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Neoadjuvant Therapy for Triple-Negative Breast Cancer: The Challenge of Translating Biological Concepts into Effective Treatments

  • Translational Research (V Stearns, Section Editor)
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Abstract

With the help of ever more powerful research tools triple-negative breast cancer (TNBC) is slowly yielding its secrets. The neoadjuvant setting gives us the best opportunity to address questions raised by the biologic heterogeneity of the disease, and eventually design individualized treatment plans for patients who are identified as likely to have a suboptimal response to chemotherapy. However, given a plethora of aberrantly activated pathways, exacerbated by its genomic instability, the challenge is to separate what drives the behavior of TNBC from the consequences of that behavior. This article reviews our current understanding of TNBC, including recent efforts to identify clinically relevant subsets of the disease, the role of treatments that exploit defects in DNA repair, including chemotherapeutic agents such as the platinum analogues, and biologic agents such as the poly ADP-ribose polymerases (PARP) inhibitors, and then discusses potential targeted approaches to its treatment, most of which are still early in development.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Millikan RC, Newman B, Tse CK, et al. Epidemiology of basal-like breast cancer. Breast Cancer Res Treat. 2008;109:123–9.

    Article  PubMed  Google Scholar 

  2. Trivers KF, Lund MJ, Porter PL, et al. The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control. 2009;20:1071–82.

    Article  PubMed  Google Scholar 

  3. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor-negative, progesterone receptor-negative and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California Cancer Registry. Cancer. 2007;109:1721–8.

    Article  PubMed  Google Scholar 

  4. Amirikia KC, Mills P, Bush J, Newman LA. Higher population-based incidence rates of triple-negative breast cancer among young African-American women. Cancer. 2011;111:2747–53.

    Article  Google Scholar 

  5. • Foulkes WM, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48. Excellent brief review of the clinical and biological issues associated with TNBC.

    Article  PubMed  CAS  Google Scholar 

  6. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA. 2006;295:1658–67.

    Article  PubMed  CAS  Google Scholar 

  7. Mieog JS, van der Hage JA, van der Velde CJ. Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst Rev. 2007;2:CD005002.

    PubMed  Google Scholar 

  8. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778–85.

    Article  PubMed  Google Scholar 

  9. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11:5678–85.

    Article  PubMed  CAS  Google Scholar 

  10. • von Minckwitz G, Untch M, Blohmer J-U, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796–804. In a large, retrospective analysis, pathologic complete response has the greatest impact on DFS and OS when defined as the absence of residual invasive or in situ disease in the breast and axillary nodes, but even then is prognostic only in patients with aggressive tumor histologies such as TNBC.

    Article  Google Scholar 

  11. Esserman LJ, Berry DA, Demichele A, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 Trial -CALGB 150007/150012, ACRIN 6657. J Clin Oncol. 2012 (in press).

  12. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13:2329–34.

    Article  PubMed  CAS  Google Scholar 

  13. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–81.

    Article  PubMed  Google Scholar 

  14. Fisher CS, Ma CX, Gillanders WE, et al. Neoadjuvant chemotherapy is associated with improved survival compared with adjuvant chemotherapy in patients with triple-negative breast cancer only after complete pathologic response. Ann Surg Oncol. 2012;19:253–8.

    Article  PubMed  Google Scholar 

  15. Prowell TM, Pazdur R. Pathologic compete response and accelerated drug approval in early breast cancer. New Engl J Med. 2012;366:2438–41.

    Article  PubMed  CAS  Google Scholar 

  16. Eiermann W, Bergh J, Cardoso, et al. Triple negative breast cancer: proposals for a pragmatic definition and implications for patient management and trial design. Breast. 2012;21:20–6.

    Article  PubMed  CAS  Google Scholar 

  17. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Path Lab Med. 2010;134:907–32.

    PubMed  Google Scholar 

  18. • Cheang MCU, Martin M, Nielsen TO, et al. Quantitative hormone receptors, triple-negative breast cancer (TNBC), and molecular subtypes: a collaborative effort of the BIG-NCI NABCG. J Clin Oncol. 2012;30(Suppl):abstract 1008. Highlights the limitations of IHC analysis in differentiating breast cancer subtypes; there is significant ‘contamination’ of TNBC with luminal and HER2+ subtypes even when using a stringent definition for TNBC. Suggests the need for real-time gene expression analysis to optimally classify and treat patients with breast cancer.

