521 Background: The addition of trastuzumab to chemotherapy improves responses to therapy and extends survival among patients with metastatic HER2 breast cancer. Several mechanisms have been proposed for the activity of this combination therapy. Trastuzumab, specifically, is thought to activate NK cells and blunt HER2 signaling. Prior work from us has shown that combination trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy. Despite that, it remains unclear whether the immunity that was induced was due to complexing of non-tumor derived HER2 or antigen derived from the tumor site. In the present work, we addressed this question by assessing if combination therapy induced epitope spreading to tumor antigens other than HER2. Methods: Pre-and post-treatment sera were obtained from 56 women enrolled in 2 NCCTG clinical trials, N0337 and 98-32-52. IgG antibodies to HER2 intracellular domain (HER2), p53, IGFBP2, CEA and tetanus toxoid (TT) were examined using ELISAs. Sera from an age-matched group (N=56) of controls and 12 patients treated in the adjuvant setting were also examined. Results: Prior to therapy, metastatic patients had higher IgG levels (≥ 2-fold) to p53 and HER2 but not CEA, IGFBP2 and TT, relative to the controls. Similarly, adjuvant patients had elevated IgGs to multiple tumor antigens prior to therapy, relative to controls. Following therapy, levels of IgG to IGFBP2, HER2, and p53 increased in 81% of metastatic patients, with mean increases of 3.2 (±0.6 sem), 6.2 (±2.7) and 2.7 (±0.7) fold, respectively (p<0.05). Levels of antibodies to TT and CEA were not elevated by treatment. In contrast, IgGs were not increased in adjuvant patients; consistent with the idea that immunity depends on the presence of threshold levels of antigens. Conclusions: These results show that combination treatment induces adaptive immunity to antigens released by tumor and that metastatic patients remain capable of responding immunologically to their cancer. Thus, in metastatic breast cancer patients, combination trastuzumab and chemotherapy may behave as a vaccine.
Clinical benefit of treatment after trastuzumab emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study in Japan (WJOG12519B)
