Cancer Research Highlights
Smoking Declines Helped Prevent More Lung Cancer Deaths than Expected
Reductions in smoking have helped to save more lives from lung cancer than previously thought, an NCI-funded study has found, but many more deaths could have been averted with even greater declines in smoking. In the study, researchers in NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET) used computer models to quantify the impact of falling smoking rates on lung cancer mortality in the United States. The findings appeared March 14 in the Journal of the National Cancer Institute.
The researchers modeled three different scenarios: one based on actual smoking behaviors, one in which all smoking ceased following publication of the first Surgeon General’s report on smoking and health in 1964, and one in which smoking rates remained at the high levels that existed prior to the report’s publication (representing what might have occurred if no tobacco control policies had been implemented).
It was estimated that, on average, 795,000 deaths from lung cancer were averted between 1975 and 2000 due to actual declines in smoking. (This calculation does not include deaths from other forms of cancer or smoking-related diseases.) Had all smoking ceased in 1965—the first full year after the 1964 Surgeon General’s Report—2.5 million deaths from lung cancer would have been averted during the same period, a number slightly less than the current population of Chicago.
The estimated mortality reductions are much larger than several earlier studies predicted. “[Our study] was a much more detailed analysis” than had been performed in those earlier studies, explained study co-author Dr. Suresh Moolgavkar of the Fred Hutchinson Cancer Research Center. “We essentially reconstructed smoking histories and the associated lung cancer risks for the entire U.S. population.”
The CISNET study “should serve as a model for future analyses in public health more broadly,” wrote Dr. Thomas Glynn of the American Cancer Society in an accompanying commentary. The results, he continued, “are tantalizing—especially in the ‘what could have been’ scenario—but, more important, they give us a clear view to what should be the future of tobacco control in the United States.”
The study’s findings “show that we’ve come a long way since the first Surgeon General’s report and [have] done a very good job of reducing tobacco use,” said study co-author Dr. Eric “Rocky” Feuer of NCI’s Division of Cancer Control and Population Sciences. “But they also show that we still have a long way yet to go and cannot relax our efforts.”
Study Identifies a Mechanism behind Pancreatic Cancer Treatment Resistance
Researchers have discovered a physical mechanism that prevents chemotherapy from reaching pancreatic cancer cells, as well as a way to reverse that mechanism. Dr. Sunil Hingorani of the Fred Hutchinson Cancer Research Center and his colleagues reported their results March 19 in Cancer Cell.
Pancreatic adenocarcinoma, the most common type of pancreatic cancer, is notoriously resistant to chemotherapy and radiation therapy, leading to an overall 5-year relative survival rate of less than 5 percent. Using mice with tumors that are genetically similar to human pancreatic adenocarcinomas, the researchers found that, as the tumors grow, a thick matrix develops and surrounds the tumors’ cells.
The matrix exerts tremendous pressure on the tumors—pressure that greatly exceeds the normal pressure found within blood vessels—causing the tumors’ blood vessels to collapse. This collapse prevents chemotherapy drugs in the blood stream from reaching the tumor cells.
Dr. Hingorani and his colleagues identified a substance called hyaluronic acid that forms a large part of this pressurized matrix. When they treated the mice with an enzyme called PEGPH20, which breaks down hyaluronic acid, the pressure within the tumors returned to normal, and the blood vessels regained their normal shape and function.
When the researchers treated mice with a combination of PEGPH20 and the chemotherapy drug gemcitabine, 83 percent of tumors within the pancreas shrank after only one cycle of treatment, and all tumors shrank after three cycles. Similar responses were seen in metastatic tumors. Mice that received the combination therapy survived almost twice as long as mice that received PEGPH20 plus a placebo.
“When able to penetrate the tumor bed, gemcitabine can indeed be an effective agent against this disease,” wrote the authors. An early phase clinical trial is testing the combination of PEGPH20 and gemcitabine in people with metastatic pancreatic cancer.
Expanded Tumor Profiling Yields Clues about Acute Myeloid Leukemia
Testing the cancer cells of patients with acute myeloid leukemia (AML) for alterations in a panel of 18 genes could help doctors predict the risk of relapse for individual patients, according to a retrospective analysis of data from a large clinical trial. This approach—sometimes called cancer profiling—could also provide information about which patients may benefit most from certain treatments. The findings appeared in the March 14 New England Journal of Medicine.
