Last week, several health organizations issued new cervical cancer screening guidelines that extend the time interval between screening tests for most women.
Based on comprehensive reviews of available data—including NCI-funded research—the new guidelines seek to maximize the benefits of current screening tests while minimizing their potential harms. Read more > >
A Conversation with Dr. Thomas Smith on the Growing Role of Palliative Care for Patients with Cancer
Recent research has shown that some cancer patients who received early palliative care not only had improved quality of life, but lived longer than patients who received standard treatment alone. Dr. Thomas J. Smith, director of palliative care for the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, talked with the NCI Cancer Bulletin about the growing importance of palliative care in oncology practice.
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- New Complementary and Alternative Medicine Report and Information Posted Online
Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.
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Leading Health Organizations Revise Cervical Cancer Screening Guidelines
Last week, several health organizations issued new cervical cancer screening guidelines that extend the time interval between screening tests for most women. Based on comprehensive reviews of available data—including NCI-funded research—the new guidelines seek to maximize the benefits of current screening tests while minimizing their potential harms.
The United States Preventive Services Task Force (USPSTF) released one set of guidelines, and a group of three health organizations—the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP)—released a second set. Although the two sets of guidelines were developed independently, their recommendations are consistent.
The ACS/ASCCP/ASCP guidelines were published jointly in CA: A Cancer Journal for Clinicians, Journal of Lower Genital Tract Disease, and American Journal of Clinical Pathology on March 15. The USPSTF recommendation statement appeared the same day in the Annals of Internal Medicine.
A better understanding of the role of persistent oncogenic human papillomavirus (HPV) infection in the initiation and progression of cervical cancer, as well as results from numerous studies evaluating the performance of HPV DNA testing in screening, prompted this re-evaluation of cervical cancer screening guidelines.
"These recommendations ensure that women receive the benefits of testing while minimizing the harms," said Dr. Diane Solomon of the Breast and Gynecologic Cancer Research Group in NCI's Division of Cancer Prevention, who helped develop the ACS/ASCCP/ASCP guidelines. "We're screening less often, but we're screening smarter."
The guidelines apply to women who have a cervix, whose immune systems have not been compromised, and who were not exposed in utero to substances such as diethylstilbestrol (DES) that would increase their risk. The recommended intervals are for women with normal test results; those with abnormal test results need to be followed more frequently.
When to Screen
Both sets of guidelines call for screening to start at age 21, regardless of when a woman becomes sexually active. The groups concluded that most HPV infections, which are spread through sexual contact, and cervical changes that are detected before this age will likely resolve on their own and not become cancerous.
The recommendations also extend the time interval between tests. Women ages 21 to 65 should be screened with the Pap test every 3 years. Women ages 30 to 65 who have the HPV DNA test and the Pap test (co-testing) can be screened every 5 years. ACS, ASCCP, and ASCP preferred co-testing over the Pap test alone, whereas the USPSTF deemed co-testing acceptable based on recently published data, including a study of women enrolled in the co-testing program at Kaiser Permanente Northern California, which was conducted in collaboration with NCI researchers. (See "HPV and Pap Co-Testing Safely Extend Cervical Cancer Screening Intervals".)
—Dr. Debbie Saslow
The ACS/ASCCP/ASCP guidelines also provide follow-up recommendations for women who have a positive HPV DNA test result and a normal Pap test result or a negative HPV DNA test result and mildly abnormal Pap test result.
"This is good news for women," said USPSTF Chair Dr. Virginia Moyer, professor of pediatrics at the Baylor College of Medicine, in a press release, "because evidence shows that an annual Pap smear is not necessary to prevent deaths from cervical cancer. Screening every 3 years [with the Pap test] saves the same number of lives as annual screening, but with half the number of colposcopies and fewer false-positive tests."
"Pap tests have been done yearly in the past, but we now know that annual screening is not needed and can lead to harm from treatment of cell changes that would never go on to cause cancer," said Dr. Debbie Saslow, first author of the ACS/ASCCP/ASCP guidelines and director of breast and gynecologic cancer for the ACS, in a statement. "With the addition of the HPV [DNA] test, we can test even less frequently, as the risk of precancer and cancer when both tests are negative is so low."
