Pathologic Complete Response in HER2 Positive Breast Cancer Treated with Neoadjuvant Therapy

  • Trastuzumab:
    • Is a monoclonal antibody:
      • That targets the HER2 protein
  • After trastuzumab was shown to be efficacious:
    • In the metastatic and adjuvant settings:
      • It was investigated in the neoadjuvant setting:
  • In this setting:
    • Significantly increased rates of pCR were observed in HER2+ patients:
      • Treated with trastuzumab in combination with chemotherapy versus chemotherapy alone
  • In an initial:
    • Small trial conducted by Buzdar and colleagues:
      • The increase in pCR rates when trastuzumab was combined with chemotherapy:
        • Was so dramatic:
          • 65.2% vs 26.3%
            • p=.016:
            • That the study was terminated early by the data safety monitoring board
  • Other trials have investigated dual HER2 targeting:
    • In the neoadjuvant setting:
      • With each regimen having different mechanisms of action and toxicity
  • The NeoSphere study:
    • Was a randomized multicenter phase II trial:
      • Investigating the addition of pertuzumab to trastuzumab:
        • With or without docetaxel
    • In patients that received dual HER2-targeting therapy in combination with chemotherapy:
      • There was almost a doubling of the pCR rates in the breast compared to patients that received trastuzumab and chemotherapy alone:
        • 46% vs 29%
          • p=.014
    • In the treatment arm that received dual HER2-targeted therapy without any chemotherapy:
      • The pCR rate:
        • In the breast was 17% and in the axilla was 11%:
          • Suggesting some patients may benefit from HER2-directed therapy alone, without chemotherapy
  • Both the CHER-LOB and Tryphaena trials:
    • Show the addition of an anthracycline to dual HER2 blockade:
      • Further improves pCR rates
  • To date:
    • Physical exam and imaging (any imaging):
      • Are unable to confirm achievement of a pCR:
        • Therefore, all patients are advised to undergo surgery:
          • There is interest in conducting clinical trials to evaluate MRI with biopsy of the tumor site:
            • To identify patients who may be watched after achieving a complete response to neoadjuvant chemotherapy plus HER2-targeted therapy
  • Recent single institution data:
    • Suggest the response to neoadjuvant chemotherapy:
      • May vary according to location:
        • With the axilla demonstrating higher pCR rates than the breast:
          • In all tumor subtypes.
  • References:
    • 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(16):3676-3685.
    • 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): 2024-2031.
    • 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 randomized controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375(9712):377-384.
    • Untch M, Fasching PA, Konecny GE, et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol. 2011;29(25):3351-3357.
    • Buzdar AU, Suman VJ, Meric-Bernstam F, 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 randomized controlled, phase 3 trial. Lancet Oncol. 2013;14(13):1317-1325.
    • 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(1):25-32.
    • Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomized, open-label, multi-centre, phase 3 trial. Lancet. 2012;379(9816):633-640.
    • 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): 1989-1995.
    • Rimawi MF, Mayer IA, Forero A, 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(14):1726-1731.
    • 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(9): 2278-2284.
    • Mamtani A, Barrio AV, King TA, et al. How often does neoadjuvant chemotherapy avoid axillary dissection in patients with histologically confirmed nodal metastases? Results of a prospective study. Ann Surg Oncol. 2016;23(11):3467-3474.

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