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Mutations in Glioblastoma Multiforme Predict Response to Targeted Therapies
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Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer and one of the most resistant to treatment. The epidermal growth factor receptor (EGFR),
an important regulator of cellular signaling, is frequently mutated in GBM, and the EGFR kinase inhibitors erlotinib (Tarceva) and gefitinib (Iressa) have shown some efficacy in a subset of patients with this tumor. However, no clear correlation between mutations in the EGFR kinase domain and response to these drugs has been found.
A study, funded in part by NCI and reported in the November 10 New England Journal of Medicine, sheds new light on the molecular pathways associated with the response of GBM to EGFR kinase inhibitors. Investigators analyzed tumor tissue from patients with GBM who did or did not respond to treatment with erlotinib or gefitinib, and verified their results using several different molecular techniques. As in previous studies, neither mutations in the EGFR kinase domain nor amplification of EGFR were associated with the response to the drugs. However, expression of a mutant version of EGFR, known as EGFRvIII, and expression of the tumor-suppressor protein PTEN both corresponded favorably with response. Coexpression of both proteins correlated with the greatest likelihood of response. Lack of PTEN expression corresponded to resistance to the inhibitors.
A perspective in the same issue called the results "an important first step in rational, tumor-specific therapy for glioblastoma multiforme."
Pancreatic Cancer Vaccine Tested in Phase II Trial
An experimental vaccine to be administered along with standard treatments for pancreatic cancer may have prolonged the survival of some patients with the disease, according to preliminary results from a phase II clinical trial. The vaccine is designed to boost a patient's immune response against cancer cells that have survived surgery, chemotherapy, and radiation.
In the study, 88 percent of the 56 patients tested were alive 1 year after treatment, and 76 percent were alive after 2 years. By comparison, the historical survival rates are approximately 60 and 40 percent, respectively. Drs. Daniel Laheru and Elizabeth Jaffee of the Johns Hopkins Kimmel Cancer Center led the trial.
Although the results are preliminary, they compare "very favorably" with the available published data, the researchers said last week at the Molecular Targets and Cancer Therapeutics International Conference in Philadelphia. Drs. Laheru and Jaffee intend to begin multi-institutional trials of the vaccine in about a year.
Patients in the study received one vaccine injection about 8 to 10 weeks after surgery, and then four booster shots along with chemotherapy and radiation over the next few months. The vaccine was made from irradiated pancreatic cancer cells that cannot grow and have been genetically altered to secrete a molecule called GM-CSF, which is capable of inducing antitumor immune responses in some patients.
Pancreatic cancer is the fourth-leading cause of cancer-related deaths in the United States. Each year, approximately 30,000 Americans are diagnosed with the disease, and about the same number die from it.
Higher Calcium Intake Increases Prostate Cancer Risk
Men with the highest levels of dietary calcium intake had nearly double the risk of developing prostate cancer compared with men who had the lowest intake of calcium, according to results from a large study that NCI researchers reported November 1 during a conference of the American Association for Cancer Research in Baltimore.
Researchers with NCI's Division of Cancer Epidemiology and Genetics (DCEG) reported the latest findings from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, conducted on a cohort of 29,133 male smokers in Finland aged 50 to 69 years. Although the study mainly focused on whether dietary supplements of vitamin E and beta-carotene reduced cancer risk, it also examined a suspected link between consumption of dietary calcium
and dairy products, and prostate cancer risk.
After 17 years of follow-up, there were 1,269 cases of prostate cancer in the cohort. "Dietary calcium intake of more than 1,000 mg/day - about 3 cups of milk - compared to intake of less than 1,000 mg/day was positively associated with prostate cancer risk," said lead author Dr. Panagiota N. Mitrou with DCEG. "The highest risk was seen among men who consumed more than 2,000 mg/day, almost doubling the risk."
They also found increased risk from dairy products. "Although this association largely disappeared when we controlled for calcium, we could not completely exclude an independent role for dairy products," Dr. Mitrou added. The study found no links between intakes of vitamin D or phosphorus and prostate cancer risk.
Given calcium's potential beneficial effects on osteoporosis and colorectal cancer, the DCEG scientists urge further research within other large prospective studies, examination of other noncalcium components of dairy products, and investigation of the molecular mechanisms of calcium
metabolism and ways in which they could modulate prostate carcinogenesis.
NSAIDs Reduce Risk of Esophageal Cancer
Regular use of aspirin and similar painkillers reduces the risk of developing esophageal cancer, according to a prospective study from Fred Hutchinson Cancer Research Center. The development is important, the authors write, because incidence of the disease has risen sharply of late.
The researchers followed 350 people with a condition called Barrett's esophagus, an abnormality of cells in the throat. About 10 percent of people with gastroesophageal reflux disease develop the precancerous condition, and about 1 percent of those
go on to develop esophageal cancer.
During regular checkups, researchers performed endoscopies and biopsied throat cells in the areas that showed signs of Barrett's esophagus. Pathologists reviewed the biopsies and determined if the cells had turned cancerous.
The researchers collated that data with survey results asking about the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Volunteers were classified as never users, current users (had used an NSAID at least once a week for 6 months), and former users (those who previously used NSAIDs but had not in the preceding year).
In the November 8 online edition of Lancet Oncology, the researchers reported that the 5-year cumulative risk for esophageal cancer was 14.3 percent for never users, 9.7 percent for former users, and 6.6 percent for current users.
Previous research has shown NSAIDs to be effective in reducing the risk of colon cancer in people with risk factors such as polyps.
Cetuximab Plus Radiation Proving Effective in HNSCC
Updated results from an international phase III trial testing cetuximab (Erbitux) plus radiation therapy in patients with head and neck cancer continue to show favorable results.
The 424 patients in the study had locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC). With a median of 45 months of follow-up, the addition of cetuximab to radiation improved median duration of locoregional control - the study's primary endpoint - by 9.5 months, and improved median survival by 20 months, compared with patients treated with radiation alone (49 months vs. 29 months). The results were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Philadelphia.
According to ImClone Systems, which manufactures the drug, the Food and Drug Administration (FDA) has accepted for priority review an application to approve the drug for marketing for this indication. Cetuximab, an antibody that blocks EGFR, is already approved by the FDA for use in combination with irinotecan to treat patients with metastatic colorectal cancer.
Initial results from the trial were presented at the American Society for Clinical Oncology Annual Meeting in 2004.
"If approved by the FDA," says Dr. Scott Saxman, from NCI's Cancer Therapy Evaluation Program, "this will become a standard for patients who cannot tolerate or are marginal candidates for cisplatin-based chemotherapy."
But it's not known, he adds, whether cetuximab can eventually replace chemotherapy, or should be given in addition to chemo and radiation to improve outcomes. NCI is funding a Radiation Therapy Oncology Group-led, phase III clinical trial, which began enrolling patients today, that will compare a standard regimen of radiation and cisplatin to the same regimen plus cetuximab in patients with locally advanced head and neck carcinomas.
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