When Not to Screen
Women who have had a hysterectomy and no longer have a cervix should not be screened, according to the new guidelines. Likewise, women over age 65 should not be screened if they have had three consecutive negative Pap tests or two consecutive negative co-tests within 10 years, and the last test was administered within 5 years. However, women with a history of cervical precancer or a cancer diagnosis should continue screening as recommended by their physician, according to the new guidelines, for at least 20 years, even if it means testing after age 65.
In addition, the guidelines recommend against using the HPV DNA test alone in women of any age or using co-testing in women younger than 30 years of age because, HPV is common in young women, but the vast majority of HPV infections are transient. "HPV testing kicks in as a primary screening tool at age 30 as the prevalence of HPV infection declines and the underlying risk of there being something clinically relevant is higher with a positive HPV result," said Dr. Solomon.
Women who have had a previous diagnosis of cervical cancer or precancer or who are at higher risk for cervical cancer, including women with compromised immune systems or who were exposed to DES before birth, may need more intensive or alternative screening.
Whether gynecologists and family physicians will follow the new guidelines remains to be seen and will likely be the subject of future research. "We need to emphasize education," said Dr. Solomon. "As clinicians understand the rationale and the scientific basis behind these recommendations, I think they will be accepted and implemented. But it is going to take some time.
"Decades ago, we did a very good job of inculcating in clinicians' minds and in women's minds that they needed an annual Pap test. And we were so successful that it is hard to move people past that now," Dr. Solomon continued. "Cervical screening is best done using the most sensitive testing strategy at the longest safe interval. This provides safety for women and reduces the 'noise' of over-screening. When you find things that are not really clinically relevant but that need to be worked up, that causes anxiety and needless additional procedures."
Regardless, the authors of both sets of guidelines stressed that the greatest gains in reducing the incidence and mortality of cervical cancer will be attained only by increasing access to screening among women who are unscreened or screened too infrequently.
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.
A Conversation With
A Conversation with Dr. Thomas Smith on the Growing Role of Palliative Care for Patients with Cancer
The American Society of Clinical Oncology (ASCO) recently released a Provisional Clinical Opinion (PCO) recommending that palliative care be integrated with cancer treatment early in the course of illness for any patient who has metastatic cancer or is greatly burdened by symptoms. The ASCO authors based their recommendation on the results of seven randomized trials that tested the addition of palliative care to traditional cancer care. One of the most recent of these studies showed that patients with advanced non-small cell lung cancer who received early palliative care not only had improved quality of life but lived longer than patients who received standard treatment alone. Dr. Thomas J. Smith, director of palliative care for the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and lead author of the PCO, talked with the NCI Cancer Bulletin about the growing role of palliative care in oncology practice.
Is palliative care integrated into traditional oncology training?
Palliative care is becoming more integrated into oncology training, but if you trained more than 10 years ago, you probably didn't learn much about it. Many oncologists don't really know how to integrate palliative care directly into their practice. I am still learning.
I think we oncologists typically have very good working relationships with our surgeons and our radiation therapy colleagues, but not often with palliative care providers. In fact, we should have the same sort of preferred provider relationship with hospice as we do with other specialties. By that, I mean we should choose one or two providers that we work with closely, get to know them really well, get to know what they can do and what they can't do, and get feedback from those hospice programs on how we could do better [on referrals].
What could be done now to expand access to palliative care for cancer patients?
One of the things is to get hospice involved much sooner in the care of our patients. We're asking oncologists to schedule a hospice information visit when they expect that a patient has 3 to 6 months left to live, where you send a hospice team to meet the patient and the family.
It's often easier for patients and families to talk about some of these things with someone other than their oncologist. Having that palliative care team to help make sure the patient understands his or her prognosis, making sure the patient understands what the treatment options are, what the treatment goals are—to really break things down in black and white—can be very helpful for both the oncologist and the patient.
