Advertisement

Journal of Molecular Medicine

, Volume 93, Issue 2, pp 119–125 | Cite as

The future of breast cancer systemic therapy: the next 10 years

  • Melinda L. Telli
  • George W. SledgeEmail author
Review

Abstract

Over the past 50 years, substantial progress has been made in the systemic treatment of early-stage and advanced breast cancer. The use of chemotherapy in the adjuvant and metastatic settings has demonstrated proven efficacy and it has been clearly demonstrated that targeting the estrogen receptor and human growth factor receptor 2 (HER2) is efficacious in early and advanced disease. Despite these advances, vexing clinical challenges remain particularly related to the treatment of triple-negative breast cancer (TNBC; estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) where little progress has been made therapeutically in more than a decade. While recurrences of hormone-responsive breast cancer are overall less common, late relapses after cessation of endocrine therapy are a more frequent occurrence in modern times and reflect the problem of underlying tumor dormancy that as yet has not been overcome. Multiple molecular tools are now available to interrogate the biology of breast cancer, though exactly how to make this information meaningful in the clinic has proven challenging, and molecularly driven clinical trials have faced feasibility challenges. In parallel, focus has expanded from tumor to host with the ability to ascertain underlying germline alterations, such as inherited BRCA1 and BRCA2 mutations, which may be responsible for breast cancer carcinogenesis and, importantly, may have implications for treatment. These clinical advances in germline genetics, made possible by both scientific investigation as well as the courts, still face challenges related to increasing encounters with variants of unknown significance and difficulty in predicting risks associated with less well-characterized inherited cancer predisposition syndromes. In this paper, we attempt to predict the next 10 years of breast cancer, in particular focusing on how the past serves as prologue to the future in this disease.

Keywords

Breast cancer Systemic treatment Inherited breast cancer predisposition syndromes Breast cancer subtypes Late recurrence 

Notes

Disclosures

Research funding (MT): Novartis, Sanofi, Abbvie, Pharmamar; (GS): Genentech/Roche Pharmaceuticals.

