Neoadjuvant Chemotherapeutic and Targeted Therapies for Early-stage, High-risk Breast Cancer

European Oncology & Haematology, 2014;10(1):28–34


Neoadjuvant or preoperative chemotherapy is the preferred treatment for locally advanced, inflammatory and early-stage high-risk breast cancers. Patients with locally advanced breast cancers are candidates for neoadjuvant therapy because their tumours are often not amenable to resection. On the other hand, patients are candidates for neoadjuvant chemotherapy if the breast-conserving surgery is not possible. At present, anthracycline- and taxane-based chemotherapy regimens remain as the cornerstone for neoadjuvant therapy in early breast cancer, but there is a clear need for effective therapies in high-risk, early-stage patients. A number of chemotherapeutic and targeted therapies have been evaluated in clinical trials with varying results. The US Food and Drug Administration (FDA) has recently approved pertuzumab in combination with trastuzumab and cytotoxic chemotherapy as a neoadjuvant therapy option for HER2-positive breast cancer. This article reviews the neoadjuvant chemotherapeutic and targeted therapies options for early-stage, high-risk breast cancer. Possible role of molecular subtyping in triple-negative breast cancer is also described.

Keywords: Neoadjuvant, triple-negative, locally advanced, inflammatory, breast cancer, HER2, molecular subtyping
Disclosure: Clement Chung and Rosetta Lee have no conflicts of interest to declare. No funding was received for the publication of this article.
Received: March 20, 2014 Accepted June 03, 2014 Citation European Oncology & Haematology, 2014;10(1):28–34
Correspondence: Clement Chung, Pharmacist, Lyndon B Johnson General Hospital, 5656 Kelley St, Houston, TX 77026, US. E:

According to the World Health Organization (WHO), cancer-related mortalities reach 7.9 million worldwide each year.1 Among women, breast cancer is one of the most common cancers globally. Despite advances in early detection and understanding on the molecular pathogenesis of breast cancer, approximately 30 % of patients with early-stage breast cancer experience recurrent disease.2 Systemic treatment of breast cancer includes cytotoxic chemotherapy, endocrine (or hormonal) therapy and targeted therapy. These therapeutic agents are used in the adjuvant (post-surgical), neoadjuvant (pre-surgical) and metastatic settings.

Neoadjuvant therapy (also referred to as preoperative, pre-surgical, induction or primary systemic therapy) is the systemic treatment of breast cancer in the preoperative setting with curative intent. It was first evaluated more than 30 years ago for the treatment of locally advanced, inflammatory (a subtype of locally advanced breast cancer) and inoperable breast cancers.3 It is now increasingly used in patients with operable disease.3 The primary objective of the neoadjuvant therapy is to improve surgical outcomes3–5 in patients for whom a primary surgical approach is technically not feasible and in patients with operable breast cancer who desire breast conservation. Second, neoadjuvant therapy decreases the need for complete axillary lymph node dissection.6–8 It also allows an early evaluation of the systemic therapy. Third, neoadjuvant therapy gives clinicians an opportunity to obtain tumour specimens prior to and during the preoperative treatment, thus enabling researchers to investigate emerging drug therapies and predictive biomarkers.7,8 Recently, following the announcement by the US Food and Drug Administration (FDA)9 that it will consider neoadjuvant randomised trials for accelerated drug approval in early breast cancer, there has been a marked increase in clinical trials with novel agents in the neoadjuvant setting. This review focuses on the current and emerging neoadjuvant chemotherapies and targeted therapies for early-stage, high-risk9 (defined as 20–25 % risk of recurrence or death at 5 years) breast cancer.

Patient Selection
Neoadjuvant chemotherapy is the preferred treatment for locally advanced and inflammatory breast cancer. According to the American Joint Committee on Cancer,10 locally advanced breast cancer is a stage III disease. Clinically, locally advanced breast cancer includes tumours that are localised to the breast tissue without regional nodal involvement, and may also include tumour sizes greater than 5 cm in diameter, or tumours of any size with overlying oedema, chest-wall fixation, skin infiltration or inflammatory features. Among these forms of locally advanced breast cancer, only clinical stage IIIA (T0N2M0; T1-3N2M0) is considered surgically resectable; whereas clinical stage IIIB (T4N0-2M0) and stage IIIC (any TN3M0) are considered unresectable or inoperable.11 Patients with locally advanced breast cancer IIIB-C are candidates for neoadjuvant therapy. Moreover, patients with high-risk, early-stage breast cancer (clinical stage I or II) are candidates for neoadjuvant therapy if breast-conserving surgery is not possible or if the tumour subtype is associated with a higher likelihood of response (e.g. human epidermal growth factor receptor type-2 [HER2]- positive or triple-negative [oestrogen receptor [OR]-negative, progesterone receptor [PR]-negative, HER2-negative), regardless of tumour size.12,13

