International Mammography Performance Compared
A survey of international mammography practices shows that the percentage of screened women recalled for further testing does not correlate with the rates of cancer detection. The study, appearing in the current Journal of Medical Screening, found that countries with lower recall rates had fewer false-positive results and therefore increased the predictive value of further clinical visits. However, the rates of cancer detection by mammography were similar regardless of recall rates.
The International Breast Cancer Screening Network conducted the study to evaluate and compare recall rates across countries. Recall rates are the percentage of abnormal results that are recommended for further study. Low recall rates could reduce early detection, while high recall rates subject women to unnecessary follow-ups. The survey received results from 22 countries, each detailing how they read and interpreted mammograms. The countries varied widely in their methods of screening, data collection, and image interpretation. In fact, no single category was reported the same way by every country.
These differences translated into variances among recall rates, from 1.4 percent in the Netherlands to 15.1 percent in the United States. Some similarities between countries were found; recall rates generally were higher for initial screenings versus subsequent screenings, and also decreased with patient age. Cancer detection rates ranged from 3.7-10.6 per 1,000 mammograms, but did not follow the pattern of recall rates.
The authors concluded that a more standardized approach to mammography would allow for more valid international comparisons, which could potentially lead to finding optimal mammography recall rates.
Researchers at Chosun University in South Korea have demonstrated that the Bcl-2 protein, which is known to prevent programmed cell death, can also inhibit cell growth. The study, appearing in the December 26 online issue of Nature Cell Biology, shows that a major consequence of Bcl-2-mediated cell growth arrest is suppression of the cell's DNA mismatch repair mechanism. This discovery illustrates another pathway for Bcl-2 carcinogenesis and also shows that senescent cells are at high risk for becoming cancerous.
As cells grow and divide, their DNA is constantly at risk for developing mutations. One type of mutation occurs when complementary DNA base pairs become mismatched, due either to replication errors or to external agents such as radiation. Normally, cells have a system in place to repair these errors, but Dr. Ho Jin You and colleagues showed that, in cell culture, Bcl-2 can suppress the expression of the MSH2 protein, a key component of mismatch repair. The loss of this repair protein is related to Bcl-2 inhibition of other proteins involved in cell growth. "This suggests that the Bcl-2-mediated cell cycle arrest might induce genetic instability," noted the authors.
These findings show that Bcl-2 expression might promote carcinogenesis by reducing a cell's ability to repair DNA damage and by preventing apoptosis once the cell starts to become cancerous. They also link the end of cell growth with the beginning of cancer, which may help explain the dramatic increase in cancer incidence with age.
The targeted agent gefitinib (Iressa) failed to improve survival compared with placebo in a clinical trial with nearly 1,700 patients with advanced non-small-cell lung cancer (NSCLC), the drug's manufacturer, AstraZeneca, reported on December 17. Although there was a statistically significant improvement in tumor shrinkage, there was no statistically significant improvement in survival compared with placebo (median 5.6 months vs. 5.1 months). All patients in the trial, called ISEL, had advanced NSCLC that had progressed after one or two lines of chemotherapy. "The trial was well designed, the data are robust, and there is no methodological explanation for these findings," said Dr. Nick Thatcher, the study's principal investigator.
The U.S. Food and Drug Administration (FDA) cleared gefitinib for marketing in May 2003 under an accelerated approval mechanism. The approval was based on trial results showing the drug could significantly shrink tumors in approximately 10 percent of patients. Under the accelerated approval, AstraZeneca was required to conduct follow-up studies to determine whether gefitinib could extend survival. In a statement, FDA said it will determine whether gefitinib should be withdrawn from the market after the agency has fully evaluated the study results. Both the FDA and AstraZeneca recommended that patients currently taking gefitinib not change their therapies without consulting their physicians.
In the United States, the FDA has approved three drugs for second-line therapy in patients with NSCLC: erlotinib (Tarceva), docetaxel (Taxotere), and pemetrexed (Alimta). According to Dr. Scott Saxman, a senior investigator in the NCI Cancer Therapy Evaluation Program, NCI is thoroughly evaluating data from the ISEL trial as it becomes available and is working closely with trial investigators and the company to determine how the results should influence the current clinical trials involving gefitinib.
Carcinoembryonic antigen (CEA), a protein linked to metastasis, is overexpressed in a variety of cancers, including most found in the colon, breast, lung, stomach, and pancreas. In previous trials testing CEA vaccines made with recombinant vaccinia or fowlpox viruses, patients with advanced cancers showed an immune response that eventually tapered off. Research has shown, however, that costimulation of the immune system with three molecules known collectively as TRICOM can enhance the efficiency of vaccines. In light of this, a team from Georgetown University Medical Center, Therion Biologics Corporation, and the Laboratory of Tumor Immunology and Biology at NCI's Center for Cancer Research tested the first-ever vaccine that combines CEA antigen with TRICOM. Their results were published ahead of print, Dec. 21, 2004, in the Journal of Clinical Oncology.
The researchers enrolled 58 patients who had advanced CEA-expressing cancers and administered a regimen that included CEA-TRICOM vaccine made with fowlpox, either alone or in combination with CEA-TRICOM vaccine made with vaccinia. After 4 months, 40 percent of patients had stable disease; more than half of these maintained stability beyond 6 months. Eleven patients showed decreased or stable serum CEA levels, and one patient had a pathologic complete response. While the phase I nature of the study prohibits claims about overall and progression-free survival, Dr. Jeffrey Schlom, an NCI author, noted, "Patients who received both the vaccinia CEA prime vaccination and the fowlpox-CEA booster vaccinations showed a better response than those who received the fowlpox-CEA vaccine. Prolonged survival also correlated with immune response to the vaccine."