Update on Precision Medicine in Breast Cancer

  • Jasgit C. SachdevEmail author
  • Ana C. Sandoval
  • Mohammad Jahanzeb
Part of the Cancer Treatment and Research book series (CTAR, volume 178)


Precision medicine approaches have found applications in the treatment of several tumor types and have led to rapid advancement in the number of available therapies for some difficult-to-treat diseases. In comparison to tumors like EGFR-mutated lung cancer, and BRAF-mutated melanoma for example, precision medicine in breast cancer is still in its infancy despite the much earlier identification of targets like ER and HER2. Though significant progress has been made in new therapies for hormone-receptor-positive and HER2-positive breast cancers, identification of molecular heterogeneity and lack of other valid reproducible targets in triple-negative breast cancer remain a challenge. In this chapter, we outline the recent advances in technology and targeted treatments for breast cancer, the remaining challenges and ongoing efforts to address these to make precision medicine a reality for all breast cancer patients.


Breast cancer Triple-negative breast cancer (TNBC) Targeted therapy Immunotherapy Multi-omic profiling 


  1. 1.
    Ellsworth RE et al (2017) Molecular heterogeneity in breast cancer: state of the science and implications for patient care. Semin Cell Dev Biol 64:65–72CrossRefGoogle Scholar
  2. 2.
    Perou CM et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752CrossRefGoogle Scholar
  3. 3.
    Curtis C et al (2012) The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 486(7403):346–352CrossRefGoogle Scholar
  4. 4.
    Lerner HJ et al (1976) Phase II study of tamoxifen: report of 74 patients with stage IV breast cancer. Cancer Treat Rep 60(10):1431–1435PubMedGoogle Scholar
  5. 5.
    Wiggans RG et al (1979) Phase-II trial of tamoxifen in advanced breast cancer. Cancer Chemother Pharmacol 3(1):45–48CrossRefGoogle Scholar
  6. 6.
    Gradishar WJ et al (2015) NCCN guidelines insights breast cancer, version 1.2016. J Natl Compr Canc Netw 13(12):1475–1485Google Scholar
  7. 7.
    Early Breast Cancer Trialists’ Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–717Google Scholar
  8. 8.
    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):783–792CrossRefGoogle Scholar
  9. 9.
    Baselga J et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366(2):109–119CrossRefGoogle Scholar
  10. 10.
    Cardoso F et al (2014) ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast 23(5):489–502CrossRefGoogle Scholar
  11. 11.
    Wilken JA, Maihle NJ (2010) Primary trastuzumab resistance: new tricks for an old drug. Ann NY Acad Sci 1210:53–65CrossRefGoogle Scholar
  12. 12.
    Robinson DR et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45(12):1446–1451CrossRefGoogle Scholar
  13. 13.
    Chandarlapaty S et al (2016) Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol 2(10):1310–1315CrossRefGoogle Scholar
  14. 14.
    Fribbens C et al (2016) Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol 34(25):2961–2968CrossRefGoogle Scholar
  15. 15.
    Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4(10):814–819CrossRefGoogle Scholar
  16. 16.
    Thangavel C et al (2011) Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 18(3):333–345CrossRefGoogle Scholar
  17. 17.
    Finn RS et al (2016) Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375(20):1925–1936CrossRefGoogle Scholar
  18. 18.
    Goetz MP et al (2017) MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 35(32):3638–3646CrossRefGoogle Scholar
  19. 19.
    Hortobagyi GN et al (2016) Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375(18):1738–1748CrossRefGoogle Scholar
  20. 20.
    Cristofanilli M et al (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17(4):425–439CrossRefGoogle Scholar
  21. 21.
    George W, Sledge J et al (2017) MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 35(25):2875–2884CrossRefGoogle Scholar
  22. 22.
    Dickler MN et al (2017) MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer ResGoogle Scholar
  23. 23.
    Beeram M et al (2007) Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 18(8):1323–1328CrossRefGoogle Scholar
  24. 24.
    Sueta A et al (2014) An integrative analysis of PIK3CA mutation, PTEN, and INPP4B expression in terms of trastuzumab efficacy in HER2-positive breast cancer. PLoS ONE 9(12):e116054CrossRefGoogle Scholar
  25. 25.
    Baselga J et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529 CrossRefGoogle Scholar
  26. 26.
    Andre F et al (2014) Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15(6):580–591CrossRefGoogle Scholar
  27. 27.
    Hurvitz SA et al (2015) Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol 16(7):816–829CrossRefGoogle Scholar
  28. 28.
    Andre F et al (2016) Molecular alterations and everolimus efficacy in human epidermal growth factor receptor 2-overexpressing metastatic breast cancers: combined exploratory biomarker analysis from BOLERO-1 and BOLERO-3. J Clin Oncol 34(18):2115–2124CrossRefGoogle Scholar
  29. 29.