The histologically proved complete response following neoadjuvant therapy, i.e. the absence of invasive and non-invasive tumour in the breast tissue and lymph nodes (ypT0ypN0), confirmed by pathology, is known as the pathological complete response (pCR).10 It has been widely used as a surrogate marker for disease response and is an indication for complete eradication of distant micrometastasis or residual disease.11 It was first observed in patients with locally advanced breast cancer14 and was subsequently confirmed in randomised trials in patients with operable disease.14 However, the definition of pCR and the methods of assessment varied across clinical trials.15–22 Therefore, pCR alone cannot be applied as a predictor for long-term disease outcome. It is important to consider tumour involvement in both breast tissue and lymph nodes for pCR since the presence of residual disease in lymph nodes after neoadjuvant therapy may affect disease-free survival (DFS) and overall survival (OS).23,24 Of note, ductal carcinoma in situ (DCIS) does not require pCR since the presence of residual disease in DCIS does not affect DFS or OS.25,26

Neoadjuvant chemotherapy for locally advanced breast cancer is generally anthracycline- or taxane-based (see Table 1). At present, approximately 20 % of patients14–17,23 achieve pCR after an appropriate neoadjuvant regimen. Randomised trials20,27 showed that non-anthracycline and anthracycline-containing regimens are considered equally efficacious regardless of whether they are given pre- or postoperatively. Equally, long-term efficacy had been demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial in which docetaxel was administered either pre- or postoperatively.28 An important caveat is, if the goal of therapy is to treat operable breast cancer, then any patient who is indicated for adjuvant therapy should also be offered neoadjuvant therapy.14 Current US National Comprehensive Cancer Network (NCCN) guidelines29 state that preoperative chemotherapy is not indicated unless invasive breast cancer is confirmed.

