Abstract
BackgroundResected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively.MethodsPre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival.ResultsPrior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04).ConclusionsThese results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting.Trial registrationClinicalTrials.gov, NCT00005970. Registered on July 5, 2000.
Highlights
Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone
Norton et al Breast Cancer Research (2018) 20:52 (Continued from previous page). These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival
Trastuzumab induces anti-HER2 antibodies during adjuvant treatment of resected HER2+ BC patients Patient, tumor and disease characteristics were not different between the three arms with the exception that Arm C samples came from slightly younger patients (Table 1)
Summary
Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. HER2 is overexpressed in ~ 20% of invasive breast cancers, and is associated with aggressive biology and a natural history of shortened survival if not treated with targeted therapies [3] Trastuzumab has had such a tremendous impact on the management of patients with HER2+ advanced [4] and early breast cancer [2, 5,6,7], leading to the development and increased use of other HER2-targeted therapies such as pertuzumab, another IgG1 HER2-specific monoclonal antibody [8]. Our group has conducted several studies demonstrating a predictive immune component, such as tumor-infiltrating lymphocyte (TIL) [13] and gene expression profiles that are associated with outcome [14] Another significant area of interest is to determine whether the development of antibodies is correlated with outcome in the adjuvant setting
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