Doctors use various methods to diagnose AML and to classify patients according to the risk of relapse. Some patients have their cancers profiled for alterations in three genes associated with AML. The new study suggests, however, that analyzing a larger set of genes could help doctors assign patients to more precise subgroups, with favorable, intermediate, or unfavorable risk profiles.
To reach this conclusion, Dr. Ross Levine of Memorial Sloan-Kettering Cancer Center and his colleagues profiled stored samples from nearly 400 participants in a large clinical trial led by the Eastern Cooperative Oncology Group (ECOG) and published in 2009. The researchers then validated their findings using an independent group of 104 patients from the same trial.
At least one cancer-related genetic alteration was found in 97 percent of the patients. Certain mutations tended to occur together, revealing clues to the pathways that are active in AML, the researchers noted. In addition, the expanded panel yielded better prognostic information than the one currently used in the clinic.
“Some of the newly discovered mutations substantially improved the classification of patients as having either a favorable or unfavorable risk profile,” Dr. Levine said.
He noted that profiling cancers may also inform decisions about treatment. Results from the ECOG trial showed that AML patients under 50 years of age may benefit from a higher dose of daunorubicin chemotherapy early in treatment. The new analysis, however, found that some patients benefited more than others.
Specifically, higher-dose daunorubicin chemotherapy improved survival among patients whose cancer cells had DNMT3A or NPM1 gene mutations or MLL gene translocations but not among patients with cancer cells that lacked these gene alterations. These findings need to be confirmed, the authors noted.
Future studies will seek to identify additional genetic and epigenetic events that contribute to AML. “The challenge will be to not look at each alteration as an independent variable, but instead to see whether new alterations—together with other known mutations—improve prognostic models and inform the selection of treatments,” Dr. Levine said.
The new study shows what can be learned by analyzing DNA samples and data from a completed clinical trial, noted Dr. Lucy Godley of the University of Chicago Medical Center, who wrote an accompanying editorial. “Dr. Levine essentially took samples from the freezer and used them to ask new questions about AML.”
Updated European Prostate Cancer Screening Trial Data Show Little Change in Risk Reduction
After 11 years of follow up, results from a large European clinical trial continue to show a reduced risk of death from prostate cancer associated with prostate specific antigen (PSA) screening. The findings, from the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, show a 21 percent relative reduction in prostate cancer mortality among men who underwent routine PSA screening compared with men who did not—the same risk reduction previously reported after 9 years of follow-up.
Consistent with the earlier results, screening was also associated with important harms, Dr. Fritz Schröder of Erasmus University Medical Center and his colleagues reported March 15 in the New England Journal of Medicine. About half of those diagnosed on the basis of PSA screening were overdiagnosed—that is, diagnosed with prostate cancers that likely would never have threatened their lives.
Overall, the researchers found that 1,055 men would need to be invited for screening and 37 cancers would need to be detected to prevent one death from prostate cancer.
With approximately 182,000 participants, the eight-country ERSPC trial consortium is the largest randomized study of PSA screening for prostate cancer ever conducted. Earlier this year, 13-year follow-up results were published from the second-largest trial, the NCI-funded Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial of 77,000 men. In the PLCO trial, annual PSA screening did not reduce the risk of dying from prostate cancer. Screening did lead to substantial rates of overdiagnosis but lower than those in the ERSPC trial.
The conflicting results have been attributed to a number of key differences between the trials, wrote Dr. Anthony Miller of the University of Toronto in an accompanying editorial. The two trials used different PSA scores as a cutoff point and screened men at different intervals. The PLCO trial also had a substantial amount of “contamination”—more than half of men in the PLCO control arm underwent screening outside the trial. In addition, he pointed to evidence that there may have been different prostate cancer treatment in the screened versus control arms of the ERSPC study.
“We are left with an unsatisfactory situation, in which many practitioners will think there are insufficient data to recommend abandoning PSA screening for prostate cancer,” Dr. Miller wrote. Because the PLCO results are more applicable to clinical practice in the United States, Dr. Miller said it would be “advisable” to follow the recent draft recommendations of the U.S. Preventive Services Task Force, which advise against PSA screening for prostate cancer among men considered to be at low risk of the disease.