National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
December 14, 2010 • Volume 7 / Number 24

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Cancer Research Highlights

Study Estimates More than 600,000 Deaths Worldwide Caused by Secondhand Smoke

Secondhand tobacco smoke is estimated to have caused more than 600,000 deaths and the loss of more than 10 million disability-adjusted life years (DALYs) worldwide in 2004, according to the first analysis of its kind. Women and children were more likely than men to be exposed to secondhand smoke and to suffer morbidity and mortality from this exposure. The findings were published online November 25 in The Lancet.

Researchers led by Dr. Mattias Öberg of the Karolinska Institute in Stockholm, Sweden, used data for their analysis from the Global Youth Tobacco Survey and 19 additional surveys published between 1980 and 2007. They used models to estimate the burden of disease from secondhand smoke exposure for countries without direct survey data. The research team used the comparative risk assessment method, which is based on the proportion of people exposed to a pollutant and the known relative risk of disease related to that exposure.

The authors estimate that, worldwide, 40 percent of children, 35 percent of female nonsmokers, and 33 percent of male nonsmokers are exposed to secondhand smoke. In 2004, secondhand smoke caused 379,000 deaths from ischemic heart disease, 165,000 deaths from lower-respiratory infections, 36,900 deaths from asthma, and 21,400 deaths from lung cancer. Forty-seven percent of these deaths occurred among women and 28 percent occurred among children.

“Two-thirds of these deaths [among children] occur in Africa and south Asia…. The combination of infectious diseases and tobacco seems to be [deadly] for children in these regions,” wrote the authors. “Prompt attention is needed to dispel the myth that developing countries can wait to deal with tobacco-related disease until they have dealt with infectious diseases.

“The provisions of the WHO Framework Convention on Tobacco Control should be enforced immediately to create complete smoke-free environments in all indoor workplaces, public places, and on public transport,” the authors recommended.

“This landmark study documents the global magnitude of the problem of secondhand smoke exposure and its devastating consequences,” said Dr. Cathy Backinger, chief of NCI’s Tobacco Control Research Branch. “These findings should encourage a sense of urgency for ensuring that nonsmokers are protected from secondhand smoke exposure—a completely preventable health hazard.”

Zoledronic Acid Does Not Improve Disease-Free Survival in Breast Cancer

The addition of zoledronic acid, a bisphosphonate, to standard adjuvant therapy for women with stage II or III breast cancer does not extend disease-free survival (DFS), according to results from the phase III AZURE trial presented December 9 at the San Antonio Breast Cancer Symposium (SABCS). The findings run counter to those from an earlier trial, ABCSG-12, which showed improved DFS in premenopausal women with early-stage breast cancer who received zoledronic acid in addition to hormone therapy.

It is important to note, said Dr. Robert Coleman, the AZURE trial’s principal investigator, that the patient populations in the two trials were very different. AZURE enrolled both premenopausal and postmenopausal women; ABCSG-12 enrolled only premenopausal women who, as part of the trial, received the drug goserelin to induce early menopause.

The AZURE investigators enrolled 3,360 women at 174 treatment centers in the United Kingdom. The women were randomly assigned to receive either standard adjuvant treatment—chemotherapy, hormone therapy, or both, chosen by their treating physician—or to standard adjuvant treatment plus 5 years of zoledronic acid.

After almost 5 years of follow-up, no difference in DFS or overall survival (OS) was observed between the groups. However, in a preplanned subset analysis, women who had been menopausal for at least 5 years had significantly increased DFS and OS with the addition of zoledronic acid to standard treatment. Premenopausal women experienced no benefit from the addition of the bisphosphonate in the subset analysis. The updated results from ABCSG-12 presented at SABCS continued to show a statistically significant improvement in DFS and a trend toward improved OS in women who received zoledronic acid.

“Our results are strikingly different from those observed in ABCSG-12, and we need to understand why. I don’t believe one is right and one is wrong. I think we need to understand the biology as to why we’re seeing these different outcomes,” said Dr. Coleman. “Our hypothesis would be that adjuvant bisphosphonate efficacy is dependent on a low estrogen or inhibited concentration within the bone microenvironment,” he continued.

“Based on these data, I believe the routine adjuvant use of zoledronic acid to prevent recurrence is not indicated,” said Dr. Sharon Giordano from the University of Texas M. D. Anderson Cancer Center at the press conference. “The difference in outcome by menopausal status is very intriguing but not definitive.” She continued, “the AZURE trial will not be the final word on this topic.” Ongoing large trials testing bisphosphonates for the adjuvant treatment of breast cancer include NSABP B-34, the Gain trial, the NATAN trial, and SWOG-S0307.

Regular Sunscreen Use May Reduce Invasive Melanoma Risk

Regular sunscreen use may reduce the risk of developing melanoma, according to results of a randomized controlled trial that were reported December 6 in the Journal of Clinical Oncology. The trial is the first prospective, randomized study to investigate the link between sunscreen use and melanoma, the most deadly type of skin cancer.