  19. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26:2568–81.

    Article  PubMed  Google Scholar 

  20. Sorlie T, Wang Y, Xiao C, et al. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analysis across 3 different platforms. BMC Genomics. 2006;7:127–41.

    Article  PubMed  Google Scholar 

  21. Keller PJ, Arendt LM, Skibinski A, et al. Defining the cellular precursors to human breast cancer. PNAS. 2012;109:2772–7.

    Article  PubMed  CAS  Google Scholar 

  22. Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4:814–9.

    Article  PubMed  CAS  Google Scholar 

  23. Lips EH, Mulder L, Hannermann J, et al. Indicators of homologous recombination deficiency in breast cancer and association with response to neoadjuvant chemotherapy. Ann Oncol. 2011;22:870–6.

    Article  PubMed  CAS  Google Scholar 

  24. • Gonzalez-Angulo AM, Timm KM, Liu S, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res. 2011;17:1082–9. Up to 20 % of ‘unselected’ TNBC patients have BRCA mutations; argues in favor of testing all patients independent of family history.

    Article  PubMed  CAS  Google Scholar 

  25. Grushko TA, Nwachukwu N, Charoenthammaraksa S, et al. Evaluation of BRCA1 inactivation by promoter methylation as a marker of triple-negative and basal-like breast cancers. J Clin Oncol. 2010;28(Suppl):abstract 10510.

  26. Graeser M, McCarthy A, Lord CJ, et al. A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res. 2010;16:6159–68.

    Article  PubMed  CAS  Google Scholar 

  27. Vollebergh MA, Lips EH, Nederlof PM, et al. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann Oncol. 2011;22:1561–70.

    Article  PubMed  CAS  Google Scholar 

  28. Tassone P, Tagliaferri P, Perricelli A, et al. BRCA1 expression modulates chemosensitivity of BRCA1-deficient HCC1937 human breast cancer cells. Br J Cancer. 2003;88:1285–91.

    Article  PubMed  CAS  Google Scholar 

  29. Byrski T, Dent R, Blecharz P, et al. Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res. 2012;14:R110.

    Article  PubMed  Google Scholar 

  30. Byrski T, Huzarski T, Dent R, et al. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat. 2009;115:359–63.

    Article  PubMed  CAS  Google Scholar 

  31. Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28:1145–53.

    Article  PubMed  CAS  Google Scholar 

  32. Sikov WM, Dizon DS, Strenger R, et al. Frequent pathologic complete responses in aggressive stages II to III breast cancers with every-4-week carboplatin and weekly paclitaxel with or without trastuzumab: a Brown University Oncology Group Study. J Clin Oncol. 2009;27:4693.

    Article  PubMed  CAS  Google Scholar 

  33. Chen XS, Nie XQ, Chen CM, et al. Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer. Ann Oncol. 2010;21:961.

    Article  PubMed  CAS  Google Scholar 

  34. Chang HR, Glaspy J, Allison MA, et al. Differential response of triple-negative breast cancer to a docetaxel and carboplatin-based neoadjuvant treatment. Cancer. 2012;116:4227–37.

    Article  Google Scholar 

  35. Irshad S, Ellis P, Tutt A. Molecular heterogeneity of triple-negative breast cancer and its clinical implications. Curr Opin Oncol. 2011;23:566–77.

    Article  PubMed  CAS  Google Scholar 

  36. Glendenning J, Tutt A. PARP inhibitors–current status and the walk towards early breast cancer. Breast. 2011;20(S3):S12–9.

    Article  PubMed  Google Scholar 

  37. Kaelin Jr WG. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5:689–98.

    Article  PubMed  CAS  Google Scholar 

  38. Goncalves A, Finetti P, Sabatier R, et al. Poly(ADP-ribose) polymerase-1 mRNA expression in human breast cancer; a meta-analysis. Breast Cancer Res Treat. 2010.

  39. von Minckwitz G, Müller BM, Loibl S, et al. Cytoplasmic poly (adenosine-diphosphate-ribose) polymerase expression is predictive and prognostic in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol. 2011;29:2150–7.

