Trial Suggests HRT Increases Breast Cancer Recurrence Risk

Long-term follow-up data from a randomized clinical trial indicate that, in women previously treated for breast cancer, use of hormone replacement therapy (HRT) significantly increases the risk of recurrence or contralateral breast cancer - a new cancer in the opposite breast. Published online March 25 by the Journal of the National Cancer Institute (JNCI), the analysis shows a 2.4-fold increased risk of recurrence or contralateral breast cancer in women randomized to receive HRT to treat menopausal symptoms compared with women given the best, nonhormonal treatments for such symptoms.

The trial, called HABITS, conducted in Scandinavia, was halted in 2003 after an interim analysis showed a 3.5-fold increased risk of cancer in women in the HRT arm. This longer-term analysis followed 442 women for a median of 4 years. Of the 221 women in the HRT arm, 39 had a "breast cancer event," compared with 17 of 221 in the control arm.

The results "suggest that [HRT] not only induces and promotes breast cancer, but also may stimulate the growth of tumor microdeposits in breast cancer survivors," concluded the study's lead author, Dr. Lars Holmberg from the King's College London School of Medicine, and colleagues.

Several observational studies have found no increased recurrence risk among breast cancer survivors taking HRT. However, the authors argued, "The majority of these observational studies were not formal studies that could control sufficiently for bias and confounding."

In addition, a similar randomized trial launched in Sweden at about the same time as HABITS showed a decreased risk of breast cancer recurrence associated with HRT. The two trials had several design differences that could account for the discrepancies, the researchers noted, including the use among many HABITS participants of a more potent progestagen in their HRT regimen. (No single HRT type was prescribed for the trial.)

In a related commentary in JNCI, Dr. Kathleen Pritchard from Sunnybrook Odette Cancer Center in Toronto, Canada, indicated that the HABITS data are convincing.

"It seems that the harmful side effects of HRT [in breast cancer survivors] have finally been clearly demonstrated in what is, by today's standards, a small randomized trial, carried out in a few relatively small countries," Dr. Pritchard wrote.

Vaccine Treats Breast Tumors in Mice

A new therapeutic vaccine designed to stimulate the body's immune system so that it recognizes cancer as an invader shows promise in eradicating some advanced breast cancer tumors in mice. The study results appeared March 15 in Cancer Research.

The research team, led by Dr. Jay Berzofsky of the Vaccine Branch in NCI's Center for Cancer Research, engineered a vaccine using a modified adenovirus to code for portions of a protein called neu, which corresponds to human epidermal growth factor 2 (HER2) in humans - a surface receptor overexpressed in 20 to 25 percent of women who have breast cancer.

Mice were injected with mouse breast cancer cells called TUBO cells to generate tumors with high levels of neu. When the TUBO cells and vaccine were given at the same time, no tumors formed. When the vaccine was given after the TUBO cell injection, small tumors formed, but they disappeared within 45 days and did not reappear.

The larger the tumor load, the more difficult it was for a vaccine-induced immune response to cause these tumors to shrink and disappear. Tumors up to 2 cubic centimeters continued to grow for a week after immunization but disappeared within a month. Even tumors up to 3.5 cubic centimeters eventually disappeared. But tumors that were 5.5 cubic centimeters at the time of vaccination resumed growth after initial shrinkage.

The sooner the vaccine was given after TUBO cell injection, the lower the incidence of metastasis to the lungs, as well. With metastasis, it took longer for the immune response to clear the cancer if a large number of tumors were present. Mice with more than 200 metastases were tumor-free within 38 days.

"A vaccine offers several advantages over a monoclonal antibody treatment, which targets a single region on a receptor," said Dr. Berzofsky. "A vaccine may induce the production of several different antibodies and target multiple regions on a receptor, making it harder for the tumor to mutate and escape the effects of therapy."

Dr. Berzofsky added, "These results in mice show the potential for producing a vaccine that induces antibodies to an overexpressed cell surface receptor such as HER2 in breast cancer patients."

Guidelines for Colonoscopy Follow-up Assessed

The size and number of polyps removed during colonoscopy may be of limited use in predicting a recurrence that leads to cancer, new research suggests. The findings, in the March 18 Annals of Internal Medicine, raise questions about the current guidelines on follow-up colonoscopies, which define a schedule for surveillance exams based on detected polyps, or adenomas.

For patients with an advanced adenoma - considered high risk for becoming cancerous - or with at least three adenomas, the guidelines recommend follow-up within 3 years. For patients with fewer, nonadvanced polyps, repeat exams are recommended in 5 to 10 years. Surveys show, however, that many physicians schedule follow-up colonoscopies earlier than the guidelines suggest.

One reason may be that the guidelines have not been assessed in a prospective study. To explore this question, Dr. Adeyinka O. Laiyemo of NCI's Division of Cancer Prevention and his colleagues studied 1,905 patients in the Polyp Prevention Trial. Participants had an adenoma removed at baseline and underwent repeat colonoscopy at 1 year and 4 years.

In this study, the risk stratification model used in the current guidelines did not reliably predict the recurrence of advanced adenomas. Overall, 6.6 percent of participants had an advanced adenoma recurrence at 4 years. The advanced adenoma rates were 9 percent and 5 percent in patients with high-risk and low-risk adenomas at baseline colonoscopy, respectively.

An editorial accompanying the paper notes that while this difference is statistically significant, it may not be meaningful to patients and clinicians, given that the predictive accuracy of the current risk model is only 71 percent. (By contrast, the predictive accuracy of flipping a coin is 50 percent.)

Dr. Laiyemo stresses the need for more reliable tools to identify individuals at the highest risk for advanced adenoma recurrence. The misclassification of cases may mean that preventable colon cancers are missed or that limited medical resources are allocated poorly.

The researchers also found that patients are at high risk if they have two adenomas and one is on the right side of the colon, near the small intestine. The reason for this apparent association, which has been suggested in other studies, is not yet clear.

Oncogene Identified in Diffuse Large B-Cell Lymphoma

Researchers have identified how mutations in a gene called CARD11 contribute to cancer cell survival in a type of diffuse large B-cell lymphoma (DLBCL) with poor prognosis, called activated B-cell-like (ABC) DLBCL. The study results, published March 21 in Science, identify CARD11 as a possible future target for new therapies.

To prevent cell death, malignant ABC DLBCL cells rely on the nuclear factor-kappa B (NF-κB) signaling pathway - a cell-signaling pathway that plays an important role in cell proliferation, differentiation, and survival. NCI researchers previously reported that CARD11 stimulates abnormal cellular signaling of the NF-κB signaling pathway in ABC DLBCL. However, the underlying mechanism for this abnormal cellular signaling was not known.

To determine how CARD11 contributes to cancer, the researchers sequenced the gene in samples taken from ABC DLBCL biopsies and cell lines. They found that all of the CARD11 mutations coded for a region of the CARD11 protein called the coiled-coil domain.

As determined by fluorescence microscopy, mutant CARD11 proteins were more likely to aggregate (bunch together), and the degree of aggregation correlated with the protein's ability to activate the NF-κB pathway, thereby helping malignant cells survive. In a set of experiments using small hairpin RNAs to knock out mutant CARD11 function, cells from an ABC DLBCL line with mutant CARD11 died when the gene was blocked; these cells were not saved when researchers introduced a normal CARD11 gene, indicating an "addiction" to the mutant signaling pathway.

"Our results demonstrate that CARD11 is a bona fide cancer-causing gene in DLBCL, thus providing a genetic rationale for the development of drugs that could block the CARD11 pathway," concludes Dr. Louis Staudt from NCI's Center for Cancer Research, senior author of the study.