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Emerging Biomarkers of the Future: Changing Clinical Practice for 2020

  • Biomarkers (S Dawood, Section Editor)
  • Published:
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Abstract

Progress in biomarker development has greatly enhanced our ability to categorize breast cancer into several clinical subtypes and to deliver better personalized therapies. Technological advances in gene expression profiling, signaling pathways, proliferation markers and tumor monitoring through detection of circulating tumor cells and free DNA, and measurements of genomic instability and germline mutations are being vigorously pursued in breast cancer research. Their application in routine clinical practice is increasing and helping further development of precision medicine. Ongoing challenges include assessing the utility and feasibility of these tests, interpreting the large amounts of genomic data that are being generated, translating the information to clinical practice, and constructing clinical trials on molecularly driven approaches. In this article, we will review current and emerging promising biomarkers and their roles in the management of patients with breast cancer.

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References

  1. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–312.

    Article  CAS  PubMed  Google Scholar 

  2. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    Article  CAS  PubMed  Google Scholar 

  3. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869–74.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kourea HP, Zolota V, Scopa CD. Targeted pathways in breast cancer: molecular and protein markers guiding therapeutic decisions. Curr Mol Pharmacol. 2014;7(1):4–21.

    Article  CAS  PubMed  Google Scholar 

  5. Massihnia D, Perez A, Bazan V, et al. A headlight on liquid biopsies: a challenging tool for breast cancer management. Tumour Biol. 2016 Jan 20.

  6. Malvezzi M, Bertuccio P, Rosso T, Rota M, Levi F, La Vecchia C, et al. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann Oncol. 2015;26(4):779–86.

    Article  CAS  PubMed  Google Scholar 

  7. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.

    Article  PubMed  Google Scholar 

  8. Sharma K, Costas A, Shulman LN, Meara JG. A systematic review of barriers to breast cancer care in developing countries resulting in delayed patient presentation. J Oncol. 2012;2012:121873.

    Article  PubMed  PubMed Central  Google Scholar 

  9. El Saghir NS, Khalil MK, Eid T, et al. Trends in epidemiology and management of breast cancer in developing Arab countries: a literature and registry analysis. Int J Surg. 2007;5(4):225–33.

    Article  PubMed  Google Scholar 

  10. Anderson BO, Ilbawi AM, El Saghir NS. Breast cancer in low and middle income countries (LMICs): a shifting tide in global health. Breast J. 2015;21(1):111–8.

    Article  PubMed  Google Scholar 

  11. World Health Organization. Cancer rates could increase by 50% to 15 million by 2020. WHO; 2010.

  12. Rodríguez-Antona C, Taron M. Pharmacogenomic biomarkers for personalized cancer treatment. J Intern Med. 2015;277(2):201–17.

    Article  PubMed  CAS  Google Scholar 

  13. American Cancer Society. Cancer facts & figures 2012. American Cancer Society; 2012. p. 11.

  14. Andre F, McShane LM, Michiels S, Ransohoff DF, Altman DG, Reis-Filho JS, et al. Biomarker studies: a call for a comprehensive biomarker study registry. Nat Rev Clin Oncol. 2011;8(3):171–6.

    Article  PubMed  Google Scholar 

  15. Diamandis EP. Cancer biomarkers: can we turn recent failures into success? J Natl Cancer Inst. 2010;102(19):1462–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gerdes J, Schwab U, Lemke H, Stein H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer. 1983;31(1):13–20.

    Article  CAS  PubMed  Google Scholar 

  17. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360(8):790–800.

    Article  CAS  PubMed  Google Scholar 

  18. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thürlimann B, Senn HJ, et al. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009;20(8):1319–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11(2):174–83.

    Article  CAS  PubMed  Google Scholar 

  20. Jackisch C, Harbeck N, Huober J, et al. 14th St. Gallen International Breast Cancer Conference 2015: Evidence, controversies, consensus - primary therapy of early breast cancer: opinions expressed by German experts. Breast Care (Basel). 2015;10(3):211–9.