Researchers led by Dr. Adèle Green of the Queensland Institute of Medical Research examined the incidence of melanoma among 1,621 white adults in a township in Queensland, Australia. They divided the study participants, age 20 to 69, into two groups. From 1992 to 1996, the participants in one group were given an unlimited supply of a broad-spectrum sunscreen with a sun protection factor (SPF) of 16 and were asked to apply it every morning to their head, neck, arms, and hands, and reapply it after heavy sweating, bathing, or long sun exposure. The control group continued using sunscreen of any SPF at their usual discretionary frequency, which for some included no use.

Dr. Green and her colleagues followed the study participants for 10 additional years and tracked all cases of primary melanoma newly diagnosed between 1993 and 2006. They found 11 new cases of melanoma in the daily sunscreen group compared with 22 cases in the discretionary sunscreen group, a 50 percent reduction. Invasive melanoma was reduced by 73 percent in the daily sunscreen group compared with the control group (3 versus 11 cases).

The authors noted that their results are of borderline statistical significance and suggested that their findings for invasive melanoma in particular “should be interpreted cautiously.” Nevertheless, they concluded, “among adults age 25 to 75 years, regular application of SPF 15+ sunscreen in a 5-year period appeared to reduce the incidence of new primary melanomas for up to 10 years.”

In an accompanying editorial, Drs. Phyllis Gimotty and Karen Glanz of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine wrote: “To our knowledge, the trial’s findings are the first to provide strong evidence for a reduction in the incidence of invasive melanoma after regular application of broad-spectrum sunscreen in adults…. It is unlikely that another trial of comparable scope and rigor will be conducted in the foreseeable future.”

Furthermore, they wrote, although “the question of its efficacy with respect to melanoma prevention should no longer deter scientists or clinicians from recommending sunscreen use,” effective skin cancer prevention should also include avoiding exposure to ultraviolet rays, using clothing to shield skin from the sun, and performing regular skin self examinations.

“This study provides important evidence regarding the role of sunscreen use as part of a range of sun-protective behaviors that effectively reduce risk of melanoma,” commented Dr. Margaret Tucker of NCI’s Division of Cancer Epidemiology and Genetics.

Hormone Therapy for Low-Risk Prostate Cancer Declines When Medicare Reimbursements Are Reduced

Reducing physician reimbursements for androgen suppression therapy (AST) led to a 40 percent drop in prescriptions for men with low-risk prostate cancer, while AST use among men with metastatic disease remained stable, according to findings published online December 3 in the Journal of the National Cancer Institute.

AST with a gonadotropin-releasing hormone (GnRH) agonist or surgical removal of the testicles (orchiectomy) is standard therapy for metastatic prostate cancer. So far, no study has shown a benefit for men with local-regional disease, yet use of AST for prostate cancer increased more than threefold in the 1990s “irrespective of whether the treatment was considered clinically indicated or not,” wrote Dr. Sean Elliot of the University of Minnesota and his colleagues. The 2003 Medicare Modernization Act reduced reimbursements of AST by 64 percent between 2004 and 2005.

The researchers used the SEER-Medicare Linked Database to analyze data from more than 72,000 men over the age of 66 who were diagnosed with prostate cancer between 1992 and 2005. They found that AST use among men with low-risk prostate cancer peaked at 10.2 percent in 2003 and then fell to 7.1 percent in 2004 and 6.4 percent in 2005, a statistically significant decrease. AST use among men with metastatic disease remained constant at 60 percent even after the payment change, the authors said.

Increased risks of diabetes, cardiovascular disease, bone fractures, and colorectal disease have been associated with the use of GnRH agonists, “highlighting the importance of targeting these drugs to patients who are likely to benefit and avoiding them for patients who will not,” wrote Dr. Nancy Keating of Brigham and Women’s Hospital and Harvard Medical School in an accompanying editorial. This study demonstrates “that the decreased reimbursement for GnRH agonists was associated with a substantial decrease in their use for an indication that very likely reflected overuse,” she wrote.

Study Shows Strong Link between Obesity and Mortality

The largest study of its kind has confirmed a strong association between overweight and obesity and an increased risk of death. The study also identified a range of body-mass index (BMI) at which mortality risk is lowest, confirming earlier studies indicating that people who are in the normal weight range have a significantly lower risk of dying from a host of causes compared with those who are overweight. The findings were published December 2 in the New England Journal of Medicine.

Obesity and overweight continue to be major health problems in the United States. Approximately two-thirds of the adult U.S. population are overweight or obese, meaning that they have a BMI of 25 or higher.

Researchers from NCI and other NIH institutes, as well as from other U.S. and foreign health agencies and universities, pooled data on 1.46 million people from 19 long-term prospective cohort studies. The participants in these cohort studies were white and from more industrialized countries, limiting the extent to which the findings can be extrapolated to other populations, the researchers explained. The analysis focused on participants who had never smoked and did not have cardiovascular disease or cancer at study entry, eliminating “potentially strong confounders” of mortality risk that have affected some earlier studies, explained the study’s lead author, Dr. Amy Berrington de Gonzalez of NCI’s Division of Cancer Epidemiology and Genetics.

