The Academy: June 2007

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â–º The University of Texas M.D. Anderson Cancer Center, Houston

Assessment Model for Lung Cancer Risk

Researchers at The University of Texas M.D. Anderson Cancer Center in Houston, TX have developed a model that could help clinicians assess which smokers are at higher risk for developing lung cancer. It is the first to use standard clinical and epidemiological data such as smoking habits; exposure to environmental tobacco smoke; family history of cancer; hay fever; and exposure to dust or asbestos.

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Smoking is the primary cause of 85% of all lung cancers, less than 20% of lifetime heavy smokers actually develop lung cancer, the study’s lead author Margaret Spitz, MD, professor and chair of the department of epidemiology at M.D. Anderson told . “It is important to be able to identify high risk subgroups of smokers for intensive smoking cessation and screening interventions,” she said. “More importantly, we could intensively screen this population with modalities that might not be appropriate for the average at-risk population.”

The new model assigns a score that represents a patient’s estimated risk for developing the disease. Clinicians can use the new model to compute a patient’s ordinal risk score and the patient’s absolute chance of developing lung cancer within a year. They can then classify patients into high-, moderate-, or low-risk groups. Currently, the model’s prediction accuracy is about 60%, which is on par with that of the Gail model for breast cancer, according to the researchers. The researchers are in the process of developing a web-based version of their tool, which Dr. Sptiz said will be available for clinicians soon.

Dr. Spitz and colleagues developed and tested the new model by comparing the medical history of 1,851 lung cancer patients with the same data from 2,001 healthy people. The population included current and former smokers as well as people who had never smoked. The researchers divided the cases and controls into two groups. They used one for building the model and the second for testing and validating the model.

The key risk factors in the targeted groups were predictable in some cases. For example, in people who had never smoked, the risk came from exposure to secondhand smoke and family history of cancer. But in current and former smokers, the researchers found that there was a strong impact of a prior history of emphysema as a risk factor.

â–º Dana-Farber Cancer Institute and Harvard Medical School, Boston

Diabetes Drug Boosts Efficacy of Platinum Chemotherapy Agents

Cancer Cell

A widely used diabetes drug and a platinum-based chemotherapy drug have proven to be a potent combination in targeting cancer when administered together to a variety of cancer cell lines and to mice with tumors, according to a study published in the May issue of . Researchers at the Dana-Farber Cancer Institute in Boston, MA reported in the study that a combination of carboplatin and the diabetes drug Avandia (rosiglitazone maleate) was as much as three times more effective at halting or shrinking mouse tumors than either drug given alone.

The drug combination could improve control of ovarian, lung, and other cancers that are typically treated with platinum-based drugs, to which tumors eventually develop resistance, the researchers said.

Avandia, which enhances the sensitivity of insulin receptors in diabetics, was approved in 1999 for use by patients with type 2 diabetes. The drug works by activating PPAR-gamma, a transcription factor that acts as a master regulator of fat development in the body. Bruce Spiegelman, PhD, professor of cell biology at the Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA, and his colleagues had discovered this function of PPAR-gamma in 1994. They had also found that certain PPAR-gamma-activating compounds halted cancer cell growth and differentiation.

Since previous studies had shown that rosiglitazone alone was ineffective against various cancers, the researchers tried these agents in combination with platinum-based chemotherapy agents. They also tested a similar diabetes drug pioglitazone and an experimental compound by GlaxoSmith¬Kline, combining these drugs with the commonly used chemotherapy agents cisplatin, carboplatin and oxalyplatin.

Dr. Spiegelman and his colleagues found that treating non small-cell lung cancer cell lines with rosiglitazone alone did not have any effect on growth, while carboplatin alone reduced cell growth by 60%. But when used together, the drugs reduced cell growth by 80%. The drug combination reduced ovarian cancer cell growth by 90%, and even reduced the growth of colorectal cancer cells by 70%—colorectal cancer is not usually treated with platinum drugs. Moreover, the drug combination dramatically suppressed tumor growth when administered to mice with human lung and ovarian tumors implanted under their skin.

