• Neoadjuvant chemotherapy (NAC):
    • Has traditionally been the standard approach in patients with locally advanced and inflammatory breast cancer:
      • Allowing for a reduction in disease volume and therefore optimizing surgical resection of the disease in the breast
  • The use of NAC has evolved over time to include:
    • Large operable cancers in patients who desire breast conservation and now is commonly used in patients with early-stage breast cancer based on tumor biology:
      • Especially in HER-2-positive and triple-negative tumors
    • Delivery of chemotherapy in the neoadjuvant setting:
      • Allows assessment of response to therapy
        • Pathologic complete response (pCR):
          • Which indicates eradication of invasive disease in the breast and the lymph nodes:
            • Has been shown to correlate with outcome
          • The achievement of a pCR in HER-2-positive breast cancer with the use of trastuzumab in combination with chemotherapy:
            • Has been shown to correlate with improved survival and patient outcome
  • Neoadjuvant trials of anti-HER-2 therapy have included:
    • Single-arm trastuzumab or lapatinib trials
    • Trials investigating the addition of trastuzumab to NAC
    • Trials that compare HER-2 targeted approaches:
      • Individually or in combination
  • The earliest study of trastuzumab in the neoadjuvant setting was published in 2005:
    • This trial from MD Anderson Cancer Center (MDACC) randomized women (N = 42) to:
      • Treatment with taxane with trastuzumab and sequential taxane and anthracycline chemotherapy with or without trastuzumab
    • The pCR rate was 65% in the combination arm compared with 26% in women who received chemotherapy alone
    • This study was closed early due to the remarkable response seen
  • The Neoadjuvant Herceptin (NOAH) trial:
    • Was a larger trial of 235 women with locally advanced HER-2-positive breast cancer who were randomized to receive:
      • Neoadjuvant anthracycline– and taxane-based chemotherapy with or without trastuzumab
    • The study reported an increase in the pCR rates in the breast and axilla with the addition of trastuzumab to chemotherapy compared with no trastuzumab:
      • 38% and 19%, respectively, p = .001
    • Of note, patients in the NOAH trial had more advanced disease compared with the MDACC trial:
      • Accounting for the lower pCR rate
  • Similar results have been demonstrated in the:
    • Phase II Remagus 02 trial:
      • pCR rates with trastuzumab therapy 26%
    • The Austrian Breast and Colorectal Cancer Study Group (ABCSG-24) trial:
      • pCR rates with trastuzumab therapy 40%
    • GeparQuinto:
      • pCR rates with trastuzumab therapy 30.3%
  • Furthermore, the role of dual HER-2 targeted therapy in the neoadjuvant setting was addressed in several trials:
    • The NeoALLTO trial investigated the addition of the reversible tyrosine kinase inhibitor lapatinib to trastuzumab and chemotherapy:
      • This resulted in an increase in pCR rates compared with treatment with trastuzumab and chemotherapy alone:
        • 46.8% versus 27.6%, p = .0007
      • In study arms with single-agent trastuzumab or lapatinib:
        • pCR rates were 27.6% and 20%, respectively
      • Around one third of patients in the lapatinib arm did not complete treatment:
        • Due to grade 3 diarrhea and alterations of liver enzymes
    • Similar results were demonstrated in the CHER-LOB trial (Chemotherapy, Herceptin and Lapatinib in Operable Breast cancer):
      • Which also investigated trastuzumab and lapatinib alone or in combination with chemotherapy
      • The rates of pCR were 25% in the trastuzumab arm, 26% in the lapatinib arm, and 47% in the combination arm
  • Furthermore, the NSABP-B41 trial:
    • Reported and showed rates of breast and axillary pCR with AC-T in combination with either trastuzumab or lapatinib:
      • As high as 62%
    • There was no statistically significant difference in the pCR rates with trastuzumab and chemotherapy alone or in combination with lapatinib (p = .095)
  • Pertuzumab is a humanized monoclonal antibody:
    • Is a second-generation anti-HER-2 agent that binds to HER-2 and prevents its dimerization with itself or other members of the EGFR family:
      • Resulting in inactivation of downstream signaling pathways
  • The results from the NeoSphere trial:
    • Demonstrated a pCR rate of 45.8% in patients receiving pertuzumab plus trastuzumab and chemotherapy compared with a pCR of 29% in patients who received trastuzumab and chemotherapy
  • Similar results were demonstrated in the Trastuzumab plus Pertuzumab in Neoadjuvant HER2-Positive Breast Cancer (TRYPHAENA) trial:
    • Where  treatment with the dual HER-2 targeting agents resulted in pCR rates up to 52%
  • Furthermore, the addition of pertuzumab was not found to be associated with an increased rate of cardiac dysfunction when used in conjunction with trastuzumab and chemotherapy
    • These remarkable results demonstrated by the addition of pertuzumab to trastuzumab and chemotherapy resulted in the FDA approval of pertuzumab in the neoadjuvant setting in September 2013
    • Many patients today with HER-2-positive breast cancer are treated with chemotherapy together with both trastuzumab and pertuzumab.
  • Novel anti-HER-2 agents are currently being investigated in ongoing neoadjuvant trials these include:
    • Neratinib (oral dual-activity irreversible PNA inhibitor of EGFR tyrosine kinases)
    • Trastuzumab-emtansine (trastuzumab linked to emtansine, a microtubule inhibitor)
    • Afatinib (an irreversible receptor tyrosine kinase inhibitor targeting HER-1 and HER-2) 
  • A question regarding the optimal duration of neoadjuvant therapy remains unclear:
    • The results from recent trials have suggested that shorter treatment durations are effective and feasible. However, further work and study in this area are essential

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