Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer

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.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0989-8) contains supplementary material, which is available to authorized users.

Rapid Generation of Sustainable HER2-specific T-cell Immunity in Patients with HER2 Breast Cancer using a Degenerate HLA Class II Epitope Vaccine

“…Indeed, in that prior study, only 12 of 20 evaluable patients demonstrated FRa expression, which could have skewed the time to maximal immunity. In addition, in the FRa trial, patients were not previously exposed to immune therapy, whereas the patients in this trial received trastuzumab, which has been shown to induce endogenous immunity including activation of helper CD4 T cells as previously described above (7)(8)(9).…”

“…While many mechanisms of action have been ascribed to the clinical activity of trastuzumab, recent studies have demonstrated an important role for the adaptive immune response. Foremost among immune effectors, endogenously generated HER2-specific antibodies, cytotoxic T cells, and helper CD4 T (Th) cells are important in disease protection mediated by trastuzumab-containing regimens and have been associated with greater objective tumor responses and significantly improved disease-free, progression-free, and overall survival in both humans and murine models (6)(7)(8)(9).…”

Novel evolutionary dynamics of small populations in breast cancer adjuvant and neoadjuvant therapy

“…In HER2 + BC, trastuzumab (Herceptin) increase the overall cell death rate by directly targeting HER2. However, it also elicits an immune response and the subsequent intratumoral lymphocytic infiltration predicts treatment efficacy [69][70][71] . Interestingly, as the targeted response will occur immediately, but the immune response requires some time to develop, trastuzumab therapy effectively applies a sequence of perturbations to the cancer, which may account for its superiority to other tyrosine kinase inhibitors.…”

What is the role of HER2-specific antibody immunity in patients with HER2-positive early breast cancer receiving chemotherapy plus trastuzumab?

“…In addition, patients who experienced elevation in the levels of posttreatment HER2-specific antibodies had improved DFS compared to those in whom antibody levels remained normal. The 5-year DFS rate after adjuvant trastuzumab was 84% among patients with elevated antibodies, contrarily to 60% in patients with normal levels (11).…”

“…The investigators of the NCCTG N9831 trial had previously shown evidence on the important role of immunity in HER2-positive early breast cancer by both gene expression profile analyses (9) and the evaluation of tumors infiltrating lymphocytes (TIL) (10). In the recently published analysis by Norton and colleagues conducted within the NCCTG N9831 trial, the investigators showed that the serum levels of endogenous antibody immunity specifically developed against HER2 (i.e., HER2-specific antibodies) increased only with the use of adjuvant trastuzumab (given sequentially or concurrently to chemotherapy as per study design) and not following the administration of chemotherapy alone (11). In addition, patients who experienced elevation in the levels of posttreatment HER2-specific antibodies had improved DFS compared to those in whom antibody levels remained normal.…”