J Breast Cancer.  2017 Jun;20(2):119-131. 10.4048/jbc.2017.20.2.119.

Recent Advances in the Neoadjuvant Treatment of Breast Cancer

• Rubovszky
• Horváth Z

• KMID: 2389749
• DOI: http://doi.org/10.4048/jbc.2017.20.2.119

Abstract

In the last few decades, neoadjuvant therapy for breast cancer has gained considerable therapeutic importance. Despite extensive clinical investigations, it has not yet been clarified whether neoadjuvant therapy would result in improved survival in comparison with the standard adjuvant setting in any subgroups of patients with breast cancer. Chemotherapy is especially effective in the treatment of endocrine insensitive tumors, and such ther-apeutic benefit can be assumed for patients with triple-negative, or hormone receptor-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, dose escalation, modification of the therapeutic regimens according to early tumor response, as well as the optimal sequence of administration are still matters of debate. There is a current debate between clinical experts regarding the concomitant and sequential administration of carboplatin and capecitabine, respectively, as part of the standard neoadjuvant treatment, as well as the use of bevacizumab, as part of the preoperative treatment. In case of HER2 positive tumors, an anti-HER2 agent can be administered as part of the preoperative treatment, and according to preliminary clinical data, dual HER2 blockade can also be reasonable. Further, chemotherapy-free regimens can be justified in highly endocrine sensitive tumors, while immune modulating agents may also gain particular importance in the case of certain subtypes of breast cancer. Several small-molecule targeted therapies are under clinical investigation and are expected to provide new neoadjuvant treatment options. However, novel, more predictive biomarkers are required for further evaluation of the neoadjuvant therapies, as well as the effect of novel targeted agents intended to be incorporated into neoadjuvant therapy.

Keyword

Antineoplastic agents; Breast neoplasms; Molecular targeted therapy; Neoadjuvant therapy

MeSH Terms

Antineoplastic Agents
Bevacizumab
Biomarkers
Breast Neoplasms*
Breast*
Capecitabine
Carboplatin
Drug Therapy
Humans
Molecular Targeted Therapy
Neoadjuvant Therapy*
Receptor, Epidermal Growth Factor
Antineoplastic Agents
Bevacizumab
Biomarkers
Capecitabine
Carboplatin
Receptor, Epidermal Growth Factor

Reference

1. AGO. Guidelines of the AGO Breast Committee. 2016. Accessed April 26th, 2017. http://www.ago-online.de/en/guidelines-mamma/march-2016/.

2. Kümmel S, Holtschmidt J, Loibl S. Surgical treatment of primary breast cancer in the neoadjuvant setting. Br J Surg. 2014; 101:912–924.

3. Schwartz GF, Hortobagyi GN. Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26-28, 2003, Philadelphia, Pennsylvania. Cancer. 2004; 100:2512–2532.

4. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005; 97:188–194.

5. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014; 384:164–172.

6. Broglio KR, Quintana M, Foster M, Olinger M, McGlothlin A, Berry SM, et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol. 2016; 2:751–760.

7. Korn EL, Sachs MC, McShane LM. Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. Ann Oncol. 2016; 27:10–15.

8. Berruti A, Amoroso V, Gallo F, Bertaglia V, Simoncini E, Pedersini R, et al. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol. 2014; 32:3883–3891.

9. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012; 30:1796–1804.

10. Abramson VG, Lehmann BD, Ballinger TJ, Pietenpol JA. Subtyping of triple-negative breast cancer: implications for therapy. Cancer. 2015; 121:8–16.

11. Lehmann BD, Pietenpol JA, Tan AR. Triple-negative breast cancer: molecular subtypes and new targets for therapy. Am Soc Clin Oncol Educ Book. 2015; e31–e39.

12. Kalimutho M, Parsons K, Mittal D, López JA, Srihari S, Khanna KK. Targeted therapies for triple-negative breast cancer: combating a stubborn disease. Trends Pharmacol Sci. 2015; 36:822–846.

13. Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, et al. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26:Suppl 5. v8–v30.

14. Evans TR, Yellowlees A, Foster E, Earl H, Cameron DA, Hutcheon AW, et al. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an anglo-celtic cooperative oncology group study. J Clin Oncol. 2005; 23:2988–2995.

15. von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005; 23:2676–2685.

16. Vriens BE, Aarts MJ, de Vries B, van Gastel SM, Wals J, Smilde TJ, et al. Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer. 2013; 49:3102–3110.

17. Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, et al. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011; 29:3877–3884.

18. Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010; 362:2053–2065.

19. Moylan EJ, Connell LC, O'Reilly S. Are dose-dense and triplet chemotherapy regimens optimal adjuvant therapy in the majority of women with node-positive early breast cancer? J Clin Oncol. 2014; 32:605–606.

20. Petrelli F, Coinu A, Lonati V, Cabiddu M, Ghilardi M, Borgonovo K, et al. Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs. 2016; 27:702–708.

21. Lemos Duarte I, da Silveira Nogueira Lima JP, Passos Lima CS, Deeke Sasse A. Dose-dense chemotherapy versus conventional chemotherapy for early breast cancer: a systematic review with meta-analysis. Breast. 2012; 21:343–349.

22. Petrelli F, Cabiddu M, Coinu A, Borgonovo K, Ghilardi M, Lonati V, et al. Adjuvant dose-dense chemotherapy in breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res Treat. 2015; 151:251–259.

23. Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol. 2002; 20:1456–1466.

24. Hutcheon AW, Heys SD, Sarkar TK. Aberdeen Breast Group. Neoadjuvant docetaxel in locally advanced breast cancer. Breast Cancer Res Treat. 2003; 79:Suppl 1. S19–S24.

25. Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008; 26:778–785.

26. Diéras V, Fumoleau P, Romieu G, Tubiana-Hulin M, Namer M, Mauriac L, et al. Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer. J Clin Oncol. 2004; 22:4958–4965.

27. von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014; 15:747–756.

28. Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, et al. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016; 17:345–356.

29. Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, et al. ETNA (evaluating treatment with neoadjuvant abraxane) randomized phase III study comparing neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) both followed by anthracycline regimens in women with HER2-negative high-risk breast cancer: a MICHELANGO study. In : 2016 ASCO Annual Meeting; 2016. p. 34. Abstract #502.

30. Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, et al. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an openlabel, 2×2 factorial randomised phase 3 trial. Lancet Oncol. 2014; 15:201–212.

31. Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, et al. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013; 14:1317–1325.

32. Bines J, Earl H, Buzaid AC, Saad ED. Anthracyclines and taxanes in the neo/adjuvant treatment of breast cancer: does the sequence matter? Ann Oncol. 2014; 25:1079–1085.

33. Hofmann D, Nitz U, Gluz O, Kates RE, Schinkoethe T, Staib P, et al. WSG ADAPT: adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial. Trials. 2013; 14:261.

34. Loibl S, Denkert C, von Minckwitz G. Neoadjuvant treatment of breast cancer: clinical and research perspective. Breast. 2015; 24:Suppl 2. S73–S77.

35. von Minckwitz G, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Eiermann W, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2013; 31:3623–3630.

36. von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†. Ann Oncol. 2014; 25:2363–2372.

37. Wang-Lopez Q, Mouret-Reynier MA, Savoye AM, Abrial C, Kwiatkowski F, Garbar C, et al. Is it important to adapt neoadjuvant chemotherapy to the visible clinical response? An open randomized phase II study comparing response-guided and standard treatments in HER2-negative operable breast cancer. Oncologist. 2015; 20:243–244.

38. von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, et al. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol. 2010; 28:2015–2023.

39. von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, et al. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst. 2008; 100:552–562.

40. von Minckwitz G, Untch M, Nüesch E, Loibl S, Kaufmann M, Kümmel S, et al. Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials. Breast Cancer Res Treat. 2011; 125:145–156.

