Low-Fat Diet May Have Small Impact on Breast Cancer in Women

Results from the Women's Health Initiative (WHI) Dietary Modification (DM) prevention study show that reducing dietary fat and increasing fruits, grains, and vegetables may reduce risk of invasive breast cancer in some women, but has no effect on invasive colorectal cancer. Although more than 19,500 postmenopausal women followed the modified diet, the overall breast cancer risk reduction of 9 percent was not statistically significant after an average of 8.1 years. Women whose diets were highest in fat before they entered the study, however, were 22 percent less likely to develop breast cancer than the comparison group.

Dr. Ross L. Prentice of the Fred Hutchison Cancer Research Center in Seattle and colleagues write that the risk reduction seen in this and other subgroups "would not be expected if the intervention had no effect on breast cancer risk." Citing other trends in the data in favor of DM, they note the benefit increased to 15 percent among women who most closely followed the dietary regimen. Also, citing the small impact of DM on breast cancer, which begins to occur after about 4 years and appears to be increasing, the authors note that "the health implications of a low-fat dietary pattern may take years to be fully realized." In an accompanying editorial, Dr. Aman U. Buzdar from the University of Texas M.D. Anderson Cancer Center said the study is another indication that breast cancer oncologists "are beginning to understand which approaches may be effective for particular subsets of patients."

Dr. Leslie Ford of NCI's Division of Cancer Prevention noted that "Breast cancer is an exceedingly complex disease. The more we learn about the molecular underpinnings of the disease, the better we will understand how a healthy eating pattern and exercise may contribute to a reduction in risk for some women."

Regarding the colorectal study, lead author Dr. Shirley A.A. Beresford of the University of Washington in Seattle and colleagues also say that currently planned longer follow-up "may reveal delayed benefit," though, unlike the breast cancer study, "no time trends…have been seen."

The WHI DM study is the largest randomized controlled clinical trial of low-fat dietary interventions ever conducted. Results were published in the February 8 Journal of the American Medical Association.

Leukemia Risk after Hodgkin Lymphoma Reduced in Recent Decades

The risk of developing acute myeloid leukemia (AML) after treatment for Hodgkin lymphoma (HL) has decreased over the last three decades. In the early 1980s, the chemotherapy regimen changed in a way that may have influenced the development of secondary AML in HL survivors, a new study reports.

To determine whether patients treated after 1984 have decreased risks for AML, the researchers analyzed data on more than 35,000 1-year Hodgkin lymphoma survivors who were reported to population-based cancer registries in North America and in Nordic countries between 1970 and 2001.

Of the survivors, 217 developed AML. The risks were higher for patients over age 35 at the time of their HL treatment, and if that treatment occurred between 1970 and 1984 (versus 1985-2001). The decline over time in the risk of secondary AML was particularly apparent among HL survivors who initially received any chemotherapy, the researchers report in the February 1 Journal of the National Cancer Institute (JNCI).

The analysis showed that excess absolute risk for secondary AML was highest during the first 10 years after HL diagnosis but remained elevated thereafter. Excess absolute risk is the risk that occurs in addition to the "background" risk for a disease that exists in the general population.

In the analysis, Dr. Lois B. Travis of NCI and colleagues simultaneously evaluated the effects of age, calendar year of and time since HL diagnosis, and initial course of treatment. More research is needed to correlate decreases in risk of secondary AML with changes in HL therapy because population-based cancer registries do not contain detailed data on treatment regimens or information on subsequent therapy.

The findings "demonstrate an overall reduction, although not elimination, in the burden of AML over calendar year time," the researchers write. "This likely reflects in part the changes in chemotherapy (given initially or at relapse) that were implemented over the last few decades."

IL-12 Demonstrates Unique Capabilities in Neuroblastoma Mouse Model

Immunotherapy using the cytokine interleukin 12 (IL-12) in mouse models of advanced neuroblastoma induced complete tumor regression and long-term survival in the majority of mice, NCI researchers report. In this study, the team discovered that IL-12 achieved this regression not only by improving the immune system's ability to recognize tumor cells, but also by potently inhibiting a key protein that supports tumor survival.

