:R25

    Article  PubMed  Google Scholar 

  66. Aulmann S, Waldburger N, Penzel R, Andrulis M, Schirmacher P, Sinn HP (2010) Reduction of CD44+/CD24− breast cancer cells by conventional cytotoxic chemotherapy. Hum Pathol 41:574–581

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from Fondo de Investigaciones Sanitarias (FIS PI07/0316), Red Temática de Investigación Cooperativa en Cáncer (RD06/0020/0021), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation; SEOM (Spanish Society for Medical Oncology); the NCI Breast SPORE program to UNC-CH (P50-CA58223-09A1); the Breast Cancer Research Foundation; and the V Foundation for Cancer Research. MCU Cheang is supported by Terry Fox Foundation Postdoctoral Fellowship.

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Authors and Affiliations

  1. Servicio de Oncología Médica, Hospital Universitario Gregorio Marañón, Universidad Complutense, c/Dr Esquerdo 46, 28007, Madrid, Spain

    M. Martin & Sara Lopez-Tarruella

  2. Hospital Clinico San Carlos, Madrid, Spain

    A. Romero, J. A. López García-Asenjo, J. A. García-Saenz, J. M. Román, A. Casado, J. de la Torre, V. Furio, J. Puente, T. Caldés, J. A. Vidart, Sara Lopez-Tarruella & E. Diaz-Rubio

  3. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    M. C. U. Cheang, X. He & C. M. Perou

  4. Instituto Carlos III, Madrid, Spain

    B. Oliva

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  1. M. Martin
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Correspondence to M. Martin.

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Martin, M., Romero, A., Cheang, M.C.U. et al. Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer. Breast Cancer Res Treat 128, 127–136 (2011). https://doi.org/10.1007/s10549-011-1461-y

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