    Baselga J et al (2017) Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(7):904–916CrossRefGoogle Scholar
  30. 30.
    Di Leo A et al (2018) Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 19(1):87–100CrossRefGoogle Scholar
  31. 31.
    Baselga J, Dent SF, Cortés J, Im Y-H, Diéras V, Harbeck N, Krop IE, Verma S, Wilson TR, Jin H, Wang L, Schimmoller F, Hsu JY, He J, DeLaurentiis M, Drullinsky P, Jacot W (2018) Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) versus FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. In: 2018 ASCO annual meetingGoogle Scholar
  32. 32.
    Conley BA, Chen AP, O’Dwyer PJ, Arteaga CL, Hamilton SR, Williams PM, Little RF, Takebe N, Patton D, Sazali K, Zhang J, Zwiebel JA, Mitchell EP, Gray RJ, McShane L, Li S, Rubinstein L, Flaherty K (2016) NCI-MATCH (Molecular analysis for therapy choice)—a national signal finding trial. In: 2016 ASCO annual meetingGoogle Scholar
  33. 33.
    Azad N, Overman M, Gray R, Schoenfeld J, Arteaga C, Coffey B, Patton D, Li S, McShane L, Rubenstein L, Harris L, Comis R, Abrams J, Williams PM, Mitchell E, Zweibel J, Sharon E, Streicher H, Dwyer PJ, Hamilton S, Conley B, Chen AP, Flaherty K (2017) Nivolumab in mismatch-repair deficient (MMR-d) cancers: NCI-MATCH Trial (Molecular analysis for therapy choice) arm Z1D preliminary results. In: SITC 2017Google Scholar
  34. 34.
    Schwaederle M et al (2015) Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials. J Clin Oncol 33(32):3817–3825CrossRefGoogle Scholar
  35. 35.
    del Rivero J, Kohn EC (2017) PARP inhibitors: the cornerstone of DNA repair-targeted therapies. Oncology (Williston Park) 31(4):265–273Google Scholar
  36. 36.
    Livraghi L, Garber JE (2015) PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med 13:188CrossRefGoogle Scholar
  37. 37.
    Robson M et al (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377(6):523–533CrossRefGoogle Scholar
  38. 38.
    Litton JK et al (2017) A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity. NPJ Breast Cancer 3:49CrossRefGoogle Scholar
  39. 39.
    Konstantinopoulos PA et al (2010) Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol 28(22):3555–3561CrossRefGoogle Scholar
  40. 40.
    Telli ML et al (2016) Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 22(15):3764–3773CrossRefGoogle Scholar
  41. 41.
    Tutt A, Ellis P, Kilbum L (2014) TNT: a randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA 1/2 breast cancer. In: 2014 San Antonio breast cancer symposiumGoogle Scholar
  42. 42.
    Verma S et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367(19):1783–1791CrossRefGoogle Scholar
  43. 43.
    Perez EA et al (2017) Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol 35(2):141–148CrossRefGoogle Scholar
  44. 44.
    Bardia A, Vahdat LT, Diamond J, Kalinsky K, O’Shaughnessy J, Moroose RL, Isakoff SJ, Tolaney SM, Santin AD, Abramson V, Shah NC, Govindan SV, Maliakal P, Sharkey RM, Wegener WA, Goldenberg DM, Mayer IA (2017) Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results. In: 2017 San Antonio breast cancer symposiumGoogle Scholar
  45. 45.
    Trail PA, Dubowchik GM, Lowinger TB (2018) Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacol Ther 181:126–142CrossRefGoogle Scholar
  46. 46.
    Alsaab HO et al (2017) PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol 8:561CrossRefGoogle Scholar
  47. 47.
    Nanda R et al (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 34(21):2460–2467CrossRefGoogle Scholar
  48. 48.
    Adams S et al (2016) Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 34(15_suppl):1009CrossRefGoogle Scholar
  49. 49.
    Tolaney S et al (2018) Abstract PD6-13: Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Cancer Res 78(4 Supplement):PD6-13Google Scholar
  50. 50.
    Rugo HS et al (2018) Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Clin Cancer Res 24(12):2804–2811CrossRefGoogle Scholar
  51. 51.
    Tolaney S et al (2017) Abstract P5-15-02: Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Cancer Res 77(4 Supplement):P5-15-02Google Scholar
  52. 52.
    Schmid P, Cruz C, Braiteh FS, Eder JP, Tolaney S, Kuter I, Nanda R, Chung C, Cassier P, Delord J-P, Gordon M, Li Y, Liu B, O’Hear C, Fasso M, Molinero L, Emens LA (2017) Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analyses. In: 2017 AACR annual meetingGoogle Scholar
  53. 53.
    Dirix LY et al (2018) Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN solid tumor study. Breast Cancer Res Treat 167(3):671–686CrossRefGoogle Scholar
  54. 54.
    Kwa MJ, Adams S (2018) Checkpoint inhibitors in triple-negative breast cancer (TNBC): Where to go from here. Cancer 124(10):2086–2103CrossRefGoogle Scholar
  55. 55.
    Hendrickx W et al (2017) Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology 6(2):e1253654CrossRefGoogle Scholar
  56. 56.
    Rugo H et al (2018) Abstract P1-09-01: A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Cancer Res 78(4 Supplement):P1-09-01Google Scholar
  57. 57.
    Vinayak S et al (2018) TOPACIO/Keynote-162: niraparib plus pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial. J Clin Oncol 36(15):abstr 1011Google Scholar
