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Biomarkers for Predicting Response to Anti- HER2 Agents

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Novel Biomarkers in the Continuum of Breast Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((BCRF,volume 882))

Abstract

The HER2 receptor is amplified or overexpressed in approximately 20 % of all breast cancers, but despite significant efforts of the clinical research community and a growing number of anti-HER2 agents, a significant number of patients with HER2-positive breast cancer either progress or suffer disease relapse within 5–10 years. The development of robust biomarkers that predict response to anti-HER2 agents is therefore an important clinical need to prevent overtreatment and to enable earlier assignment of patients to more optimal therapies. Here we review some of the recent advances in the field by focusing on pathways mediating resistance to anti-HER2 therapies, and the role of the immune system and cancer stem cells in therapy response. We also review preoperative treatment strategies and research paradigms that show promise in identifying novel biomarkers of response while also enabling the delineation of the mechanisms underlying clinical benefit from anti-HER2 therapies.

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References

  1. Slamon DJ et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  CAS  PubMed  Google Scholar 

  2. Singh JC, Jhaveri K, Esteva FJ (2014) HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. Br J Cancer 111(10):1888–1898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Slamon DJ et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792

    Article  CAS  PubMed  Google Scholar 

  4. Arteaga CL et al (2012) Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 9(1):16–32

    Article  CAS  Google Scholar 

  5. Perez EA et al (2014) Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32(33):3744–3752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Harris LN et al (2007) Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin Cancer Res 13(4):1198–1207

    Article  CAS  PubMed  Google Scholar 

  7. Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12(8):553–563

    Article  CAS  PubMed  Google Scholar 

  8. Arteaga CL, Chinratanalab W, Carter MB (2001) Inhibitors of HER2/neu (erbB-2) signal transduction. Semin Oncol 28(6 Suppl 18):30–35

    Article  CAS  PubMed  Google Scholar 

  9. Holbro T et al (2003) The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A 100(15):8933–8938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Neve RM, Lane HA, Hynes NE (2001) The role of overexpressed HER2 in transformation. Ann Oncol 12(Suppl 1):S9–13

    Article  PubMed  Google Scholar 

  11. Neve RM et al (2000) Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells. Oncogene 19(13):1647–1656

    Article  CAS  PubMed  Google Scholar 

  12. Lane HA et al (2000) ErbB2 potentiates breast tumor proliferation through modulation of p27(Kip1)-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol 20(9):3210–3223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hynes NE (1996) ErbB2 activation and signal transduction in normal and malignant mammary cells. J Mammary Gland Biol Neoplasia 1(2):199–206

    Article  CAS  PubMed  Google Scholar 

  14. Berns K et al (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4):395–402

    Article  CAS  PubMed  Google Scholar 

  15. Yakes FM et al (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62(14):4132–4141

    CAS  PubMed  Google Scholar 

  16. Nagata Y et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127

    Article  CAS  PubMed  Google Scholar 

  17. Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70

    Article  Google Scholar 

  18. Esteva FJ et al (2010) PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 177(4):1647–1656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chandarlapaty S et al (2012) Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer. Clin Cancer Res 18(24):6784–6791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Loi S et al (2013) Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst 105(13):960–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Johnston S et al (2008) Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 26(7):1066–1072

    Article  CAS  PubMed  Google Scholar 

  22. Holmes FA et al (2013) Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling. BMC Res Notes 6:507

    Article  PubMed  PubMed Central  Google Scholar 

  23. Guiu S et al (2013) Predictive factors of response in HER2-positive breast cancer treated by neoadjuvant therapy. J Oncol 2013:854121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Perez EA et al (2013) Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. J Clin Oncol 31(17):2115–2122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lu Y et al (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93(24):1852–1857

    Article  CAS  PubMed  Google Scholar 

  26. Creighton CJ et al (2008) Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 26(25):4078–4085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mu L et al (2012) Favorable outcome associated with an IGF-1 ligand signature in breast cancer. Breast Cancer Res Treat 133(1):321–331

