Studies Examine Racial Disparity in Survival Among Endometrial Cancer Patients

NCI researchers, in conjunction with Walter Reed Army Medical Center and other institutions, have completed two studies that suggest biological factors can contribute to the disparity in endometrial cancer survival rates between African Americans and Caucasians. Both studies were presented at the Society of Gynecologic Oncologists 2005 Annual Meeting on Women's Cancer, March 19-23, 2005, in Miami.

In the first study, the researchers compared the survival rates for 168 African American and 997 Caucasian women with advanced or recurrent endometrial cancer who were enrolled in one of four trials performed by the NCI-funded Gynecologic Oncology Group. The analysis showed that, in a setting where all patients received equal care, African American women have a 25 percent greater chance of dying than Caucasian women with the same diagnosis.

In the second study, the investigators evaluated global gene expression for a small cohort that included 18 African American and 27 Caucasian women with endometrial cancer. They looked for any specific differences that may account for biological disparity. In the initial analysis, the researchers could not identify expression profiles unique to each race. However, when they excluded early-stage cancers and focused only on advanced-stage cancers, they observed expression profiles that did cluster according to race.

Although based on a small number of patients, author Dr. Larry Maxwell, LTC, of Walter Reed's Department of Obstetrics and Gynecology and NCI stated, "Both of these studies suggest that underlying molecular differences may partially explain the disparity in survival outcome for endometrial cancer for these two groups."

Medicare Adds Coverage of Smoking Cessation Services

The Centers for Medicare and Medicaid Services (CMS) announced March 23 that it is adding coverage for smoking and tobacco use cessation counseling for certain Medicare beneficiaries to help them quit the habit.

The coverage decision, which was proposed for public comment in December, involves Medicare beneficiaries who have an illness caused or complicated by tobacco use, including heart disease, cerebrovascular disease, lung disease, weak bones, blood clots, and cataracts - diseases that account for the bulk of Medicare spending today. It also applies to beneficiaries who take certain medications, including insulin and medicines for high blood pressure, blood clots, and depression, the effectiveness of which is complicated by tobacco use.

"Covering smoking and tobacco use cessation counseling for seniors has great potential to save and improve lives for millions of seniors," said Dr. Mark B. McClellan, CMS administrator. "This is another step in turning Medicare into a prevention-oriented health program."

The Centers for Disease Control and Prevention has estimated that 9.3 percent of Americans aged 65 and older smoke cigarettes. About 440,000 people die annually from smoking-related disease, with 300,000 of those deaths in smokers aged 65 and older. Research has shown that smoking cessation has significant health benefits, even after decades of smoking.

This announcement builds on a series of HHS initiatives designed to help Americans quit smoking, including the launch of a new national network of quitlines (1-800-QUITNOW) and designating all HHS campuses as tobacco-free. Medicare's upcoming prescription drug benefit will also cover smoking cessation treatments that are prescribed by a physician.

FDA Guidance Aimed at Expanding Individualized Medicine

The Food and Drug Administration (FDA) has issued a final guidance on the submission of genetic data associated with drugs and biologics under clinical investigation or being reviewed by the agency for marketing approval. The guidance document on the submission of such pharmacogenomic data, explained Dr. Janet Woodcock, acting deputy commissioner for operations at FDA, is aimed at speeding the movement toward personalized medicine.

Researchers increasingly are relying on sophisticated genetic tests to root out gene expression profiles that correlate with a drug's efficacy or toxicity. Increased collection of pharmacogenomic data, Dr. Woodcock said, "will allow medicines to be uniquely crafted to maximize their therapeutic benefits and minimize their potential risks for each patient."

Cancer is an area in which pharmacogenomics already is playing an expanded role. Tests are available to determine whether patients with metastatic breast cancer, for instance, overexpress the HER-2 gene, making them candidates for the targeted agent trastuzumab (Herceptin). The FDA also recently approved the first laboratory test to look for gene variations that are predictive of how well a patient will metabolize drugs for a broad range of conditions, including cancer.

Pharmaceutical and biotechnology companies have been reluctant to collect and submit pharmacogenomic data to the FDA, the guidance explains, "because of uncertainties in how the data will be used by the FDA in the drug review process." The final guidance is intended to address industry concerns by clarifying how pharmacogenomic data will be evaluated, including what data will be required for regulatory decision making, as well as details on a new mechanism for industry to voluntarily submit pharmacogenomic research data that can help advance this relatively new area of research.

Researchers Find Genetic Link Between Blood Clotting Disorders and Cancer Onset

Researchers at the University of Turin Medical School have discovered that the MET oncogene can trigger both tumor development and blood clotting problems in mice. This finding, appearing in the March 17 Nature, provides the first genetic link to a 140-year-old enigma: the close relationship between the activation of blood coagulation and cancer.

Dr. Carla Boccaccio and colleagues engineered mice to overexpress the MET oncogene in adult liver cells. Three months after MET activation, the mice began displaying multiple, abnormally growing nodules in their livers, indicating the onset of tumors. However, even before the first nodules appeared, all of the engineered mice began developing numerous venous blood clots and internal hemorrhages. Most of the mice died after 6 months as a result of these blood disorders, while the few that survived developed hepatocarcinomas.

The researchers found that MET activation increased the activity of many blood clotting genes, including a significant increase in production of two key enzymes: PAI-1 and COX-2, both of which have been associated with cancer. Treating the mice with the COX-2 inhibitor rofecoxib both reduced the severity of the blood clotting and increased degeneration of the precancerous nodules.

Previous studies had demonstrated that MET activation could help drive tumor invasion and metastasis, and the authors suggest that MET's control over the blood clotting pathway is likely interdependent. "Oncogenic activation of MET triggers a genetic programme that not only transforms cells but also creates an extracellular environment that is fertile for tumor cell expansion and invasion," the authors wrote.

Enzyme Mutations Improve Aspirin's Protection Against
Colorectal Cancer

A genetic mutation that impairs the body's ability to metabolize aspirin appears to decrease the risk of colorectal cancer among women who regularly use aspirin, researchers from Harvard University and Massachusetts General Hospital report. The research team conducted a nested, case-control study of participants in the long-running Nurses' Health Study. They found that, among women with a common variant polymorphism in the UGT1A6 enzyme, which plays a key role in aspirin metabolism, regular aspirin use was associated with a 34 percent decreased risk of colorectal adenoma compared with nonregular users. Regular aspirin use among those with the normal, or wild-type, enzyme was not associated with reduced risk.

A number of studies have indicated that regular aspirin use can reduce the risk of colon polyps, established precursors to colorectal cancer. Two randomized, controlled clinical trials published in 2003 in the New England Journal of Medicine, for example, showed regular aspirin use reduced the development of colorectal polyps among those at high risk of colorectal cancer by as much as 35 percent.

In the new study, published in the March 16 Journal of the National Cancer Institute, the risk reduction associated with regular aspirin use in participants with UGT1A6 polymorphisms was greater at higher aspirin doses. As with lower doses, higher doses had no benefit for regular aspirin users with the wild-type enzyme.

"Certain subsets of the population, defined by genotype, may obtain differential benefit from aspirin chemoprevention," Dr. Andrew T. Chan and colleagues concluded. Whether UGT1A6 polymorphism status should influence who should receive aspirin for chemoprevention - and at what dose - remains uncertain, they added, and should be addressed in larger studies.