    Article  Google Scholar 

  21. Coates AS, Winer EP, Goldhirsch A, et al. Panel Members. Tailoring therapies-improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015;26(8):1533–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. de Azambuja E, Cardoso F, de Castro Jr G, et al. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer. 2007;96(10):1504–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Petrelli F, Viale G, Cabiddu M, et al. Prognostic value of different cut-off levels of Ki-67 in breast cancer: a systematic review and meta-analysis of 64,196 patients. Breast Cancer Res Treat. 2015;153(3):477–91.

    Article  PubMed  Google Scholar 

  24. Dowsett M, Smith IE, Ebbs SR, et al. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res. 2005;11:951–8.

    Google Scholar 

  25. Alba E, Lluch A, Ribelles N, et al. High proliferation predicts pathological complete response to neoadjuvant chemotherapy in early breast cancer. Oncologist. 2016 Jan 19. pii: theoncologist.2015-0312.

  26. Criscitiello C, Disalvatore D, De Laurentiis M, et al. High Ki-67 score is indicative of a greater benefit from adjuvant chemotherapy when added to endocrine therapy in luminal B HER2 negative and node-positive breast cancer. Breast. 2014;23(1):69–75. doi:10.1016/j.breast.2013.11.007.

    Article  PubMed  Google Scholar 

  27. Ricciardi GRR, Adamo B, Ieni A, Licata L, Cardia R, Ferraor G, et al. Androgen Receptor (AR), E-Cadherin, and Ki-67 as emerging targets and novel prognostic markers in triple-negative breast cancer (TNBC) patients. PLoS ONE. 2015;10(6), e0128368.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kim T, Han W, Kim MK, Lee JW, Kim J, Ahn SK, et al. Predictive significance of p53, Ki-67, and Bcl-2 expression for pathologic complete response after neoadjuvant chemotherapy for triple-negative breast cancer. J Breast Cancer. 2015;18(1):16–21.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cheang MC, Chia SK, Voduc D, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101(10):736–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103(22):1656–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–82.

    Article  CAS  PubMed  Google Scholar 

  32. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–12.

    Article  CAS  PubMed  Google Scholar 

  33. Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357:39–51.

    Article  CAS  PubMed  Google Scholar 

  34. Press MF, Bernstein L, Thomas PA, et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol. 1997;15:2894–904.

    CAS  PubMed  Google Scholar 

  35. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.

    Article  CAS  PubMed  Google Scholar 

  36. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.

    Article  CAS  PubMed  Google Scholar 

  37. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.

    Article  CAS  PubMed  Google Scholar 

  38. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABPB-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005;23:3676–85.

    Article  CAS  PubMed  Google Scholar 

  41. Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol. 2010;28:2024–31.

    Article  CAS  PubMed  Google Scholar 

  42. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375(9712):377–84.

    Article  CAS  PubMed  Google Scholar 

  43. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.

    Article  CAS  PubMed  Google Scholar 

  44. Di Leo A, Gomez HL, Aziz Z, et al. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol. 2008;26:5544–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379(9816):633–40.

    Article  CAS  PubMed  Google Scholar 

  46. Arribas J, Baselga J, Pedersen K, et al. p95HER2 and breast cancer. Cancer Res. 2011;71:1515–9.

    Article  CAS  PubMed  Google Scholar 

  47. Scaltriti M, Rojo F, Ocana A, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38.

    Article  CAS  PubMed  Google Scholar 

  48. Pedersen K, Angelini PD, Laos S, et al. A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis. Mol Cell Biol. 2009;29:3319–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Duchnowska R, Sperinde J, Chenna A, et al. Quantitative measurements of tumoral p95HER2 protein expression in metastatic breast cancer patients treated with trastuzumab: independent validation of the p95HER2 clinical cutoff. Clin Cancer Res. 2014;20:2805–13.

    Article  CAS  PubMed  Google Scholar 

  50. Loibl S, Bruey J, Von Minckwitz G, et al. Validation of p95 as a predictive marker for trastuzumab-based therapy in primary HER2-positive breast cancer: a translational investigation from the neoadjuvant GeparQuattro study. J Clin Oncol. 2011;29(Suppl):abstr 530.

