Interim results from the first large-scale randomized clinical trial testing an intervention to reduce dietary fat intake as part of postsurgical breast cancer management have shown that women who reduce their consumption of fat after treatment for early-stage breast cancer may also reduce their risk of recurrence. This report from the NCI-sponsored Women's Intervention Nutrition Study (WINS) was published in the December 20 Journal of the National Cancer Institute.
Between 1994 and 2001, WINS investigators recruited 2,437 women with invasive breast cancer who were between the ages of 48 and 79 at the time of enrollment into the study. At the start of the study, both groups consumed similar amounts of calories from fat. At the end of the first year of observation, the women in the dietary intervention group had reduced their fat intake by an average of 23 grams per day compared with only a 5-gram-per-day drop in the control group.
The difference between the two groups was maintained throughout the trial. By the fifth year of the trial, the women in the intervention group weighed an average of 6 pounds less than the women in the control group. After a median of 5 years of follow-up, breast cancer had recurred in 9.8 percent of the women on the low-fat diet and 12.4 percent of those on the standard diet. This amounted to a 24-percent reduction in the relative risk of recurrence for the women on the low-fat diet.
The authors acknowledge several limitations to their study, including the possibility that weight loss in the intervention group or other dietary factors may have influenced the outcome. However, stated lead author Dr. Rowan Chlebowski of the Los Angeles Biomedical Research Institute in an accompanying press release, "Although further confirmation is needed…these results suggest that an intervention aimed at reducing dietary fat consumption can reduce the risk of breast cancer recurrence."
Bevacizumab with Platin-Based Chemo Improves NSCLC Outcomes
The results of a phase III study performed by the Eastern Cooperative Oncology Group show that when the monoclonal antibody bevacizumab is added to a paclitaxel-carboplatin chemotherapy regimen for patients with non-small-cell lung cancer (NSCLC), their overall survival, progression-free survival, and response rates significantly increase. These benefits, however, are tempered by an increased risk of treatment-related death. Study results were published December 14 in the New England Journal of Medicine.
Researchers recruited 878 patients with recurrent or advanced NSCLC, excluding those with squamous-cell tumors, brain metastases, or who were coughing blood or bloody sputum. Nearly half of the participants received paclitaxel and carboplatin every 3 weeks for 6-week cycles, while the remaining group received bevacizumab every 3 weeks in addition to the same chemotherapy, until their disease progressed or the side effects became intolerable.
Regardless of baseline vascular endothelial growth factor levels, the results showed that patients who received bevacizumab had a median overall survival of 12.3 months, compared with 10.3 months for those who did not. Also, 35 percent of patients who received the bevacizumab showed a response to treatment, compared with 15 percent in the group that did not receive it. These results are expected to change clinical management of NSCLC patients.
The authors note that the risks of side effects, including neutropenia, pulmonary hemorrhage, and toxicity, should be weighed against the survival benefit conferred by adding bevacizumab to NSCLC chemotherapy.
Study Suggests Viruses Play Larger Role in Cancer
A new study suggests that common viral infections may play a larger role in cancer than has been previously thought. The nearly 29,000-participant population-based cohort study, conducted in Australia, found a significantly increased risk of 25 different cancers following kidney transplantation, including a more than threefold risk for 18 of those cancer sites.
The study authors argued that the immune system suppression required to carry out a kidney transplant was behind this increased risk, demonstrating a broader role of "common viral infections in the etiology of cancer."
Published in the December 19 Journal of the American Medical Association, the study included participants with end-stage kidney disease (ESKD) enrolled in an Australian dialysis and transplant registry between 1982 and 2003. They evaluated cancer incidence during three periods: the 5 years before participants started to receive therapy related to eventually undergoing a kidney transplant, the time from dialysis initiation to a first transplant, and from the date of the first transplant forward.
In addition to the increased risk following transplantation, a significant increase in the incidence of nine cancers also was seen during dialysis, with a greater than twofold increase for seven of them.
Analyzing the three separate time periods, the authors argued, "demonstrates that preexisting personal cancer risk factors, and factors related to primary renal disease, ESKD, or dialysis can be excluded as major contributors to the posttransplantation excess risk."
Zoledronic Acid Decreases Aromatase Inhibitor-Induced Bone Loss
Preliminary results from two randomized clinical trials published online December 11 in theJournal of Clinical Oncology indicate that zoledronic acid can prevent treatment-induced bone loss in both premenopausal and postmenopausal women taking aromatase inhibitors after surgery for hormone-receptor-positive breast cancer.
The first study tested whether zoledronic acid could prevent treatment-induced bone loss in premenopausal women undergoing hormonal suppression with an aromatase inhibitor or tamoxifen and the drug goserelin after surgery for early-stage hormone-receptor-positive breast cancer. All patients underwent bone densitometry of the lumbar spine and the upper part of the thigh bone at the start of the study and after 6, 12, and 36 months of treatment.