41. Toi M, Lee SJ, Lee ES, Ohtani S, Im YH, Im SA, et al. phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). In : 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2016. p. 76. Abstract #S1-07.

42. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013; 24:2278–2284.

43. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012; 13:25–32.

44. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012; 379:633–640.

45. Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, 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. 2016; 34:542–549.

46. Guarneri V, Diecl MV, Carbognin L, Maiorana A, Bettelli S, Tortora G, et al. Activity of neoadjuvant lapatinib plus trastuzumab for early breast cancer according to PIK3CA mutations: pathological complete response (pCR) rate in the CherLOB study and pooled analysis of randomized trials. Ann Oncol. 2014; 25:Suppl 4. iv85–iv109.

47. Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, et al. 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. 2013; 14:1183–1192.

48. Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012; 13:135–144.

49. Rimawi MF, Cecchini RS, Rastogi P, Geyer CE, Fehrenbacher L, Stella PJ, et al. A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG oncology/NSABP B-52. In : 39th Annual San Antonio Breast Cancer Symposium; 2017. p. 77. Abstract #S3-06.

50. Rimawi MF, Aleixo SB, Rozas AA, Nunes de, Caleffi M, Figueira AC, et al. A neoadjuvant, randomized, open-label phase II trial of afatinib versus trastuzumab versus lapatinib in patients with locally advanced HER2-positive breast cancer. Clin Breast Cancer. 2015; 15:101–109.

51. Park JW, Liu MC, Yee D, Yau C, van't Veer LJ, Symmans WF, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016; 375:11–22.

52. Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013; 31:1726–1731.

53. Harbeck N, Gluz O, Christgen M, Braun M, Kuemmel S, Schumacher C, et al. Final analysis of WSG-ADAPT HER2+/HR+ phase II trial: efficacy, safety, and predictive markers for 12-weeks of neoadjuvant TDM1 with or without endocrine therapy versus trastuzumab+endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer. In : 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2016. p. 76. Abstract #S5-03.

54. Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang CS, Thompson AM, et al. Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K])+pertuzumab (P) vs docetaxel+ca rboplatin+trastuzumab+P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). In : 2016 ASCO Annual Meeting; 2016. p. 34. Abstract #500.

55. Guarneri V, Frassoldati A, Piacentini F, Jovic G, Giovannelli S, Oliva C, et al. Preoperative chemotherapy plus lapatinib or trastuzumab or both in HER2-positive operable breast cancer (CHERLOB Trial). Clin Breast Cancer. 2008; 8:192–194.

56. Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E, 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; 33:1334–1339.

57. Loibl S, von Minckwitz G, Schneeweiss A, Paepke S, Lehmann A, Rezai M, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (HER2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol. 2014; 32:3212–3220.

58. Gianni L, Bianchini G, Kiermaier A, Bianchi G, Im YH, Pienkowski T, et al. Neoadjuvant pertuzumab (P) and trastuzumab (H): biomarker analyses of a 4-Arm randomized phase II study (NeoSphere) in patients (pts) with HER2-positive breast cancer (BC). In : 34th Annual CTRCAACR San Antonio Breast Cancer Symposium; 2011. p. 71. Abstract #S5-1.

59. Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015; 33:13–21.

60. Sharma P, Kimler BF, Ward C, O'Dea A, Hoffmann MS, Klemp JR, et al. Prognosis of triple negative breast cancer patients who attain pathological complete response with neoadjuvant carboplatin/docetaxel and do not receive adjuvant anthracycline chemotherapy. In : 2016 ASCO Annual Meeting; 2016. p. 34. Abstract #1015.

61. Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010; 28:1145–1153.

62. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015; 16:1037–1048.

63. Steger GG, Greil R, Lang A, Rudas M, Fitzal F, Mlineritsch B, et al. Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol. 2014; 25:366–371.