  1. “Raising awareness about breast cancer.” WHO. Available at: breast_cancer_20091030/en/ (accessed 3 March 2014).
  2. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN, Overview of resistance to systemic therapy in patients with breast cancer, Adv Exp Med Biol, 2007;608:1–22.
  3. Gralow JR, Zujewski JA, Winer E, Preoperative therapy in invasive breast cancer: review the state of the science and exploring new research directions, J Clin Oncol, 2008;26:696–7.
  4. Fisher B, Brown A, Mamounas E, et al., Effect of pre-operative chemotherapy on local regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18, J Clin Oncol, 1997;15:2483–93.
  5. Fisher B, Bryant J, Wolmark N, et al., Effect of preoperative chemotherapy on the outcome of women with operable breast cancer, J Clin Oncol, 1998;16:2672–85.
  6. Gianni L, Baselga J, Eiermann W, et al., Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable breast cancer, J Clin Oncol, 2009;27:2474–81.
  7. Bardia A, Baselga J, Neoadjuvant therapy as a platform for drug development and approval in breast cancer, Clin Cancer Res, 2013;19:6360–70.
  8. Bates SE, Amiri-Kordestani L, Giaccone G, Drug development: portals of discovery, Clin Cancer Res, 2012;18:23–32.
  9. Prowell TM, Pazdur R, Pathological complete response and accelerated drug approval in early breast cancer, N Eng J Med, 2012;366:2438–41.
  10. American Joint Commission on Cancer. Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds. Cancer Staging Handbook (from the AJCC Cancer Staging Manual). 7th edition. New York, NY: Springer, 2010;419–60.
  11. Yalcin B, Oveview on locally advanced breast cancer: defining, epidemiology, and overview on neoadjuvant therapy, Exp Oncol, 2013;35:250–2.
  12. Von Minckwitz G, Eidtmann H, Rezai M, et al., Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer, N Eng J Med, 2012;366:299–309.
  13. 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.
  14. Kaufmann M, von Minckwitz G, Mamounas EP, et al., Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer, Ann Surg Oncol, 2012;19:1508–16.
  15. Chevallier B, Roche H, Oliverier JP, et al., Inflammatory breast cancer: pilot study of intensive induction chemotherapy (FEC-HD) results in a higher histologic response rate, Am J Clin Oncol, 1993;16:223–8.
  16. Sataloff DM, Mason BA, Prestipino AJ, et al., Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome, J Am Coll Surg, 1995;180:297–306.
  17. Connolly RM, Stearns V, Current approaches for neoadjuvant chemotherapy in breast cancer, Eur J Pharmacol, 2013:717:58–66.
  18. Honkoop AH, van Diest PJ, de Jong JS, et al., Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer, Br J Cancer, 1998;77:621–6.
  19. Pierga JY, Mouret E, Dieras V, et al., Prognostic value of persistent node involvement after neoadjuvant chemotherapy in patients with operable breast cancer, Br J Cancer, 2000;83:1480–7.
  20. Van der Hage JA, van de Velde CJ, Julien JP, et al., Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer Trial 10902, J Clin Oncol, 2001;19:4224–37.
  21. Ogston KN, Miller ID, Payne S, et al., A new histological grading system to assess response of breast cancers to primary chemotherapy: Prognostic significance and survival, Breast, 2003;12:320–7.
  22. 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;25:2650–5.
  23. Goldhirsch A, Winer EP, Coates AS, et al., Personalizing the treatment of women with early breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2013, Ann Oncol, 2013;24:2206–23.
  24. Hunt KK, Yi M, Mittendorf EA, et al., Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients, Ann Surg, 2009;250:558–66.
  25. Bear HD, Anderson S, Brown A, et al., The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project B-27, J Clin Oncol, 2003;21:4165–74.
  26. Mauri D, Pavlidis N, Loannidis JP, Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis, J Natl Cancer Inst, 2005;97:188–94.
  27. Scholl SM, Fourquet A, Asselain B, et al., Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomized trial S6, Eur J Cancer, 1994;30:645–52.
  28. Bear HD, Anderson S, Smith RE, et al., A randomized trial comparing preoperative (Preop) doxorubicin/ cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: Results of NSABP B-27, Breast Cancer Res Treat, 2004;88:16 (abstract).
  29. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Breast Cancer. Version 1. 2014. Available at: (accessed 14 March 2014).
  30. Von Minckwitz G, Rezai M, Loibl S, 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;28:2015–23.
  31. Green MC, Buzdar AU, Smith T, et al., Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks, J Clin Oncol, 2005;23:5982–92.
  32. Cortazar P, Zhang L, Untch M, et al., Meta-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC), Cancer Res, 2012;72(Suppl. 24):S1–S11.
  33. 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;30:1796–1804.
  34. Perou CM, Sørlie T, Eisen MB, et al., 2000 Molecular portraits of human breast tumours, Nature, 2000;406:747–52.
  35. Morris GJ, Naidu S, Topham AK, et al., Differences in breast carcinoma characteristics in newly diagnosed African- American and Caucasian patients—A single-institution compilation compared with the National Cancer Institute’s Surveillance, Epidemiology, and End Results Database, Cancer, 2007;110:876–84.
  36. Stockmans G, Deraedt K, Wildiers H, et al., Triple-negative breast cancer, Curr Opin Oncol, 2008;20:614–20.
  37. Reis-Filho JS, Tutt AN, Triple negative tumours: a critical review, Histopathology, 2008;52:108–18.