  51. Majewski IJ, Nuciforo P, Mittempergher L, et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol. 2015;33(12):1334–9.

    Article  CAS  PubMed  Google Scholar 

  52. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19.

    Article  CAS  PubMed  Google Scholar 

  53. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91.

    Article  CAS  PubMed  Google Scholar 

  54. Carey LA, Berry DA, Cirrincione CT, et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2015 Nov 2.

  55. Loi S, Savas P. Looking deep into the heterogeneity of Human Epidermal Growth Factor Receptor 2 – Positive breast cancer: Can we understand it better? J Clin Oncol. Published online before print January 11, 2016.

  56. Yang Z, Barnes CJ, Kumar R. Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells. Clin Cancer Res. 2004;10(11):3621–8.

    Article  CAS  PubMed  Google Scholar 

  57. Parra-Palau JL, Pedersen K, Peg V, et al. A major role of p95/611-CTF, a carboxy-terminal fragment of HER2, in the down-modulation of the estrogen receptor in HER2-positive breast cancers. Cancer Res. 2010;70(21):8537–46.

    Article  CAS  PubMed  Google Scholar 

  58. Ithimakin S, Day KC, Malik F, et al. HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res. 2013;73:1635–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3:224–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ciccolini J, Fanciullino R, Serdjebi C, Milano G. Pharmacogenetics and breast cancer management: current status and perspectives. Expert Opin Drug Metab Toxicol. 2015;11(5):719–29.

    Article  CAS  PubMed  Google Scholar 

  61. Bidard FC, Fehm T, Ignatiadis M, Smerage JB, Alix-Panabières C, Janni W, et al. Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev. 2013;32(1–2):179–88.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–31.

    Article  CAS  PubMed  Google Scholar 

  63. Allred DC, Clark GM, Elledge R, Fuqua SA, Brown RW, Chamness GC, et al. Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst. 1993;85(3):200–6.

    Article  CAS  PubMed  Google Scholar 

  64. Olivier M, Langerød A, Carrieri P, Bergh J, Klaar S, Eyfjord J, et al. The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res. 2006;12(4):1157–67.

    Article  CAS  PubMed  Google Scholar 

  65. Dookeran KA, Dignam JJ, Ferrer K, Sekosan M, McCaskill-Stevens W, Gehlert S. p53 as a marker of prognosis in African American women with breast cancer. Ann Surg Oncol. 2010;17:1398–405.

    Article  PubMed  Google Scholar 

  66. Bozovic-Spasojevic IAmeye L, Paesmans M, Larsimont D, Di Leo A, Dolci S, et al. Prognostic, predictive abilities and concordance of BCL2 and TP53 protein expression in primary breast cancers and axillary lymph-nodes: a retrospective analysis of the Belgian three arm study evaluating anthracycline vs CMF adjuvant chemotherapy. Breast. 2014;23:473–81.

    Article  Google Scholar 

  67. Soerjomataram I, Louwman MW, Ribot JG, Roukema JA, Coebergh JW. An overview of prognostic factors for long-term survivors of breast cancer. Breast Cancer Res Treat. 2008;107(3):309–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bernards R. Reaction to American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2008;26(12):2057–8.

    Article  PubMed  Google Scholar 

  69. Hosokawa Y, Gadd M, Smith AP, Koerner FC, Schmidt EV, Arnold A. Cyclin D1 (PRAD1) alternative transcript b: full-length cDNA cloning and expression in breast cancers. Cancer Lett. 1997;113:123–30.

    Article  CAS  PubMed  Google Scholar 

  70. Arnold A, Papanikolaou A. Cyclin D1 in breast cancer pathogenesis. J Clin Oncol. 2005;23:4215–24.

    Article  CAS  PubMed  Google Scholar 

  71. Mohamed A, Krajewski K, Cakar B, Ma CX. Targeted therapy for breast cancer. Am J Pathol. 2013;183:1096–112.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  73. Mangini NS, Wesolowski R, Ramaswamy B, Lustberg MB, Berger MJ. Palbociclib: a novel cyclin-dependent kinase inhibitor for hormone receptor-positive advanced breast cancer. Ann Pharmacother. 2015;49(11):1252–60.