64. Zhimin S, Li J, Pang D, Wang C, Jiang J, Yang S, et al. Cbcsg-10: adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for triple negative breast cancer. In : 2016 ASCO Annual Meeting; 2016. p. 34. Abstract #1012.

65. Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, et al. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015; 16:656–666.

66. Nahleh ZA, Barlow WE, Hayes DF, Schott AF, Gralow JR, Sikov WM, et al. SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer. Breast Cancer Res Treat. 2016; 158:485–495.

67. Nahleh ZA, Dodoo C, Dwivedi AK, Botrus G; Texas Tech University HSC, Paso E, et al. A meta-analysis of randomzied controlled trials comparing the effect of neoadjuvant chemotherapy with or without bevacizumab (Bev) in the treatment of breast cancer (BC). In : 2016 ASCO Annual Meeting; 2016. p. 34. Abstract #577.

68. Arce-Salinas C, Alamilla G, Flores-Diaz D, Deneken CZ, Mendoza-Galindo L, Ramirez-Morales R, et al. Randomized, double blind trial to evaluate the safety and efficacy of metformin vs placebo plus neoadjuvant chemotherapy in locally advanced breast cancer. In : 2016 ASCO Annual Meeting; 2016. p. 34. Abstract #579.

69. Rugo HS, Olopade OI, DeMichele A, van't Veer L, Buxton M, Hylton N, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for highrisk breast cancer: first efficacy results from the I-SPY 2 trial. In : 36th Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2013. p. 73. #Abstract S5-02.

70. Carbognin L, Pilotto S, Nortilli R, Brunelli M, Nottegar A, Sperduti I, et al. Predictive and prognostic role of tumor-infiltrating lymphocytes for early breast cancer according to disease subtypes: sensitivity analysis of randomized trials in adjuvant and neoadjuvant setting. Oncologist. 2016; 21:283–291.

71. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499:214–218.

72. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016; 34:2460–2467.

73. Emens LA, Braiteh FS, Cassier P, DeLord JP, Eder JP, Shen X, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. In : 37th Annual CTRCAACR San Antonio Breast Cancer Symposium; 2015. p. 75. Abstract #PD1-6.

74. Elarre PS, Mejias LD, Solans BP, Ceniceros L, Santamaria IE, Espinos J, et al. Impact of CD8 stromal lymphocytes in BC patients with the addition of autologous dendritic CELL vaccination to neoadjuvant chemotherapy. In : 2016 ASCO Annual Meeting; 2016. p. 34. Abstract #1081.

75. An ADC for triple-negative breast cancer. Cancer Discov. 2016; 6:OF8.

76. Barroso-Sousa R, Silva DD, Alessi JV, Mano MS. Neoadjuvant endocrine therapy in breast cancer: current role and future perspectives. Ecancermedicalscience. 2016; 10:609.

77. National Comprehensive Cancer Network. Breast cancer. 2016. Accessed April 26th, 2017. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.

78. Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, et al. 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. 2010; 11:55–65.

79. Alba E, Calvo L, Albanell J, De la Haba JR, Arcusa Lanza A, Chacon JI, et al. Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter, randomized, phase-II study. Ann Oncol. 2012; 23:3069–3074.

80. Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007; 110:244–254.

81. Spring LM, Gupta A, Reynolds KL, Gadd MA, Ellisen LW, Isakoff SJ, et al. Neoadjuvant endocrine therapy for estrogen receptor-positive breast cancer: a systematic review and meta-analysis. JAMA Oncol. 2016; 2:1477–1486.

82. Rugo HS, Vidula N, Ma C. Improving response to hormone therapy in breast cancer: new targets, new therapeutic options. Am Soc Clin Oncol Educ Book. 2016; 35:e40–e54.

83. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009; 27:2630–2637.

84. Guarneri V, Generali DG, Frassoldati A, Artioli F, Boni C, Cavanna L, et al. Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol. 2014; 32:1050–1057.

85. Smith IE, Walsh G, Skene A, Llombart A, Mayordomo JI, Detre S, et al. A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol. 2007; 25:3816–3822.