Overall, the lowest mortality risk was seen for those with a BMI between 20 and 24.9. Above that level, every 5-unit increase in BMI increased the risk of death by 31 percent. The risk of death was substantially elevated in the severely obese, those with a BMI of 40 or higher. Women who fell into this category had a 2.5-fold higher risk of death compared with women in the lowest risk BMI range. The risk relationship was similar for men.

Across the BMI levels that correspond with overweight and obesity, the relationship between BMI and mortality was strongest for participants who were younger than 50 at study entry, Dr. Berrington de Gonzalez added.

Although the cancer-specific mortality risk was smaller than the mortality risk associated with cardiovascular disease, the study only assessed overall cancer risk, she said. “Based on previous studies, we know that the relationship between obesity and cancer varies by cancer type,” she continued. So, while obesity is strongly associated with an increased risk of postmenopausal breast cancer and renal cancer, for example, it is not associated with some other cancers. As a result, when cancer is considered as a single disease, the overall association is weaker, Dr. Berrington de Gonzalez said.

New Subtype of Acute Myeloid Leukemia Identified

By profiling epigenetic changes in the genomes of patients with acute myeloid leukemia (AML), researchers have identified a biologically distinct subtype of the disease that could be amenable to new forms of molecularly targeted therapy. Epigenetic changes, such as DNA methylation, include chemical modifications to DNA that alter the activity of genes without changing their coding sequence. In this study, patients whose tumors had mutations in the genes IDH1 or IDH2 showed widespread DNA methylation changes, including changes to key genes associated with leukemias, the researchers reported online in Cancer Cell on December 2.

The research team, co-led by Dr. Ari Melnick of the Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, were surprised by the results because IDH1 and IDH2 are involved in cell metabolism and have not been linked previously to epigenetic changes. But once these genes are mutated, the researchers found, they encode abnormal proteins that produce an aberrant metabolite that, in turn, increases DNA methylation. This increased methylation causes genes to function abnormally and causes hematopoietic cells to develop leukemic features.

To make the discovery, the researchers compared gene activity and DNA methylation patterns in tumors from 750 patients with AML. They also sequenced selected genes, including IDH1 and IDH2, which have been implicated in AML and in glioma, a form of brain cancer. The gene-expression patterns of patients with IDH1 or IDH2 mutations were not distinct from those of other AML patients, but clear differences were seen in the epigenetic profiles.

In additional experiments, the researchers found that the abnormal metabolite produced by the mutant IDH1 and IDH2 proteins disrupts the functions of a factor called TET2 that can otherwise reduce DNA methylation. They also showed that some AML patients have genetic mutations that inactivate the TET2 gene, and this causes the same abnormal patterns of DNA methylation as IDH1 and IDH2 mutations.

“This study marks the first time that genes involved in energy balance and abnormalities in cancer epigenetic programming have been linked,” said Dr. Melnick, who led the work with Drs. Craig Thompson and Ross Levine of Memorial Sloan-Kettering Cancer Center. The study further suggests that a gene can acquire an entirely new function when it is mutated. “In these kinds of studies, it is important to expect the unexpected,” Dr. Melnick added.

Screening Compliance, Stage of Cancers Detected Vary by Demographic

New national population-based data on screening, prevalence, and incidence of three cancer types show that about a third of breast cancers and half of colorectal and cervical cancers were diagnosed at a late stage, which means that timely and effective screening might have detected them earlier at a more treatable stage. The findings were reported by the CDC in the November 26 MMWR Surveillance Summaries.

Cancer incidence and prevalence trends were collected from state cancer registries according to sex, age, and race/ethnicity from 2004 to 2006, the latest data available, and then compared with 2008 self-reported data in the Behavioral Risk Factor Surveillance System, reflecting national rates of compliance with screening procedures recommended by the U.S. Preventive Services Task Force.

More than 82.1 percent of women age 50 to 74 received the recommended screening for breast cancer, and 87.6 percent of women age 21 to 64 were screened for cervical cancer as recommended. “Screening rates seem to have plateaued for cervical and breast cancer screening but are increasing steadily for colorectal cancer screening,” wrote the researchers.

Overall, 61.9 percent of men age 50 to 75 received colorectal screening as recommended, but the rates were lower for younger men (52.6 percent for men age 50 to 59), American Indians/Alaskan Natives (53.0 percent), Asian-Pacific Islanders (50.7 percent), and Hispanic men (46.5 percent). Similar trends were found for women, although the drop off in rates for those groups was not quite as large. Although black women and men had screening rates nearly as high as their white counterparts, they also had colorectal cancer incidence rates higher than all other groups.

Patterns of cancer incidence and prevalence for all three cancers varied geographically, and the CDC researchers suggested that state cancer control planners look at national and state data to explore whether these patterns might reflect demographic variables, ineffective screening, or poor follow-up of abnormal screening results. They noted that “social and economic disparities, lack of awareness of the need for screening, lack of physician recommendation, and lack of insurance coverage are major factors in the underuse of cancer screening.”

NCI has initiated a request for applications (RFA), called PROSPR, to evaluate the screening process in community practice and provide further insights into factors associated with late-stage cancers. The RFA will fund 9 to 12 research sites and a statistical coordinating center over 5 years.

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