    Article  Google Scholar 

  40. Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol. 2009;27:CRA501–18s(meeting abstracts).

  41. Isakoff S, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib (ABT-888) and temozolomide for metastatic breast cancer. J Clin Oncol. 2010;28(15s);abstract 1019.

    Google Scholar 

  42. O’Shaughnessy J, Osborne C, Pippen J, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205–14.

    Article  PubMed  Google Scholar 

  43. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011;29:(Suppl);abstract 1007.

  44. Ji J, Lee MP, Kadota M, et al. Pharmacodynamic and pathway analysis of 3 presumed inhibitors of poly (ADP-ribose) polymerase: ABT-888, AZD2281, and BSI201. AACR. 2011;71:meeting abstract 4527.

  45. Dent RA, Lindeman GJ, Clemons M, et al. Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the first- or second-line treatment of patients with metastatic triple-negative breast cancer: results from the safety cohort of a phase I/II multicenter trial. J Clin Oncol. 2010;28(15s);abstract 1018.

    Google Scholar 

  46. Linderholm BK, Hellborg H, Johansson U, et al. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol. 2009;20:1639–46.

    Article  PubMed  CAS  Google Scholar 

  47. O’Shaughnessy J, Dieras V, Glaspy J, et al. Comparison of subgroup analyses of PFS from 3 phase III studies of bevacizumab in combination with chemotherapy in patients with HER2-negative metastatic breast cancer. Cancer Res. 2009;69(24 Suppl):207.

    Google Scholar 

  48. von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012;366:299–309.

    Article  Google Scholar 

  49. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310–20.

    Article  PubMed  CAS  Google Scholar 

  50. Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008;26:1810–6.

    Article  PubMed  CAS  Google Scholar 

  51. Bergh J, Greil R, Voytko N, et al. Sunitinib in combination with docetaxel (D) vs D alone for the first-line treatment of advanced breast cancer (ABC). J Clin Oncol. 2010;28(15s):abstract LBA 1010.

  52. Crown J, Dieras V, Staroslawska E, et al. Phase III trial of sunitinib in combination with capecitabine (C) vs C in previously treated advanced breast cancer. J Clin Oncol. 2010;28(15s):abstract LBA 1011.

  53. Wildiers H, Fontaine C, Vuylsteke P, et al. SUCON Trial (SUnitinib CONsolidation Therapy in Metastatic Breast Cancer): A Belgian multicenter phase II randomized trial in HER2-negative metastatic breast cancer evaluating consolidation antiangiogenic therapy with sunitinib after objective response to taxane chemotherapy. Cancer Res. 2009;69(24 Suppl):203.

    Google Scholar 

  54. Miller K, Estes M, Perkins S, et al. An exploratory study of the biological activity of sunitinib as a component of neoadjuvant therapy for breast cancer. Cancer Res. 2009;69(24 Suppl):202.

    Google Scholar 

  55. Hoadley KA, Weigman VJ, Fan C, et al. EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics. 2007;8:258.

    Google Scholar 

  56. Green MD, Francis PA, Gebski V, et al. Gefitinib treatment in hormone-resistant and hormone receptor-negative advanced breast cancer. Ann Oncol. 2009;20:1813–7.

    Article  PubMed  CAS  Google Scholar 

  57. von Minckwitz G, Jonat W, Fasching P, et al. A multicentre phase II study on gefitinib in taxane- and anthracycline-pretreated metastatic breast cancer. Breast Cancer Res Treat. 2005;89:165–72.

    Article  CAS  Google Scholar 

  58. Gutteridge E, Agrawal A, Nicholson R, et al. The effects of gefitinib in tamoxifen-resistant and hormone-insensitive breast cancer: a phase II study. Int J Cancer. 2010;126:1806–16.

    Google Scholar 

  59. Dickler MN, Cobleigh MA, Miller KD, et al. Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat. 2009;115:115–21.

    Article  PubMed  CAS  Google Scholar 

  60. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer. J Clin Oncol. 2008;26(Meeting Suppl):abstract 1009.