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University of Wisconsin-Madison Medical School

Virtual Colonoscopy Safer and More Cost-efficient than Optical Colonoscopy

Using virtual colonoscopy as a primary screening tool for detecting colorectal cancer polyps is a safer and more cost-effective option than using optical colonoscopy, according to a new study published in the June 1 issue of the journal Cancer. Previous cost-effectiveness studies falsely assumed that virtual colonoscopy would detect diminutive polyps—those that are 5 millimeter or smaller in size. But targeting these small lesions that have a low malignancy rate costs more, causes complications, and gives a minimal reduction in colorectal cancer incidence.

For the past few decades, physicians have primarily used optical colonoscopy and flexible sigmoidoscopy as screening tools. These methods are associated with complications ranging from abdominal pain to life-threatening bowel perforation and bleeding. Virtual colonoscopy, or computed tomography colonography (CTC) gets rid of these problems and is better tolerated by patients. It uses x-rays and imaging software to develop two- and three-dimensional images of the gastrointestinal tract.

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“Primary care physicians should be aware that CTC is both a safe and highly effective colorectal cancer screening test,” the study’s lead researcher Perry Pickhardt, MD, a radiologist at the University of Wisconsin-Madison Medical School told . “Offering patients an additional effective option has the potential to significantly increase screening compliance for this deadly but readily preventable disease.”

Dr. Pickhardt and his colleagues used a mathematical model, based on 100,000 people over 50 years old, to evaluate the clinical and economic impact of CTC compared to the two commonly used methods. They found that all three tools were cost-effective compared with no screening, with each costing less than $10,000 for each additional year of life gained. At $7,138 per year of life gained, virtual colonoscopy was the least expensive. It was followed closely by flexible sigmoidoscopy at $7,407, while optical colonoscopy was the least favorable option economically costing $9,180 per year of life gained. Moreover, the researchers found that CTC was even more economical when it was used to target and remove only polyps larger than 6 millimeters—it cost $4,361 per year of life gained. Targeting smaller polyps led to considerable complications, and did not improve screening efficacy, reducing colorectal cancer incidence by a mere 1.3%.

“Now that CTC has been clinically validated for screening and as a highly cost effective approach, widespread implementation is the next logical step,” said Dr. Pickhardt. “However, reimbursement coverage by Medicare and other third-party payers is needed before such implementation is achievable.”

â–º Johns Hopkins University School of Medicine, Baltimore

New Blood Test for Prostate Cancer Screening

Researchers have developed a new screening test for prostate cancer based on a blood protein they have recently identified. The protein, called early prostate cancer antigen-2 (EPCA-2) might pave the way for more accurate screening and diagnostics for prostate cancer, the researchers said.

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The current standard in screening is prostate-specific antigen (PSA) tests combined with a digital rectal examination. But PSA screening leads to false positives and false negatives more often than the new test, according to the researchers. “In a number of published studies, PSA has a false positive rate of 75% to 80% and a false negative rate of about 15 percent,” Robert Getzenberg, PhD, professor of urology at the Johns Hopkins University School of Medicine in Baltimore, MD who led the work told . “Our studies on EPCA-2 demonstrate that we have false positives 3% of the time and false negatives 6% of the time.” According to Dr. Getzenberg, elevated PSA levels lead to prostatic biopsies in approximately 1.6 million men in the U.S. every year, and about 80% of these men have negative results.

Dr. Getzenberg and his colleagues demonstrated the effectiveness of an EPCA-2 blood test in the April issue of Urology. The research team measured EPCA-2 levels in the blood of 330 Hopkins patients separated in several different groups: men with normal PSA levels and no evidence of disease; men with elevated PSA levels who had negative biopsies; men with benign prostatic hypertrophy who did not receive biopsies; men with prostate cancer but normal PSA levels; men with confined prostate cancer; men with prostate cancer that had spread outside the gland; and men with benign conditions of other organs as well as those with other cancers.