After 36 months of treatment, patients receiving anastrozole without zoledronic acid lost 17.4 percent of the bone mass in their lumbar spine and 11.3 percent in their thigh bone. Bone-mineral density remained stable in patients who received zoledronic acid in addition to anastrozole. No patients given zoledronic acid in addition to anastrozole developed osteoporosis of the lumbar spine, though osteopenia did increase by 15 percent from levels measured at the beginning of the study.
The second study examined whether zoledronic acid could prevent loss of bone-mineral density in postmenopausal women taking the aromatase inhibitor letrozole after surgery for invasive, hormone-receptor-positive breast cancer. All women in the ongoing trial are scheduled to receive letrozole for 5 years or until their cancer recurs, and were randomly assigned to receive zoledronic acid intravenously every 6 months starting either at the beginning of the study or delayed until bone loss reached a specified level or a nontraumatic bone fracture was observed.
All patients underwent dual-energy x-ray absorptiometry scans to measure bone-mineral density at the beginning of the study, and after 6 and 12 months of treatment. The percent change in bone-mineral density in the lumbar spine and hip was compared between patients who received upfront or delayed zoledronic acid. After 12 months of therapy, there was a mean difference in bone density of 4.4 percent in the lumbar spine and 3.3 percent in the hip between the two groups, with the upfront group retaining more of their bone density.
NCI Researchers Modify Immunotoxin for Cancer Therapy
NCI researchers have developed a genetically modified version of a Pseudomonas-based immunotoxin (PE38) that may improve its effectiveness in humans. PE38-based immunotherapy already is used to treat certain leukemias and lymphomas, and the new agent may open immunotherapy to a broader range of cancers, according to study results published in the December 15 Journal of Immunology.
Dr. Ira Pastan of the Laboratory of Molecular Biology at NCI's Center for Cancer Research (CCR) and colleagues have used recombinant DNA techniques to make immunotoxins by combining a 38 kDa piece of Pseudomonas exotoxin A (PE38) with portions of several different mouse antibodies. One of the difficulties encountered by patients who chose PE38 immunotherapy is that their own immune systems can interfere with the treatment. To investigate how PE38 provokes production of neutralizing antibodies in some patients, the researchers used the mouse as a model. Mice immunized with PE38 produced 60 different types of reactive antibodies. The researchers found that these 60 antibodies were directed to only 7 regions on PE38, and these same regions were the sites that triggered an immune response in patients.
Researchers then used the mouse antibodies to identify the specific amino acids in these seven regions that trigger the neutralizing immune response in mice. Based on this information seven mutant immunotoxins were created that did not react with the antibodies, but were able to kill cancer cells in these animals. Studies are under way to incorporate these seven mutations into a single immunotoxin molecule that is anticipated to be less reactive with the mouse's immune system during immunotherapy.
Crosstalk Between Tumor and its Microenvironment Marks Cancer Progression
A new study from NCI researchers has found that the expression of CLIC4, a protein that promotes cell death, is reduced in human cancer cells but increased in cells of the normal connective tissue, or stroma, in the tumor microenvironment.
In a study published in the January 1 Clinical Cancer Research, Dr. Stuart Yuspa, in NCI's CCR, and colleagues used tissue array analysis to compare CLIC4 protein levels in normal and tumor tissues derived from patients. In about 80 percent of all major cancer types tested, CLIC4 was absent in the nucleus of tumor cells and reduced in tumor tissue, but increased in the stroma surrounding the tissue. Decreases in CLIC4 levels in the tumor and increases in the stroma also correlated with tumor progression and disease severity.
"At the moment, we're not sure what happens in tumor cells to silence production of the CLIC4 protein, since the gene is still intact," said Dr. Yuspa. "Hopefully, once we have more information, targeting CLIC4 in the tumor, the stroma, or both, will provide new opportunities for inhibiting tumor growth."
Using a mouse model, Dr. Yuspa and his colleagues also found that increased levels of CLIC4 protein in stromal cells coincides with conversion of stromal fibroblasts to myofibroblasts. This transition involves increased levels of a second protein called α-smooth muscle actin (αSMA), which has a role in cell structure and movement. In the laboratory, myofibroblasts contribute to tumor progression by secreting enzymes and promoting the development of new blood vessels.
When the team grew fibroblasts and human tumor cells together in the laboratory in such a way that the tumor cells formed a small colony with fibroblasts surrounding them, they found that the fibroblasts in the regions immediately adjacent to the tumor cells increased their production of both CLIC4 and αSMA proteins, but fibroblasts distant from the tumor cells did not.
This observation, they explained, indicates that tumor cells somehow stimulate fibroblasts in the microenvironment to increase production of these two proteins and suggests that crosstalk between tumors and healthy tissue is essential for tumor growth.