  38. Rakha EA, Reis-Filho JS, Ellis IO, Basal-like breast cancer: a critical review, J Clin Oncol, 2008;26:2568–81.
  39. Steward L, Conant L, Gao F, et al., Predictive factors and patterns of recurrence in patients with triple negative breast cancer, Ann Surg Oncol, 2014;21:2165–71.
  40. Linderholm, BK, Hellborg H, Johansson U, et al., Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer, Ann Oncol, 2009;20:1639–46.
  41. Gerber B, Loibl S, Eidtmann H, et al., Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triplenegative primary breast cancers;results from the Geparquinto study (GBG-44), Ann Oncol, 2013;24:2978–84.
  42. Pierga JY, Petit T, Delozier T, et al., Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open label, single-arm phase 2 study, Lancet Oncol, 2012;13:375–84.
  43. Bear HD, Tang G, Rastogi P, et al., Bevacizumab added to neoadjuvant chemotherapy for breast cancer, N Engl J Med, 2012;366:310–20.
  44. Earl HM, Vallier A-L, Hiller L, 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 open-label, 2x2 factorial randomized phase 3 trial, Lancet Oncol, 2014;15:201–12.
  45. Baselga J, Bradbury I, Eidtmann H, et al., Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomized, open-label, multicentre, phase 3 trial, Lancet, 2012;379:633–40.
  46. Robidoux A, Tang G, Rastogi P, 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 Oncology, 2013;14:1183–92.
  47. Buzdar AU, Valero V, Ibrahim NK, et al., Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: An update of the initial randomized study population and data of additional patients treated with the same regimen, Clin Cancer Res, 2007;13:228–33.
  48. Gianni L, Eiermann W, Semiglazov V, et al., Neoadjuvant chemotherapy with trastuzumab followed by neoadjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomized controlled superiority trial with a parallel HER-2 negative cohort, Lancet, 2010;375:377–84.
  49. 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 randomized multicenter, open-label, phase 2 trial, Lancet Oncol, 2012;13:25–32.
  50. 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.
  51. Sulpher J, Dent R, Dent S, Neoadjuvant chemotherapy in breast cancer: what questions remain?, Curr Opin Supp Palliat Care, 2014;8:59–63.
  52. Reynolds K, Bhatia A, Cheng X, et al., Impact of single and dual neoadjuvant HER2 directed therapy on clinical outcomes among patients with HER2 positive breast cancer: systemic review and meta analyses ASCO Annual Meeting, J Clin Oncol, 2013;31(Suppl.):abstr 647.
  53. Schneeweiss A, Chia S, Hickish T, 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;24:2278–84.
  54. Phase II randomized trial evaluating neoadjuvant therapy with neratinib and/or trastuzumab followed by postoperative trastuzumab in women with locally advanced HER2-positive breast cancer. Available at: 59382&version=Patient#TrialDescription_CDR0000659382 (accessed 16 March 2014).
  55. Neo-adjuvant study in triple negative breast cancer patients (ICE). Available at: show/NCT01097642 (accessed 16 March 2014).
  56. A prospective, randomized multicenter, open-label comparison of preoperative trastuzumab emtansine (T-DM1) with or without standard endocrine therapy vs. trastuzumab with standard endocrine therapy given for twelve weeks in patients with operable HER2+/HR+ breast cancer within the ADAPT protocol. (ADAPT; T-DM1) Available at: term=nct01745965&rank=1 (accessed 16 March 2014).
  57. Li J, Gonzalez-Angulo AM, Allen PK, et al., Triple-negative subtype predicts poor overall survival and high locoregional relapse in inflammatory breast cancer, Oncologist, 2011;15:1675–83.
  58. Turner N, Lambros MB, Horlings HM, et al., Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets, Oncogene, 2010;29: 2013–23.
  59. Zell JA, Tsang WY, Taylor TH, et al., Prognostic impact of human epidermal growth factor-like receptor 2 and hormone receptor status in inflammatory breast cancer (IBC): analysis of 2,014 IBC patient cases from the California Cancer Registry, Breast Cancer Res, 2009;15:R9.
  60. Lehmann BD, Bauer JA, Chen X, et al., Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies, J Clin Invest, 2011;15:2750–67.
  61. Farmer P, Bonnefoi H, Becette V, et al., Identification of molecular apocrine breast tumours by microarray analysis, Oncogene, 2005;24:4660–71.
  62. Lehmann-Che J, Andre F, Desmedt C, et al., Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers, Oncologist, 2010;15:246–52.
  63. Masuda H, Baggerly KA, Wang Y, Differential responses to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes, Clin Cancer Res, 2013;19:5533–40.
  64. Giachetti S, Procher R, Lehmann-Che, J, et al., Long-term survival of advanced triple-negative breast cancers with a dose dose-dense cyclophosphamide/anthracycline neoadjuvant regimen, Br J Cancer, 2014;110:1413–9.
  65. Fioretti FM, Sita-Lumsden A, Bevan CL, et al., Revising the role of the androgen receptor in breast cancer, J Mol Endocrinol, 2014;52:R257–R265.
  66. Silver DP, Richardson AL, Eklund AC. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer, J Clin Oncol, 2010;28:1145-53.
  67. Von Minckwitz G, Blomer JU, Raab, et al., In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: The GEPARTRIO pilot study, Ann Oncol, 2005;16:56–63.
  68. Dieras V, Fumoleau P, Romieu G 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;22:4958–65.
Keywords: Neoadjuvant, triple-negative, locally advanced, inflammatory, breast cancer, HER2, molecular subtyping