NEOADJUVANT ANTI-HER-2 THERAPY IN BREAST CANCER

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