"This is the first evidence, to our knowledge, that IL-12 can counteract this mechanism of tumor self-defense," said the study's senior author, Dr. Jon Wigginton, of the Pediatric Oncology Branch in NCI's CCR.

In the study, published in the February 1 JNCI, the NCI team, led by Dr. Tahira Khan, discovered that IL-12 treatment inhibits the activation of Akt, a "prosurvival" protein that helps tumor cells avoid cell death, or apoptosis.

To conduct the study, the research team delivered scheduled doses of IL-12 via intraperitoneal injection to cohorts of mice bearing primary and/or metastatic neuroblastomas. In addition to assessing tumor regression and survival, the researchers treated other mice identically with IL-12 to determine IL-12's impact on the expression of pro-apoptotic genes, phosphorylated/activated Akt, and overall tumor cell apoptosis.

IL-12 administration was associated with increases in circulating levels of several pro-apoptotic cytokines, as well as potent inhibition of Akt's "prosurvival" activity. In addition, there was marked tumor cell apoptosis within the tumor microenvironment.

According to Dr. Khan, the data provide a sound preclinical rationale for the investigation of IL-12 in children with neuroblastoma and suggest that IL-12 might be an excellent choice for combination therapy with specific targeted Akt inhibitors.

Researchers Use Systems Biology Approach to Cancer Drug Development

As researchers gain a greater understanding of the complexity of the molecular events leading to the development of cancer, more interest has been shown in using systems-biology approaches to develop targeted cancer therapeutics. These approaches treat cancer as a complex biological system that can be modeled to provide predictions of behavior, prognosis, and response to therapy. Two papers published in the January 19 Nature highlight results obtained from systems-biology-based examinations of cell-signaling deregulation.

One study, from the NCI-funded Integrative Cancer Biology Program (ICBP) center at Duke University, examined whether a cancer cell's unique gene expression signature can indicate which oncogenic signaling pathways are activated, and if that signature can be used to guide treatment targeting those pathways.

The researchers used recombinant adenoviruses to activate known oncogenic pathways in human cell cultures, and detected the expressed genes that were highly correlated with each active pathway by using microarray analysis. These gene-expression signatures were then tested in mouse models with similar oncogenic pathway mutations. The signatures determined from human cells correlated with the matching mutations in the mouse models.

The signatures were then used to predict pathway deregulation in a series of breast cancer cell lines before treatment with drugs targeting those pathways. In each case there was a close correlation between the probability of pathway deregulation and the response to the targeted drugs.

A second paper in the same issue of Nature examined the variations in mutations of a known oncogenic pathway. A team lead by investigators from Memorial Sloan-Kettering Cancer Center, and including Dr. Todd Golub, ICBP center director at Dana Farber Cancer Institute, focused on mutations in the genes that encode RAS and BRAF, two signaling proteins in the MEK-ERK signaling pathway, which is known to be deregulated in many tumor types. The investigators originally hypothesized that cells with either mutation would become dependent on aberrant signaling downstream in the pathway, and that inhibition of MEK in cells with either mutation would stop cell growth.

RAS-mutant cells and BRAF-mutant cells were both treated with CI-1040, a selective inhibitor of MEK. Surprisingly, while BRAF-mutant cells were extremely sensitive to the drug, RAS-mutant cells were not. The investigators then tested a panel of drugs on another set of cancer cell lines with known RAF or BRAF mutations. Compounds that inhibited MEK were effective against BRAF mutants, but did not have a significant effect on RAS mutants.

The investigators proposed that RAS- and BRAF-mutant cells are probably not equally dependent on aberrant signaling mechanisms involving MEK. They concluded that any clinical trials testing MEK inhibitors must stratify patients by BRAF-mutation status.