    Article  CAS  PubMed  Google Scholar 

  28. Baselga J et al (2014) Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol 32(33):3753–3761

    Article  CAS  PubMed  Google Scholar 

  29. Baselga J et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366(2):109–119

    Article  CAS  PubMed  Google Scholar 

  30. Goss PE et al (2013) Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol 14(1):88–96

    Article  CAS  PubMed  Google Scholar 

  31. Konecny GE et al (2006) Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66(3):1630–1639

    Article  CAS  PubMed  Google Scholar 

  32. Moasser MM (2014) Two dimensions in targeting HER2. J Clin Oncol 32(19):2074–2077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bianchini G, Gianni L (2014) The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol 15(2):e58–e68

    Article  CAS  PubMed  Google Scholar 

  34. Gennari R et al (2004) Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 10(17):5650–5655

    Article  CAS  PubMed  Google Scholar 

  35. Denkert C et al (2011) Anti-cancer immune response mechanisms in neoadjuvant and targeted therapy. Semin Immunopathol 33(4):341–351

    Article  CAS  PubMed  Google Scholar 

  36. Loi S et al (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98. J Clin Oncol 31(7):860–867

    Article  CAS  PubMed  Google Scholar 

  37. Loi S et al (2014) Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 25(8):1544–1550

    Article  CAS  PubMed  Google Scholar 

  38. Perez EA et al (2015) Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. J Clin Oncol 33:701–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vadodkar A et al (2014) Brief exposure to trastuzumab prior to preoperative chemotherapy confirms predictors of response to treatment. In: San Antonio Breast Cancer Symposium. San Antonio, TX

    Google Scholar 

  40. Galanina N et al (2012) Evaluation of gene expression by RNA-seq after single dose of trastuzumab (T) reveals predictors of pathologic complete response (pCR) in HER2-positive early breast cancer. J Clin Oncol 30:p. (suppl; abstr 10558)

    Google Scholar 

  41. Carey L et al (2014) Gene expression signatures in pre- and post-therapy (Rx) specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer (BrCa). J Clin Oncol 32(5s):p. suppl; abstr 506

    Google Scholar 

  42. Yoshihara K et al (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612

    Article  PubMed  PubMed Central  Google Scholar 

  43. Norton N et al (2014) Association studies of fcgamma receptor polymorphisms with outcome in HER2+ breast cancer patients treated with trastuzumab in NCCTG (Alliance) Trial N9831. Cancer Immunol Res 2(10):962–969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Martin-Castillo B et al (2013) Basal/HER2 breast carcinomas: integrating molecular taxonomy with cancer stem cell dynamics to predict primary resistance to trastuzumab (Herceptin). Cell Cycle 12(2):225–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Majumder PK, Sellers WR (2005) Akt-regulated pathways in prostate cancer. Oncogene 24(50):7465–7474

    Article  CAS  PubMed  Google Scholar 

  46. Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ginestier C et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Charafe-Jauffret E et al (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69(4):1302–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li X et al (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100(9):672–679

    Article  CAS  PubMed  Google Scholar 

  50. Duru N et al (2014) Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society. J Cancer Res Clin Oncol 140(1):1–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu JC et al (2012) Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERalpha- breast cancer. Proc Natl Acad Sci U S A 109(15):5832–5837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Vinay Varadan & Maria Sandoval

  2. Seidman Cancer Center, Cleveland, OH, USA

    Lyndsay N. Harris MD

  3. School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Lyndsay N. Harris MD

Authors
  1. Vinay Varadan
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  2. Maria Sandoval
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  3. Lyndsay N. Harris MD
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Corresponding author

Correspondence to Lyndsay N. Harris MD .

Editor information

Editors and Affiliations

  1. Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Ctr., BALTIMORE, Maryland, USA

    Vered Stearns

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© 2016 Breast Cancer Research Foundation

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Varadan, V., Sandoval, M., Harris, L. (2016). Biomarkers for Predicting Response to Anti- HER2 Agents. In: Stearns, V. (eds) Novel Biomarkers in the Continuum of Breast Cancer. Advances in Experimental Medicine and Biology(), vol 882. Springer, Cham. https://doi.org/10.1007/978-3-319-22909-6_6

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