    Article  PubMed  Google Scholar 

  74. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:R77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35.

    Article  CAS  PubMed  Google Scholar 

  76. Finn R. Targeting CDK 4/6 in breast cancer [presentation]. San Antonio Breast Cancer Symposium, San Antonio, Texas, Dec 8–12, 2015.

  77. Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209–19.

    Article  CAS  PubMed  Google Scholar 

  78. Shapiro G. Beyond CDK 4/6: Targeting additional cell cycle and transcriptional CDKs in breast cancer [presentation]. San Antonio Breast Cancer Symposium, San Antonio, Texas, Dec 8–12, 2015.

  79. Kumar SK, LaPlant B, Chng WJ, et al. Mayo Phase 2 Consortium. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125(3):443–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatment strategies. Lancet. 2007;369(9574):1742–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2(8):563–72.

    Article  CAS  PubMed  Google Scholar 

  82. Uhr JW, Pantel K. Controversies in clinical cancer dormancy. Proc Natl Acad Sci U S A. 2011;108(30):12396–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kang Y, Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell. 2013;23(5):573–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Riethdorf S, Müller V, Zhang L, Rau T, Loibl S, Komor M, et al. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant geparquattro trial. Clin Cancer Res. 2010;16(9):2634–45.

    Article  CAS  PubMed  Google Scholar 

  85. Alix-Panabières C, Schwarzenbach H, Pantel K. Circulating tumor cells and circulating tumor DNA. Annu Rev Med. 2012;63:199–215.

    Article  PubMed  CAS  Google Scholar 

  86. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008;8(5):329–40.

    Article  CAS  PubMed  Google Scholar 

  87. Robertson EG, Baxter G. Tumour seeding following percutaneous needle biopsy: the real story! Clin Radiol. 2011;66:1007–14.

    Article  CAS  PubMed  Google Scholar 

  88. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kallergi G, Papadaki MA, Politaki E, et al. Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res BCR. 2011;13:R59.

    Article  PubMed  Google Scholar 

  90. Gradilone A, Raimondi C, Nicolazzo C, et al. Circulating tumour cells lacking cytokeratin in breast cancer: the importance of being mesenchymal. J Cell Mol Med. 2011;15:1066–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14(9):623–31.

    Article  PubMed  CAS  Google Scholar 

  92. Kling J. Beyond counting tumor cells. Nat Biotechnol. 2012;30:578–80.

    Article  CAS  PubMed  Google Scholar 

  93. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91.

    Article  CAS  PubMed  Google Scholar 

  94. Zhang L, Riethdorf S, Wu G, et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res. 2012;18:5701–10.

    Article  PubMed  Google Scholar 

  95. Bidard F-C, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15:406–14.

    Article  PubMed  Google Scholar 

  96. Pierga J-Y, Hajage D, Bachelot T, et al. High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients. Ann Oncol. 2012;23:618–24.

    Article  PubMed  Google Scholar 

  97. Molloy TJ, Devriese LA, Helgason HH, et al. A multimarker QPCR-based platform for the detection of circulating tumour cells in patients with early-stage breast cancer. Br J Cancer. 2011;104:1913–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ferro P, Franceschini MC, Bacigalupo B, et al. Detection of circulating tumour cells in breast cancer patients using human mammaglobin RTPCR: association with clinical prognostic factors. Anticancer Res. 2010;30:2377–82.

    CAS  PubMed  Google Scholar 

  99. Lobodasch K, Frohlich F, Rengsberger M, et al. Quantification of circulating tumour cells for the monitoring of adjuvant therapy in breast cancer: an increase in cell number at completion of therapy is a predictor of early relapse. Breast. 2007;16:211–8.

