Breast cancer vaccine shows survival benefit in subset of low HER2 expressors

SAN DIEGO-Adjuvant treatment with a HER2/neu E75 peptide vaccine significantly reduced mortality in a subset of women with breast cancer, according to a multi-institutional study led by investigators at Brooke Army Medical Center, San Antonio. The study, reported at the 2008 American Association of Cancer Research annual meeting (abstract 2545), showed a survival benefit in women who were “low expressors” of the HER2 protein (particularly IHC 1+ patients).

Linda C. Benavides, MD, a general surgery resident at Brooke Army Medical Center, reported the results. The project’s director is George Peoples, MD, director of the Cancer Vaccine Development Program and chief of surgical oncology at Brooke Army Medical Center.

E75 is a peptide sequence from the HER2/neu protein. E75 stimulates peptide-specific cytotoxic T lymphocytes, which recognize and lyse HER2 cells. It is being developed by Apthera, Scottsdale, Arizona, as NeuVax (see Figure).

The Cancer Vaccine Development Program has conducted clinical trials with the E75 vaccine in node-positive and node-negative patients with varying levels of HER2 expression. In this study, investigators wanted to determine whether the level of HER2 expression affected the response to the vaccine.

The study included 163 patients with early-stage breast cancer (node positive or high-risk node negative) who were categorized according to their level of HER2 expression. Over-expression was defined as FISH ≥ 2.0 or IHC 3+, while low-expression was defined as IHC 1+, IHC 2+, or FISH < 2.0. After HLA typing, patients who were HLA-A2+/A3+ received the novel vaccine intradermally while those who were HLA-A2-/A3- served as controls.

Results were available for 85 patients in the vaccination group (29 over-expressors and 56 low-expressors) and for 66 patients in the control group (22 over-expressors and 44 low-expressors). (Several antigen-nave, ie, IHC 0, additional patients were included in some of the analyses.)

HER2 over-expressors were similar to the low-expressors regarding prognostic and treatment factors, except that a significantly larger number of vaccinated over-expressors had hormone-receptor-negative tumors. Clinicopathologic factors were not significantly different between controls and vaccinated low-expressors.

Some interesting results

Following vaccination, immunologic responses were similar between over-expressors and low-expressors, as measured by delayed-type hypersensitivity reactions.

“The E75 vaccine was capable of inducing an immune response in all IHC categories,” Dr. Benavides said. Patients who were IHC 1+ demonstrated the greatest immunological response.

At a median follow-up of 30 months, disease recurred at a similar rate among vaccinated HER2 over-expressors and unvaccinated over-expressing controls. Recurrence rates were 18.2% and 13.8%, respectively. However, vaccinated over-expressors who had a recurrence had a 50% lower mortality rate than control patients with recurrence (25% vs 50%), although the difference did not reach statistical significance, Dr. Benavides reported.

Most interesting, she said, was that recurrences were substantially reduced for vaccinated patients with low HER2 expression. Vaccinated low-expressors had a recurrence rate of 10.7%, compared with 18.2% for unvaccinated low-expressors. Importantly, no deaths occurred among the vaccinated low-expressors, while the mortality rate was 38% among the unvaccinated low-expressors (P = .08).

IHC 1+ patients had the greatest reduction in relapses and the most significant reduction in mortality: The mortality rate was 0% for vaccinated IHC 1+ patients vs 20% for IHC 1+ controls (P = .04).

“All vaccinated patients benefited clinically. The vaccinated low-expressors and the IHC 1+ group had the greatest reduction in mortality risk,” Dr. Benavides said. “The exciting thing is that more than 50% of breast cancer patients are low-expressors.”

A theory

The investigators have a theory as to why HER2 low-expressors benefit more than over-expressors.

“We think it has to do with the mechanisms of action of the vaccine and the sensitization or tolerance of the tumor cells,” Dr. Benavides said.

She said that the vaccine stimulates the cytotoxic T-cells to kill any tumor cell expressing any amount of HER2.

“If the immune system has seen a lot of something-in this case an over-expression of HER2-it will not react as robustly,” she said. “It will be sensitized. The vaccine does work in the HER2 over-expressors, but less potently. This is different than trastuzumab [Herceptin]. Our vaccine is more applicable to the whole spectrum of HER2.”

Phase III trials

The E75 vaccine will be evaluated in two randomized phase III trials. The study in HER2 low-expressors is expected to begin within 6 months and will enroll 700 women at 80 sites worldwide. The second will enroll over-expressors who have completed trastuzumab. The vaccine will also be studied for safety in combination with trastuzumab in over-expressors.