Neoadjuvant Systemic Treatment (NST)

  • Cornelia Liedtke
  • Achim RodyEmail author


Survival rates are similar after primary systemic (“preoperative,” “neoadjuvant”) therapy (NST) and adjuvant therapy. Response to primary systemic therapy (i.e., pathological complete response, pCR) is associated with improved survival. In patients having a clear indication for adjuvant postoperative chemotherapy, primary systemic therapy may be indicated. In particular, in patient subgroups where a pCR is associated with improved survival such as in triple-negative, HER2-positive, and patients with some subtypes of hormone receptor-positive cancer (HR+/HER2neg/Grade3, high KI 67), PST (plus targeted therapy) should be the preferred therapeutic approach. In patients with TNBC, a platinum salt-containing regimen may be considered. With respect to endocrine neoadjuvant therapy, in exceptional situations endocrine treatment with GnRH analogues plus aromatase inhibitor may be considered for premenopausal women. Novel predictive factors, such as tumor cell infiltration/lymphocyte-predominant breast cancer or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation in the tumor, are promising tools but not yet applicable to the routine clinical setting. Post-neoadjuvant concepts are currently investigated in clinical trials, and trial participation is highly recommended particularly in case of non-pCR. Outside of clinical trials, there is at present no indication for further chemotherapy in case of non-pCR.


Neoadjuvant chemotherapy Pathological complete remission Breast cancer subtypes Platinum HER2-targeted agents 


