Background: The neoadjuvant treatment of breast cancer usually involves cytotoxic chemotherapy, not hormonal therapy. This study is one of the first to look at hormonal therapy as a neoadjuvant strategy in this setting. HER2-positive breast cancer accounts for 20% to 25% of all breast cancers. HER2 breast cancer is characterized by rapid cellular proliferation with frequent metastases. Of patients with overexpressed HER2, 50% are also estrogen receptor (ER)-positive. The HER2 receptor is an ideal target for monoclonal antibody therapy. Trastuzumab is an effective inhibitor of HER2 but is a weak inhibitor of HER2 heterodimers with HER1 and HER3, which lead to the downstream inhibition of the PI3K/PTEN pathway. Drug resistance is associated with PTEN loss or with PI3K mutations. Lapatinib is a dual kinase inhibitor of HER1 and HER2 and therefore inhibits the HER receptors more completely than trastuzumab alone. Preclinical and clinical studies have shown that the dual targeting of HER1 and HER2 is more effective for eradicating tumors than either agent alone.
Methods: This phase 2 study was conducted under the auspices of the Translational Breast Cancer Research Consortium and included 66 patients with stage II or III HER2-positive breast cancer. The patients were stratified by ER status, and the study was designed to detect an increase in the pathologic response from 10% to 35% in each stratum. Approximately 54% of the patients were either black or Hispanic. The median tumor size was 6 cm; 62% of the patients had tumors that were >5 cm. All patients received oral lapatinib 1000 mg daily and trastuzumab in a 4-mg/kg loading dose, followed by 2 mg/kg weekly for 12 weeks. In addition, all ER-positive patients received oral letrozole 2.5 mg daily (with a luteinizing hormone–releasing hormone antagonist for premenopausal status). The end points were the rate of pathologic complete response, the rate of pathologic response, and residual disease of <1 cm.
Results: Between June 2008 and November 2010, 65 women were evaluable for safety and 64 were evaluable for efficacy. The patients received treatment at 5 sites (Baylor College of Medicine, Vanderbilt University, University of Alabama in Birmingham, University of Chicago, and Mayo Clinic). The overall pathologic response rate was 49%; the rate for the ER-positive group was 54%, and the rate for the ER-negative group was 40%. The overall complete pathologic rate (defined as complete eradication with no residual disease in the breast or axilla) was 22% (18% in ER-positive patients and 28% in ER-negative patients). Overall, 89% of patients proceeded to surgery. The treatment was generally well tolerated, with only 6% of patients discontinuing therapy. The most common adverse effects were diarrhea (grade 1 or 2, 63%; grade 3 or 4, 3%), rash (grade 1 or 2, 55%; grade 3 or 4, 1%), fatigue, nausea, and elevated liver function tests.
Takeaway: These results are significant and show that a nonchemotherapy neoadjuvant targeted hormonal therapy can produce complete remission in a moderately high number of patients with large primary tumors. Although this study is limited by its single-arm, phase 2 design, it reports a highest pathologic response to targeted hormonal therapy without systemic chemotherapy, showing that some patients may be spared the cost and toxicity of chemotherapy. Further study is needed to determine a subset of patients who may benefit from nonchemotherapy targeted hormonal therapy. Other neoadjuvant regimens that used hormonal therapies with chemotherapy showed an even higher pathologic response. A larger phase 3 study is needed to compare an all-hormonal targeted regimen with a hormonal regimen combined with chemotherapy.
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;31:1726-1731.