The researchers found that the EPCA-2 test—based on a 30 nanograms per milliliters threshold, above which patients were considered to be at risk—was negative in 97% of patients who did not have prostate cancer. The test accurately identified 94% of the men with the disease. Levels of EPCA-2 at or above the threshold were seen in 90% of the men with organ-confined cancer, and in 98% of men with disease that had spread. The protein levels were also significantly higher in men with non-organ-confined cancer compared to those whose cancer was localized. Because of this, the EPCA-2 levels were found to be 89% accurate at differentiating between these two groups compared to the PSA test, which in the study was 63% accurate, according to Dr. Getzenberg.

The researchers are currently in the process of performing additional validation studies for this test. “We have also licensed this to a company, Onconome Inc., that is working on making it commercially available,” said Dr. Getzenberg. “We are hoping to have this test available for patient use in the next couple of years.”

â–º Radcliffe Infirmary, Oxford, UK

Aspirin Use Can Prevent Colorectal Cancer

The Lancet

A new study published in the May 12 issue of concludes that the use of 300 milligram of more of aspirin a day for five years can prevent colorectal cancer. The study’s authors caution that the widespread use of aspiring for cancer prevention cannot be recommended in the general population because of the availability of alternative prevention strategies and the potential risks of long term aspirin use at this dose. But the benefits of aspirin are likely to outweigh the risks in people who are at an increased risk of colorectal cancer.

The researchers, led by Peter Rothwell, a professor in the Department of Clinical Neurology at the Radcliffe Infirmary in Oxford, UK, followed up patients from two large randomized trials of aspirin—the British Doctors’ Aspirin Trial and the UK-TIA Aspirin Trial—that were conducted in the late 1970 and early 80s. They found that the use of aspirin for five years reduced the incidence of colorectal cancer by 37% overall and by 74% 10 to 15 years after the treatment was started.

“Long-term follow up is required from other randomised trials to establish the effects of lower or less frequent doses of aspirin,” Dr. Rothwell and his colleagues wrote in the study.

â–º James Cancer Hospital and Solove Research Institute, Ohio State University, Columbus

Molecular Marker for Pancreatic Cancer

Journal of the American Medical Association

The expression pattern of microRNA may help clinical oncologists to distinguish between chronic pancreatitis and pancreatic cancer, and may even be used to predict long- and short-term survival time for pancreatic cancer patients, according to a study in the May 2 issue of .

Researchers know that the abnormal expression of microRNAs contributes to carcinogenesis either by promoting the expression of proto-oncogenes, normal genes that have the potential to become oncogenes, or by inhibiting the expression of tumor suppressor genes. But so far, no one understands the role of microRNAs in forming malignant tumors in the pancreas.

A research team led by Mark Bloomston, MD, from the James Cancer Hospital and Solove Research Institute at Ohio State University in Columbus, Ohio, conducted a series of experiments to identify the pattern of microRNA expression in pancreatic tumors. The researchers obtained microRNA from pancreatic tumor tissue, benign pancreatic tissue and chronic pancreatitis. They analyzed the RNA to identify associations between disease prognosis and certain tissue types.

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From the global expression pattern of microRNAs, the researchers could distinguish adenocarcinomas from normal pancreatic tissue in 90% of cases, and from chronic pancreatitis with 95% accuracy. Further, they could use a subgroup of six microRNAs to differentiate between long-term survivors with node-positive disease and patients who would succumb within 24 months. Finally, they found that high expression of a certain microRNA predicted poor survival. “We have shown that not only are microRNAs important in the pathogenesis of pancreatic cancer, they also appear to help predict the biologic behavior,” Dr. Bloomston told . While these findings are very early and require validation, “they are encouraging that microRNAs might help us clinically to understand what makes pancreatic cancer so aggressive and resistant to therapy,” he added. The results provide “an initial glimpse into the future of clinical oncology,” authors of an accompanying editorial wrote in JAMA. According to Dr. Bloomston, “clinicians should take away from this encouragement that this new class of genes, once validated, may offer a new method of diagnosis, prognosis, and treatment for pancreatic cancer. These possibilities are still years away…but not decades.”