  1. 1.
    Liedtke C, Hatzis C, Symmans WF, et al. Genomic grade index is associated with response to chemotherapy in patients with breast cancer. J Clin Oncol. 2009;27(19):3185–91.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8):1275–81.CrossRefPubMedGoogle Scholar
  3. 3.
    von Minckwitz G, Blohmer JU, Raab G, et al. German Breast Group. In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: the GEPARTRIO pilot study. Ann Oncol. 2005;16(1):56–63.CrossRefGoogle Scholar
  4. 4.
    Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164–72.CrossRefPubMedGoogle Scholar
  5. 5.
    Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678–85.CrossRefPubMedGoogle Scholar
  6. 6.
    Rody A, Karn T, Solbach C, et al. The erbB2+ cluster of the intrinsic gene set predicts tumor response of breast cancer patients receiving neoadjuvant chemotherapy with docetaxel, doxorubicin and cyclophosphamide within the GEPARTRIO trial. Breast. 2007;16:235–40.CrossRefPubMedGoogle Scholar
  7. 7.
    von Minckwitz G, Untch M, Blohmer JU, 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(15):1796–804.CrossRefGoogle Scholar
  8. 8.
    Mazouni C, Peintinger F, Wan-Kau S, et al. Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol. 2007;25(19):2650–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Hennessy BT, Hortobagyi GN, Rouzier R, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol. 2005;23(36):9304–11.CrossRefPubMedGoogle Scholar
  10. 10.
    Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25(28):4414–22.CrossRefPubMedGoogle Scholar
  11. 11.
    Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33(9):983–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71.CrossRefPubMedGoogle Scholar
  13. 13.
    Loibl S, von Minckwitz G, Schneeweiss A, 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(29):3212–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Loibl S, Majewski I, Guarneri V, et al. Correlation of PIK3CA mutation with pathological complete response in primary HER2-positive breast cancer: combined analysis of 967 patients from three prospective clinical trials. J Clin Oncol. 2015;33(suppl; abstr 511).Google Scholar
  15. 15.
    Denkert C, Loibl S, Müller BM, et al. Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial. Ann Oncol. 2013;24(11):2786–93.CrossRefPubMedGoogle Scholar
  16. 16.
    von Minckwitz G, Kümmel S, Vogel P, et al. German Breast Group. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst. 2008;100(8):542–51.CrossRefGoogle Scholar
  17. 17.
    von Minckwitz G1, Blohmer JU, Costa SD, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2013;31(29):3623–30.Google Scholar
  18. 18.
    Guarneri V, Frassoldati A, Bottini A, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol. 2012;30(16):1989–95.CrossRefPubMedGoogle Scholar
  19. 19.
    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(12):2024–31.CrossRefPubMedGoogle Scholar
  20. 20.
    Untch M, Loibl S, Bischoff J, et al. German Breast Group (GBG). Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group, lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012;13(2):135–44.CrossRefPubMedGoogle Scholar
  21. 21.
    von Minckwitz G, Schneeweiss A, Loibl S, 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(7):747–56.CrossRefGoogle Scholar
  22. 22.
    Baselga J, Bradbury I, Eidtmann H, et al. NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379(9816):633–40.CrossRefPubMedGoogle Scholar
  23. 23.
    de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014;15(10):1137–46.CrossRefPubMedGoogle Scholar
  24. 24.
    Gianni L, Pienkowski T, Im YH, 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(1):25–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Lee LJ, Alexander B, Schnitt SJ, et al. Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. Cancer. 2011;117:3093–100.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–81.CrossRefPubMedGoogle Scholar
  27. 27.
    Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48.Google Scholar
  28. 28.
    Bulut N, Kilickap S, Sari E, et al. Response to taxanes in triple negative breast cancer. Cancer Chemother Pharmacol. 2008;63:189.CrossRefPubMedGoogle Scholar
  29. 29.
    Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13:2329–34.CrossRefPubMedGoogle Scholar
  30. 30.
    Gluz O, Nitz UA, Harbeck N, et al. Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial. Ann Oncol. 2008;19:861–70.CrossRefPubMedGoogle Scholar
  31. 31.
    Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012;30:11–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Lindman H, Kellokumpu-Lehtinen P-L, Huovinen R, et al. Integration of capecitabine into anthracycline- and taxane-based adjuvant therapy for triple-negative early breast cancer: final subgroup analysis of the FinXX study. Cancer Res. 2010;70:96s.CrossRefGoogle Scholar
  33. 33.
    Steger GG, Barrios C, O’Shaughnessy J, et al. Review of capecitabine for the treatment of triple-negative early breast cancer. Cancer Res. 2010;70:96s.CrossRefGoogle Scholar
  34. 34.
    Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Cancer Res. 2012;72:S6-6.CrossRefGoogle Scholar
  35. 35.
    Gluz O, Liedtke C, Gottschalk N, et al. Triple-negative breast cancer—current status and future directions. Ann Oncol. 2009;20:1913–27.CrossRefPubMedGoogle Scholar
  36. 36.
    von Minckwitz G, Schneeweiss A, Loibl S, 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;15:747–56.CrossRefGoogle Scholar
  37. 37.
    Von Minckwitz G, et al. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). SABCS 2015; Abstract S2-04.Google Scholar
  38. 38.
    Sikov WM, Berry DA, Perou CM, 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. 2014.Google Scholar
  39. 39.
    Sikov WM, et al. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: outcomes from CALGB 40603 (Alliance). SABCS 2015; Abstract S2-05.Google Scholar
  40. 40.
    Kennedy RD, Quinn JE, Mullan PB, et al. The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst. 2004;96:1659–68.CrossRefPubMedGoogle Scholar
  41. 41.
    Gluz O, Nitz U, Liedtke C, et al. Comparison of 12 weeks neoadjuvant nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple-negative breast cancer: WSG-ADAPT TN randomized phase II trial SABCS 2015, S6-07.Google Scholar
  42. 42.
    Tutt A, Ellis P, Kilburn LS, et al. TNT: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). San Antonio Breast Cancer Symp. 2014:S3-01.Google Scholar
  43. 43.
    Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013;14:933–42.CrossRefPubMedGoogle Scholar
  44. 44.
    Bear HD, Tang G, Rastogi P, et al. The effect on overall and disease-free survival (OS & DFS) by adding bevacizumab and/or antimetabolites to standard neoadjuvant chemotherapy: NSABP protocol B-40. San Antonio Breast Cancer Symp. 2014:PD2-1.Google Scholar
  45. 45.
    Colleoni M, Viale G, Zahrieh D, et al. Expression of ER, PgR, Her1, Her2, and response: a study of preoperative chemotherapy. Ann Oncol. 2008;19:465–72.CrossRefPubMedGoogle Scholar
  46. 46.
    Semiglazov VF, Semiglazov V, Ivanov V, et al. The relative efficacy of neoadjuvant endocrine therapy versus chemotherapy in postmenopausal women with ER-positive breast cancer. J Clin Oncol. 2004;23:7s.Google Scholar
  47. 47.
    Mustacchi G, Ceccherini R, Milani S, et al. Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol. 2003;14:414–20.CrossRefPubMedGoogle Scholar
  48. 48.
    Classe JM, Bordes V, Campion L, Mignotte H, Dravet F, Leveque J, Sagan C, Dupre PF, Body G, Giard S. Sentinel lymph node biopsy after neoadjuvant chemotherapy for advanced breast cancer: results of Ganglion. J Clin Oncol. 2009;27(5):726–32.CrossRefPubMedGoogle Scholar
  49. 49.
    Boughey JC, Suman VJ, Mittendorf EA. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node positive breast cancer: the ACOSOG Z 1071 (Alliance) clinical trial. JAMA. 2013;310:1455–61.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol. 2013;14:609–18.CrossRefPubMedGoogle Scholar
  51. 51.
    McGuire SE, Gonzalez-Angulo AM, Huang EH, et al. Postmastectomy radiation improves the outcome of patients with locally advanced breast cancer who achieve a pathologic complete response to neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys. 2007;68(4):1004–9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyUniversity Hospital Schleswig-Holstein/Campus LübeckLübeckGermany

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