Conflict of interest

Advisory Role (MT): Oncoplex DX, Vertex; (GS): Symphogen, Syndax

References

  1. 1.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182PubMedCrossRefGoogle Scholar
  2. 2.
    Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712PubMedCrossRefGoogle Scholar
  3. 3.
    Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  4. 4.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRefGoogle Scholar
  5. 5.
    Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRefGoogle Scholar
  6. 6.
    Slamon D, Eiermann W, Robert N et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273–1283PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Robidoux A, Tang G, Rastogi P et al (2013) Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol 14:1183–1192PubMedCrossRefGoogle Scholar
  8. 8.
    Untch M, Loibl S, Bischoff J et al (2012) Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13:135–144PubMedCrossRefGoogle Scholar
  9. 9.
    Piccart-Gebhart MJ, Holmes AP, Baselga J (2014) First results from the phase III ALTTO trial (BIG 2–06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T → L), or their combination (T + L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin Oncol;32:abstr LBA4Google Scholar
  10. 10.
    Baselga J, Cortes J, Kim SB et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109–119PubMedCrossRefGoogle Scholar
  11. 11.
    Verma S, Miles D, Gianni L et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791PubMedCrossRefGoogle Scholar
  12. 12.
    Clinical Trials.gov Identifier NCT01966471. A Study of Kadcyla (Trastuzumab Emtansine) Plus Perjeta (Pertuzumab) Following anthracyclines in comparison with herceptin (Trastuzumab) plus perjeta and a taxane following anthracyclines as adjuvant therapy in patients with operable HER2-positive primary breast cancer. Available at clinicaltrials.govGoogle Scholar
  13. 13.
    Ithimakin S, Day KC, Malik F et al (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res 73:1635–1646PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Bose R, Kavuri SM, Searleman AC et al (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Disc 3:224–237CrossRefGoogle Scholar
  15. 15.
    Early Breast Cancer Trialists’ Collaborative G, Davies C, Godwin J et al (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378:771–784PubMedCrossRefGoogle Scholar
  16. 16.
    Goss PE, Ingle JN, Martino S et al (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262–1271PubMedCrossRefGoogle Scholar
  17. 17.
    Davies C, Pan H, Godwin J et al (2013) Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381:805–816PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Turner NH, Di Leo A (2013) HER2 discordance between primary and metastatic breast cancer: assessing the clinical impact. Cancer Treat Rev 39:947–957PubMedCrossRefGoogle Scholar
  19. 19.
    Barone I, Brusco L, Fuqua SA (2010) Estrogen receptor mutations and changes in downstream gene expression and signaling. Clin Cancer Res Off J Am Assoc Cancer Res 16:2702–2708CrossRefGoogle Scholar
  20. 20.
    Fuqua SA, Gu G, Rechoum Y (2014) Estrogen receptor (ER) alpha mutations in breast cancer: hidden in plain sight. Breast Cancer Res Treat 144:11–19PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Haricharan S, Bainbridge MN, Scheet P, Brown PH (2014) Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival: an analysis of genome sequence data. Breast Cancer Res Treat 146:211–220PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Gasparini G, Biganzoli E, Bonoldi E, Morabito A, Fanelli M, Boracchi P (2001) Angiogenesis sustains tumor dormancy in patients with breast cancer treated with adjuvant chemotherapy. Breast Cancer Res Treat 65:71–75PubMedCrossRefGoogle Scholar
  23. 23.
    Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1:149–153PubMedCrossRefGoogle Scholar
  24. 24.
    Naumov GN, Akslen LA, Folkman J (2006) Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch. Cell Cycle 5:1779–1787PubMedCrossRefGoogle Scholar
  25. 25.
    Burnet F (1970) The concept of immunological surveillance. Prog Exp Tumor Res 13:1–27PubMedGoogle Scholar
  26. 26.
    Uhr JW, Pantel K (2011) Controversies in clinical cancer dormancy. Proc Natl Acad Sci U S A 108:12396–12400PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Ignatiadis M (2013) Multigene assays for late recurrence of breast cancer. Lancet Oncol 14:1029–1030PubMedCrossRefGoogle Scholar
  28. 28.
    Meng S, Tripathy D, Frenkel EP et al (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res Off J Am Assoc Cancer Res 10:8152–8162CrossRefGoogle Scholar
  29. 29.
    Beaver JA, Jelovac D, Balukrishna S et al (2014) Detection of cancer DNA in plasma of patients with early-stage breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 20:2643–2650CrossRefGoogle Scholar
  30. 30.
    Shaw JA, Page K, Blighe K et al (2012) Genomic analysis of circulating cell-free DNA infers breast cancer dormancy. Genome Res 22:220–231PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRefGoogle Scholar
  32. 32.
    Prat A, Adamo B, Cheang MC, Anders CK, Carey LA, Perou CM (2013) Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist 18:123–133PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Paik S, Shak S, Tang G et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826PubMedCrossRefGoogle Scholar
  34. 34.
    Paik S, Tang G, Shak S et al (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726–3734PubMedCrossRefGoogle Scholar
  35. 35.
    Lehmann BD, Bauer JA, Chen X et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750–2767PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Stephens PJ, Tarpey PS, Davies H et al (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486:400–404PubMedCentralPubMedGoogle Scholar
  37. 37.
    Shah SP, Roth A, Goya R et al (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486:395–399PubMedGoogle Scholar
  38. 38.
    Tran E, Turcotte S, Gros A et al (2014) Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344:641–645PubMedCrossRefGoogle Scholar
  39. 39.
    Matsushita H, Vesely MD, Koboldt DC et al (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482:400–404PubMedCrossRefGoogle Scholar
  40. 40.
    Basu GD, Ghazalpour A, Gatalica Z, et al. (2014) Expression of novel immunotherapeutic targets in triple-negative breast cancer. J Clin Oncol 32:abstract 1001Google Scholar
  41. 41.
    Byrski T, Huzarski T, Dent R et al (2009) Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 115:359–363PubMedCrossRefGoogle Scholar
  42. 42.
    Tutt A, Robson M, Garber JE et al (2010) Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376:235–244PubMedCrossRefGoogle Scholar
  43. 43.
    Abkevich V, Timms KM, Hennessy BT et al (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776–1782PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Birkbak NJ, Wang ZC, Kim JY et al (2012) Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Disc 2:366–375CrossRefGoogle Scholar
  45. 45.
    Popova T, Manie E, Rieunier G et al (2012) Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72:5454–5462PubMedCrossRefGoogle Scholar
  46. 46.
    Telli M, Jensen K, Abkevich V et al (2012) Homologous Recombination Deficiency (HRD) score predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and BRCA1/2 mutation-associated breast cancer (BC). San Antonio Breast Cancer Symposium; 2012, San AntonioGoogle Scholar
  47. 47.
    Telli ML, Jensen KC, Kurian AW (2013) PrECOG 0105: final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer. 31. J Clin Oncol;31: Abstract 1003Google Scholar
  48. 48.
    Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25:1329–1333PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Daly MB, et al. (2014) Genetic/Familial high-risk assessment: breast and ovarian. V1. Available at http://www.nccn.com
  50. 50.
    Von Minckwitz G, Hahnen E, Fasching PA, et al.(2014) Pathological complete response (pCR) rates after carboplatin-containing neoadjuvant chemotherapy in patients with germline BRCA (gBRCA) mutation and triple-negative breast cancer (TNBC): Results from GeparSixto. J Clin Oncol 32: Abstract 1005Google Scholar
  51. 51.
    United States Supreme Court, Association for molecular pathology et al. v. myriad genetics, inc., et al. In: Court USS, ed. 2013Google Scholar
  52. 52.
    Couch FJ, Nathanson KL, Offit K (2014) Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 343:1466–1470PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Castera L, Krieger S, Rousselin A, et al. (2014) Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum GenetGoogle Scholar
  54. 54.
    Kurian AW, Hare EE, Mills MA et al (2014) Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 32:2001–2009PubMedCrossRefGoogle Scholar
  55. 55.
    McCabe N, Turner NC, Lord CJ et al (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly (ADP-ribose) polymerase inhibition. Cancer Res 66:8109–8115PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Medicine, Division of OncologyStanford University School of MedicineStanfordUSA
  2. 2.Department of Medicine, Division of OncologyStanford University School of MedicineStanfordUSA

Personalised recommendations