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Trastuzumab plus HER2/neu-specific vaccine prolonged immune response in metastatic breast cancer
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Patients with HER2/neu-overexpressing metastatic breast cancer treated with trastuzumab and HER2/neu vaccine experienced minimal toxicity and prolonged antigen-specific immune responses, according to data from a phase-1/2 study.
The study included 22 patients with stage IV HER2/neu-positive breast cancer. Median age was 49. All patients were receiving therapy with trastuzumab (Herceptin, Genentech) and were vaccinated with a HER2/neu T-helper peptide-based vaccine. The researchers used National Cancer Institute criteria to grade toxicity and interferon gamma enzyme-linked immunosorbent spot assay to assess antigen specific T-cell immunity. They also collected data for PFS and OS.
During combination therapy, 15% of patients experienced asymptomatic decline in left ventricular ejection fraction below the normal range; according to the researchers, treatment was well-tolerated. The vaccine boosted and maintained pre-existing immunity specific for HER2/neu and other breast antigens, a factor common among many of the study patients during treatment with trastuzumab. New or augmented immunity occurred in 90% of patients.
The vaccine also stimulated epitope spreading within HER2/neu and additional tumor-related proteins, according to the researchers, meaning patients began to develop new immunity to their tumors. A significant inverse relationship was also noted in the amount of T-cell response with serum transforming growth factor beta levels; greater intramolecular epitope spreading T-cell response lead to a greater decrease in serum transforming growth factor beta levels (P=.0003).
As of the 36-month median follow-up from the time of first vaccination, the median OS was not reached.
“The current observed results are encouraging in light of the historical results for patients with pretreated HER2/neu-positive metastatic breast cancer,” the researchers wrote. In addition, the combination of trastuzumab and a HER2/neu-specific vaccine warrants further evaluation as a therapeutic option, they wrote.
Disis ML. J Clin Oncol. 2009;doi:10.1200/JCO.2008.20.6789
[This study] is the continuation of a long series of painstaking exploration of HER2-directed vaccines in breast cancer. This work goes back at least 10 years, probably longer. Trastuzumab is considered by many to be a form of immune therapy, since it is a monoclonal antibody and can elicit antibody dependent cellular cytotoxicity. Whether that mechanism has any influence on the clinical effectiveness of trastuzumab is a matter of controversy.
The results presented in this small, phase-1/2 trial are clearly of interest, mostly because of the robust immunological responses. I am not sure one can make much out of the clinical results, because there is no control population, and the patients included were highly selected: 11 were in complete remission as a consequence of some other treatment and the rest were stable. Therefore, this group is expected to have a much longer survival than an unselected group of patients with metastatic breast cancer, regardless of therapy. Trastuzumab alone can be associated with prolonged survival, so the role of the vaccine in this trial is a matter of speculation.
– Gabriel N. Hortobagyi, MD
Professor of Medicine, Nellie B. Connally Chair in Breast Cancer, The University of Texas M.D. Anderson Cancer Center