    Google Scholar 

  61. Baselga J, Stemmer S, Pego A, et al. Cetuximab + cisplatin in estrogen receptor-negative, progesterone receptor-negative, HER2-negative (triple-negative) metastatic breast cancer: results of the randomized phase II BALI-1 trial. Cancer Res. 2010;70(24 Suppl):95s (abstract PD01–01).

  62. Finn RS. Targeting Src in breast cancer. Ann Oncol. 2008;19:1379–86.

    Article  PubMed  CAS  Google Scholar 

  63. Finn RS, Dering J, Ginther C, et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat. 2007;105:319–26.

    Article  PubMed  CAS  Google Scholar 

  64. Huang F, Reeves K, Han X, et al. Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Cancer Res. 2007;67:2226–38.

    Article  PubMed  CAS  Google Scholar 

  65. Finn RS BC, Ibrahim N, Strauss LC, et al. Phase II trial of dasatinib in triple-negative breast cancer: results of study CA180059. San Antonio Breast Cancer Symposium. San Antonio, TX, 2008;abstract 3118.

  66. Ma CX, Cai S, Li S, et al. Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models. J Clin Invest. 2012;122:1541–52.

    Article  PubMed  CAS  Google Scholar 

  67. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68:6084–91.

    Article  PubMed  CAS  Google Scholar 

  68. Marty B, Maire V, Gravier E, et al. Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells. Breast Cancer Res. 2008;10:R101.

    Article  PubMed  Google Scholar 

  69. DeGraffenried LA, Fulcher L, Friedrichs WE, et al. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann Oncol. 2004;15:1510–6.

    Article  PubMed  CAS  Google Scholar 

  70. Mayer I BH, Bendell J, Means-Powell J, Arteaga C, Shyr Y, Pietenpol J. A Phase Ib trial of RAD001, an mTOR inhibitor, with weekly cisplatin and paclitaxel in patients with HER2-negative metastatic breast cancer. Cancer Res. 2009;69(Suppl):abstract 3093.

  71. Carigliano G. Immunity and autoimmunity: revising the concepts of response to breast cancer. Breast. 2011;S3:S71–4.

    Article  Google Scholar 

  72. West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13:R126.

    Google Scholar 

  73. Reeder-Hayes KE, Carey LA, Sikov WM. Clinical trials in triple negative breast cancer. Breast Dis. 2010/2011;32:123–36.

    Google Scholar 

  74. Nahleh Z. Neoadjuvant chemotherapy for “triple negative” breast cancer: a review of current practices and future outlook. Med Oncol. 2012;27:531–9.

    Article  Google Scholar 

  75. Karn T, Pusztai L, Holtrich U, et al. Homogeneous datasets of triple negative breast cancers enable identification of novel prognostic and predictive signatures. PLoS ONE. 2011;6:e28403.

    Article  PubMed  CAS  Google Scholar 

  76. Prat A, Parker J, Kanginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12:R68.

    Article  PubMed  Google Scholar 

  77. • Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5:5–23. Excellent review of current concepts about intrinsic subtyping of breast cancer.

    Article  PubMed  CAS  Google Scholar 

  78. Lee H, Jung S-Y, Ro JY, et al. Metaplastic breast cancer: clinicopathological features and its prognosis. J Clin Pathol. 2012;65:441–6.

    Article  PubMed  Google Scholar 

  79. •• Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750–67. TNBC consists of 6 different subtypes, each having a characteristic gene expression profile indicating potentially ‘drugable’ targets.

    Article  PubMed  CAS  Google Scholar 

  80. Shapiro CL, Cascione L, Gasparini P, et al. Use of microRNA (miR) expression profiling to identify distinct subclasses of triple-negative breast cancers (TNBC). J Clin Oncol. 2012;30(Suppl):abstract 1007.

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Disclosure

W.M. Sikov has served as a consultant to Celgene and Genomic Health, has received grants from Celgene, and has received payment for lectures from Bristol-Myers Squibb.

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Sikov, W.M. Neoadjuvant Therapy for Triple-Negative Breast Cancer: The Challenge of Translating Biological Concepts into Effective Treatments. Curr Breast Cancer Rep 4, 240–248 (2012). https://doi.org/10.1007/s12609-012-0092-6

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