A novel peptide vaccine was able to reduce the mortality rate in women with HER2/neu overexpressing breast cancer by about half, researchers report here at the American Association for Cancer Research (AACR) 2008 Annual Meeting.

“The numbers in this study are small but the concept is good,” commented William N. Hait, MD, PhD, president of the AACR and senior vice president of Worldwide Hematology and Oncology Research and Development at Johnson & Johnson. “It’s a good first step and we are cautiously optimistic.”

HER2/neu is a source of immunologic peptides and approximately 30% of early-stage breast cancers have an amplified HER2/neu gene or overexpression of its protein product. There has been a great deal of interest in the HER2 gene, explained lead author Linda C. Benavides, MD, a general surgical resident at Brooke Army Medical Center in San Antonio, Texas. “Historically, we have focused on patients because they are candidates for Herceptin. Our vaccine showed a response in patients who expressed HER2/neu at all levels, including low expressers for whom no therapy is available.”

“Most vaccine trials have been performed in the metastatic setting,” she told journalists, “But our results show that the vaccine is safe in women with minimum symptoms. It decreased mortality and morbidity.”

What was most surprising in this study was that patients with low-HER2/neu-expressing tumors responded so well to the vaccine. In fact, Dr. Benavides pointed out, the patients with low-expressing (0 to 2+ on immunohistochemistry [IHC]) HER2/neu tumors had a better response to the vaccine than women with higher-expressing tumors. They experienced not only a better immune response, but a better clinical one as well, as demonstrated by a decreased rate of breast cancer recurrence and 0% mortality after E75 peptide vaccination.

The researchers had previously conducted clinical trials with the HER2/neu E75 peptide vaccine in both node-positive and node-negative breast cancer patients who demonstrated a variety of levels of HER2/neu expression. In this study, they performed a subset analysis review that was based on the level of HER2/neu expression in the 163 patients who were enrolled in their E75 vaccine trial.

All patients were typed for human leukocyte antigen (HLA). Women who were HLA-A2+/A3+ received the vaccine; women who were HLA-A2–/A3– served as the control group. Overexpression was defined as fluorescence in situ hybridization (FISH) greater than 2.0 and IHC 3+ HER2/neu tumors; low expression was defined as IHC ranging from 0 to 2+.

Of the 92 vaccinated patients, 29 (34%) were defined as HER2 overexpressors and 56 (66%) were defined as low-expressors. The control group (n = 71) included 22 (33%) overexpressors and 44 (67%) low-expressors. The HER2/neu overexpressors were similar in regard to prognostic and treatment factors, although a statistically larger number of vaccinated women who overexpressed HER2 were also hormone-receptor negative and node negative (P = 0.007).

At a median follow-up of 30 months, the rates of disease recurrence were similar between HER2/neu overexpressors in both the vaccine and control groups (18.2% vs 13.8%). However, the researchers noted that the mortality rate was 50% lower among the vaccinated patients who had a disease recurrence (25% vs 50%).

The researchers also noted that recurrence rates were substantially reduced in vaccinated patients with low HER2/neu expression. They experienced a 10.7% recurrence rate, compared with the 18.2% seen in the control group. This subgroup showed not only a better immunologic response, but also a better mortality rate (0%).

“This may represent a new form of HER2-directed therapy, because the low expressors do not qualify for trastuzumab,” Dr. Benavides said. “The vaccine has been registered for a phase 3 trial, which will focus on low-expressing women.”

The first phase 3 trial in low-expressing women is slated to begin in the fall. Based on the data presented at AACR, the phase 3 trial has been restructured and is the first to focus on low-expressing women, explained Dr. Benavides.

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Nearly 25 million U.S. women between the ages of 14 and 59 are infected with HPV, and the annual cost of screening and treating cervical abnormalities is about $4 billion, according to a statement from the Society of Gynecologic Oncologists.

For many unvaccinated women HPV infections clear up naturally without causing any cervical problems, as do many pre-malignant lesions. In other cases, HPV prompts cell changes that can gradually put women at greater risk of cervical cancer.

A significant drop in abnormal Pap test results happened after girls and women were given the vaccine named Gardasil to prevent cervical cancer, according to a researcher at the University of Alabama at Birmingham (UAB).

While the findings are not definitive that Gardasil prevents cancer, they do signal the vaccine will spare thousands of women a diagnosis of cell abnormality or malignant changes that may lead to more tests and possibly surgery, said Warner Huh, M.D., associate professor in the UAB Division of Gynecologic Oncology and the doctor chosen to present the data.

In testing Gardasil reduced abnormal Pap test results by 43 percent compared to women not given the vaccine. The 43 percent reduction was for tests that found pre-cancerous changes called high-grade squamous intraepithelial lesions (HSIL) more than three years after women were given the vaccine.

Gardasil reduced other abnormal Pap results, including milder pre-malignant cell changes, by 16 to 35 percent compared to women not given the vaccine.

“Clearly the vaccine’s benefits include something that can be appreciated by women and daughters fairly quickly,” Huh said. “This is a positive first sign, and it will take many more years to know definitively if the vaccine prevents cancer.”

The results are a compilation of three separate trials involving more than 18,000 women, ages 16 to 26, in the United States, Europe and Asia. All test subjects had normal Pap smear readings at the start of the trial.

In addition to the drop in unwanted Pap results, the study found invasive procedures like cervical biopsies were performed up to 42 percent less in Gardasil recipients compared to women not given the vaccine, Huh said.

Gardasil is approved to fight the human papilloma virus (HPV) strains believed to cause 70 percent of cervical cancers and more than 90 percent of genital warts.

The findings were presented March 10 at the annual meeting of the Society of Gynecological Oncologists held in Tampa.

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