  58. 58.
    Santa-Maria CA et al (2018) A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer. Oncotarget 9(27):18985–18996CrossRefGoogle Scholar
  59. 59.
    Adjuvant therapy for breast cancer (2000) NIH Consens Statement 17(4):1–35Google Scholar
  60. 60.
    Paik S et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826CrossRefGoogle Scholar
  61. 61.
    Sparano JA et al (2015) Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med 373(21):2005–2014CrossRefGoogle Scholar
  62. 62.
    Albain KS et al (2010) Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 11(1):55–65CrossRefGoogle Scholar
  63. 63.
    Nitz U et al (2017) Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial. Breast Cancer Res Treat 165(3):573–583CrossRefGoogle Scholar
  64. 64.
    Roberts MC et al (2017) Breast cancer-specific survival in patients with lymph node-positive hormone receptor-positive invasive breast cancer and oncotype DX recurrence score results in the SEER database. Breast Cancer Res Treat 163(2):303–310CrossRefGoogle Scholar
  65. 65.
    Albain KS et al (2010) Prognostic and predictive value of the 21-gene recurrence score assay in a randomized trial of chemotherapy for post-menopausal, node-positive, estrogen receptor-positive breast cancer. Lancet Oncol 11(1):55–65Google Scholar
  66. 66.
    Van ‘t Veer LJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536Google Scholar
  67. 67.
    van de Vijver MJ et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009CrossRefGoogle Scholar
  68. 68.
    Cardoso F et al (2016) 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med 375(8):717–729CrossRefGoogle Scholar
  69. 69.
    Sestak I et al (2018) Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA OncolGoogle Scholar
  70. 70.
    Sgroi DC et al (2013) Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 14(11):1067–1076CrossRefGoogle Scholar
  71. 71.
    Cameron D et al (2017) 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 389(10075):1195–1205CrossRefGoogle Scholar
  72. 72.
    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):3744–3752CrossRefGoogle Scholar
  73. 73.
    Slamon, D et al (2016) Abstract S5-04: Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC → T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC → TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. Cancer Res 76(4 Supplement):S5-04Google Scholar
  74. 74.
    Gianni L et al (2016) 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 17(6):791–800CrossRefGoogle Scholar
  75. 75.
    von Minckwitz G et al (2017) Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377(2):122–131CrossRefGoogle Scholar
  76. 76.
    Schneeweiss A et al (2014) Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study. Breast Cancer Res 16(4):R73CrossRefGoogle Scholar
  77. 77.
    Prat A et al (2014) Research-based PAM50 subtype predictor identifies higher responses and improved survival outcomes in HER2-positive breast cancer in the NOAH study. Clin Cancer Res 20(2):511–521CrossRefGoogle Scholar
  78. 78.
    Pogue-Geile KL et al (2013) Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31. J Natl Cancer Inst 105(23):1782–1788CrossRefGoogle Scholar
  79. 79.
    Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70Google Scholar
  80. 80.
    Finn RS et al (2015) 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 16(1):25–35CrossRefGoogle Scholar
  81. 81.
    Tripathy D et al, Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet OncolGoogle Scholar
  82. 82.
    Andre F et al (2014) Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol 15(3):267–274CrossRefGoogle Scholar
  83. 83.
    Massard C et al (2017) High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial. Cancer Discov 7(6):586–595CrossRefGoogle Scholar
  84. 84.
    Meric-Bernstam F et al (2015) Feasibility of large-scale genomic testing to facilitate enrollment onto genomically matched clinical trials. J Clin Oncol 33(25):2753–2762CrossRefGoogle Scholar
  85. 85.
    Pezo RC et al (2018) Impact of multi-gene mutational profiling on clinical trial outcomes in metastatic breast cancer. Breast Cancer Res Treat 168(1):159–168CrossRefGoogle Scholar
  86. 86.
    Von Hoff DD et al (2010) Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol 28(33):4877–4883CrossRefGoogle Scholar
  87. 87.
    Le Tourneau C et al (2015) Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol 16(13):1324–1334CrossRefGoogle Scholar
  88. 88.
    Jameson GS et al (2014) A pilot study utilizing multi-omic molecular profiling to find potential targets and select individualized treatments for patients with previously treated metastatic breast cancer. Breast Cancer Res Treat 147(3):579–588CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Jasgit C. Sachdev
    • 1
    • 2
    Email author
  • Ana C. Sandoval
    • 3
  • Mohammad Jahanzeb
    • 3
  1. 1.HonorHealth Research InstituteScottsdaleUSA
  2. 2.Translational Genomics Research Institute (TGen)PhoenixUSA
  3. 3.Sylvester Comprehensive Cancer Center, University of MiamiMiamiUSA

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