    Article  PubMed  Google Scholar 

  100. Rack B, Schindlbeck C, Juckstock J, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014;15:106(5).

    Google Scholar 

  101. Ignatiadis M, Riethdorf S, Bidard FC, et al. International study on inter-reader variability for circulating tumor cells in breast cancer. Breast Cancer Res. 2014;16:R43.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Giuliano M, Giordano A, Jackson S, et al. Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. Breast Cancer Res. 2011;13:R67.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Giordano A, Giuliano M, De Laurentiis M, et al. Circulating tumor cells in immunohistochemical subtypes of metastatic breast cancer: lack of prediction in HER2-positive disease treated with targeted therapy. Ann Oncol. 2012;23:1144–50.

    Article  CAS  PubMed  Google Scholar 

  104. Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014;32:3483–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mego M, De Giorgi U, Dawood S, et al. Characterization of metastatic breast cancer patients with nondetectable circulating tumor cells. Int J Cancer J Int Cancer. 2011;129:417–23.

    Article  CAS  Google Scholar 

  106. Raimondi C, Gradilone A, Naso G, et al. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat. 2011;130:449–55.

    Article  CAS  PubMed  Google Scholar 

  107. Sieuwerts AM, Kraan J, Bolt J, et al. Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst. 2009;101:61–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mostert B, Kraan J, Bolt-de Vries J, et al. Detection of circulating tumor cells in breast cancer may improve through enrichment with anti-CD146. Breast Cancer Res Treat. 2011;127:33–41.

    Article  CAS  PubMed  Google Scholar 

  109. Weissenstein U, Schumann A, Reif M, Link S, Toffol-Schmidt UD, Heusser P. Detection of circulating tumor cells in blood of metastatic breast cancer patients using a combination of cytokeratin and EpCAM antibodies. BMC Cancer. 2012;12:206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yu M, Bardia A, Aceto N, et al. Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science. 2014;345:216–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Krebs MG, Metcalf RL, Carter L, et al. Molecular analysis of circulating tumour cells: biology and biomarkers. Nat Rev Clin Oncol. 2014;11:129–44.

    Article  CAS  PubMed  Google Scholar 

  112. Markou A, Farkona S, Schiza C, et al. PIK3CA mutational status in circulating tumor cells can change during disease recurrence or progression in patients with breast cancer. Clin Cancer Res. 2014;20:5823–34.

    Article  CAS  PubMed  Google Scholar 

  113. Pestrin M, Salvianti F, Galardi F, et al. Heterogeneity of PIK3CA mutational status at the single cell level in circulating tumor cells from metastatic breast cancer patients. Mol Oncol. 2015;9:749–57.

    Article  CAS  PubMed  Google Scholar 

  114. Wang Y, Waters J, Leung ML, et al. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature. 2014;512:155–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Onstenk W, Sieuwerts AM, Weekhout M, et al. Gene expression profiles of circulating tumor cells versus primary tumors in metastatic breast cancer. Cancer Lett. 2015;362:36–44.

    Article  CAS  PubMed  Google Scholar 

  116. Hodgson DR, Wellings R, Orr MC, et al. Circulating tumour-derived predictive biomarkers in oncology. Drug Discov Today. 2010;15:98–101.

    Article  CAS  PubMed  Google Scholar 

  117. Board RE, Wardley AM, Dixon JM, et al. Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat. 2010;120:461–7.

    Article  CAS  PubMed  Google Scholar 

  118. Silva JM, Gonzalez R, Dominguez G, et al. TP53 gene mutations in plasma DNA of cancer patients. Genes Chromosomes Cancer. 1999;24:160–1.

    Article  CAS  PubMed  Google Scholar 

  119. Mouliere F, Robert B, Arnau Peyrotte E, et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS ONE. 2011;6, e23418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dawson S-J, Tsui DWY, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209.

    Article  CAS  PubMed  Google Scholar 

  121. Rothe F, Laes JF, Lambrechts D, et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol. 2014;25:1959–65.

    Article  CAS  PubMed  Google Scholar 

  122. Umetani N, Giuliano AE, Hiramatsu SH, et al. Prediction of breast tumor progression by integrity of free circulating DNA in serum. J Clin Oncol. 2006;24:4270–6.

    Article  CAS  PubMed  Google Scholar 

  123. Murtaza M, Dawson S-J, Tsui DWY, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497:108–12.

    Article  CAS  PubMed  Google Scholar 

  124. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Sorensen BS, Mortensen LS, Andersen J, Nexo E. Circulating HER2 DNA after trastuzumab treatment predicts survival and response in breast cancer. Anticancer Res. 2010;30:2463–8.

    CAS  PubMed  Google Scholar 

  126. Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med. 2015;7(8):1034–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Higgins MJ, Jelovac D, Barnathan E, et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res. 2012;18:3462–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bechmann T, Andersen RF, Pallisgaard N, et al. Plasma HER2 amplification in cell-free DNA during neoadjuvant chemotherapy in breast cancer. J Cancer Res Clin Oncol. 2013;139:995–1003.

    Article  CAS  PubMed  Google Scholar 

  129. Hashad D, Sorour A, Ghazal A, Talaat I. Free circulating tumor DNA as a diagnostic marker for breast cancer. J Clin Lab Anal. 2012;26:467–72.

    Article  CAS  PubMed  Google Scholar 

  130. Leary R, Sausen M, Kinde I, Papadopoulus N, Carpten JD, Craig D, et al. Detection of chromosomal alterations in the circulation of cancer patients with whole genome sequencing. Sci Transl Med. 2012;4(162):162ra154.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–84.

    Article  CAS  Google Scholar 

  132. Ignatiadis M. Multigene assays for late recurrence of breast cancer. Lancet Oncol. 2013;14:1029–30.

    Article  PubMed  Google Scholar 

  133. Meng S, Tripathy D, Frenkel EP, et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10:8152–62.

    Article  Google Scholar 

  134. Beaver JA, Jelovac D, Balukrishna S, et al. Detection of cancer DNA in plasma of patients with early-stage breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20:2643–50.

    Article  CAS  Google Scholar 

  135. Shaw JA, Page K, Blighe K, et al. Genomic analysis of circulating cell-free DNA infers breast cancer dormancy. Genome Res. 2012;22:220–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Paoletti C, Muniz MC, Thomas DG, et al. Development of circulating tumor cell-endocrine therapy index in patients with hormone receptor positive breast cancer. Clin Cancer Res. 2015;21:2487–98.

    Article  CAS  PubMed  Google Scholar 

  137. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population based study from the California cancer Registry-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(9):1721–8.

    Article  PubMed  Google Scholar 

  138. Schneider BP, Miller KD. Angiogenesis of breast cancer. J Clin Oncol. 2005;23:1782–90.

    Article  CAS  PubMed  Google Scholar 

  139. Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2 are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.

    Article  CAS  PubMed  Google Scholar 

  140. Tryfonopoulos D, Walsh S, Collins DM, et al. Src: a potential target for the treatment of triple-negative breast cancer. Ann Oncol. 2011;22:2234–40.

    Article  CAS  PubMed  Google Scholar 

  141. Dantzer F, de La Rubia G, Ménissier-De Murcia J, et al. Base excision repair is impaired in mammalian cells lacking poly(ADPribose) polymerase-1. Biochemistry. 2000;39:7559–69.

    Article  CAS  PubMed  Google Scholar 

  142. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Balko J, Giltriane JM, Wang K, et al. Molecular profiling of the residual disease of triple-negative breast cancer after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 2014;4:232–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. A randomized Phase II trial comparing therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer (SHIVA). https://clinicaltrials.gov/ct2/show/NCT01771458.

  145. NCI-MPACT: molecular profiling-based assignment of cancer therapy for patients with advanced solid tumors. https://clinicaltrials.gov/ct2/show/NCT01827384.

  146. Molecular profiling in tissue samples from patients with cancer who are exceptional responders to treatment. https://clinicaltrials.gov/ct2/show/NCT02243592.

  147. Vazquez A, Bond EE, Levine AJ, Bond GL. The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov. 2008;7(12):979–87.

    Article  CAS  PubMed  Google Scholar 

  148. Khoo KH, Hoe KK, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014;13(3):217–36.

    Article  CAS  PubMed  Google Scholar 

  149. Tutt A, Robson M, Garber JE, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–44.

    Article  CAS  PubMed  Google Scholar 

  150. Juric D, Infante J, Krop I et al. Evaluation of tolerability and anti-tumor activity of GDC-0032, a PI3K inhibitor with enhanced activity against PIK3CA mutant tumors, administered to patients with advanced solid tumors. Presented at: European Society of Clinical Oncology Congress. Amsterdam, The Netherlands, 27 September–1 October 2013.

  151. Mayer IA, Abramson V, Lehmann B, et al. New strategies for triple negative breast cancer—deciphering the heterogeneity. Clin Cancer Res. 2014;20:782–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Rugo HS, Olopade O, DeMichele A, van’t Veer L, et al. Velaparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: first efficacy results from the I-SPY2 Trial. Proceedings of 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium, Dec 10–14, 2008, SA, TX. Philadelphia, PA: American Association for Cancer Research; [Abstract S5–02].

  153. Moore O, Foote F. The relatively favourable prognosis of medullary carcinoma of the breast. Cancer. 1949;2:635–4.

    Article  PubMed  Google Scholar 

  154. Hamlin I. Possible host resistance in carcinoma of the breast: a histological study. Br J Cancer. 1968;22(3):383–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Rody A, Karn T, Liedtke C, Puztai L, et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res. 2011;13:R97.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenco F, et al. Prognostic and predictive value of tumour 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. 2013;31:860–7.

    Article  CAS  PubMed  Google Scholar 

  157. Telli M. PrECOG 0105: final efficacy analysis from a phase II study of gemcitabine and carboplatin plus iniparib (BSI-201) as neoadjuvant therapy for triple negative and BRCA1/2 mutation associated breast cancer. Proceedings of the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO). Chicago IL: May 31-June 4, 2013; [Abstract 1003].

  158. von Minckwitz Gunter. Geparsixto: addition of carboplatin is beneficial in neoadjuvant treatment of triple negative breast cancer. Proceedings of the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago IL: May 31-June 4, 2013;[Abstract 1003].

  159. Basu G, Ghazalpour A, Gatalica Z, et al. Expression of novel Immunotherapy targets in triple negative breast cancer. Proceedings of the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO). Chicago IL: May 31-June 3, 2013; [Abstract 1001].

  160. Mazel M, Jacot W, Alix-Panabières C, et al. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 2015;9(9):1773–82.

    Article  CAS  PubMed  Google Scholar 

  161. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.

    Article  CAS  PubMed  Google Scholar 

  162. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor positive breast cancer. J Clin Oncol. 2006;24:3726–34.

    Article  CAS  PubMed  Google Scholar 

  163. Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486:400–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486:395–99.

    CAS  PubMed  Google Scholar 

  165. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329–33.

    Article  PubMed  PubMed Central  Google Scholar 

  166. 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  CAS  PubMed  Google Scholar 

  167. Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer. 2012;107:1776–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA damaging agents. Cancer Discov. 2012;2:366–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Popova T, Manie E, Rieunier G, et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 2012;72:5454–62.

    Article  CAS  PubMed  Google Scholar 

  170. Telli M, Jensen K, Abkevich V et al. 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 Antonio.

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  1. Division of Hematology-Oncology, Department of Internal Medicine, Breast Center of Excellence, NK Basile Cancer Institute, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El Solh 1107 2020, Beirut, Lebanon

    Hazem I. Assi, Rita E. Assi & Nagi S. El Saghir

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Assi, H.I., Assi, R.E. & El Saghir, N.S. Emerging Biomarkers of the Future: Changing Clinical Practice for 2020. Curr Breast Cancer Rep 8, 60–72 (2016). https://doi.org/10.1007/s12609-016-0214-7

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