About a third of patients go into hospice with less than a week to live, and everyone is scurrying around trying to get the patient comfortable when the outcome for that patient was predictable 3 to 6 months before. Most of us choose not to have discussions about things like hospice, do-not-resuscitate [orders], and advanced medical directives until there are no more chemotherapy options left. That allows us to avoid a hard conversation, but it doesn't serve as well to prepare the patients and families for what's coming.
Can palliative care help people with less-advanced cancers?
Yes, palliative care can help people who have curable cancers, too. When someone's getting bludgeoned by cancer treatment, it's really helpful to have someone else co-manage their symptoms. As an oncologist, I may not have the skills or the time—particularly the time, with a patient scheduled every 20 minutes—to help a patient with all of his or her physical and psychological symptoms. But if I have a good working relationship with a palliative care provider, a referral can be very helpful for me and the patient. Some particular examples are neuropathic pain and distress.
If the doctor recommends it, or if the advanced-practice nurse recommends it, it's a rare patient who's going to say, "Oh, I don't want to see the palliative care team." But again, it's up to us, as the treating oncologists, to refer patients. It is not as effective if we ask the social worker to handle it.
Is there work under way in the United States to standardize how palliative care is given?
There are already some very good standards. The Clinical Practice Guidelines for Quality Palliative Care, from the National Consensus Project for Quality Palliative Care, first came out in 2004. They're not proscriptive in that they don't tell you exactly what you can and can't do, but they do give you some very good ideas about what a good palliative care consultation should include.
A consultation should definitely include a symptom assessment, a screen for depression, a screen for spiritual distress, and referrals to a chaplain and psychologist, if indicated. The team itself should have some multidisciplinary components to it—not just a nurse, not just a doctor. I am concentrating on asking patients "What's important to you?" as a way into core matters.
The Joint Commission also offers an accreditation program that was just established this past year. So, the Joint Commission now approves palliative care centers, just as it approves stroke centers or heart-disease centers.
What are the most urgent research priorities for palliative care in oncology?
One is to test palliative care in diseases other than lung cancer, to do randomized trials of what we know works in lung cancer—which is a multidisciplinary palliative care intervention—in other cancers. Just like we tested stem-cell transplantation in myeloma, lymphoma, and breast cancer, let's test palliative care.
The other priority would be to try to figure out what are the main components in an effective palliative care intervention—what's necessary, what's sufficient [to see an effect]. Those results would have important implications for funding, because getting reimbursed [for palliative care] in today's environment can be really difficult.
How do caregivers benefit from palliative care?
I think that's one of the biggest areas of benefit. In several studies we looked at for the PCO, caregivers did extraordinarily better when someone other than the treating oncologist was helping to take care of the patients. Part of that has to do with knowing the prognosis, knowing the treatment goals, and knowing what's going to happen.
Patients and families want this information; the problem is that patients and families won't bring these questions up—they're waiting for us. So if we choose not to talk about these things, we're making a choice that seems easier in the moment—easier for us, easier emotionally for the families at the time—but it's a choice that will make care more difficult down the road.
And that's where having a palliative care team involved early can be so useful.
—Interviewed by Sharon Reynolds
Surgeon General's Report Finds Youth Smoking Remains a Serious Concern
Smoking rates in the United States have dropped by half over the past four decades, due in large part to a diverse array of tobacco control efforts, including advertising campaigns and public smoking bans. This decline has been a rousing public health victory, marked by significant drops in lung cancer cases and death from the disease.
A new Surgeon General's report, however, clearly indicates that significant challenges remain. Preventing Tobacco Use among Youth and Young Adults highlights some disturbing trends, including a major slowdown in the falling rates of tobacco use among adolescents and young adults and an uptick in smokeless tobacco use among certain youth groups.
Much of the blame for the changing trends, the report states, lies at the feet of the tobacco industry and its heavy marketing of tobacco products using strategies that particularly appeal to adolescents and young adults.
During a March 8 briefing on the new report, Surgeon General Dr. Regina Benjamin stressed that the stakes are high. "This report challenges us to end the [tobacco] epidemic among young people," she stated.
Tobacco control efforts must focus on adolescents and young adults, Dr. Benjamin said. Overall, about 600,000 middle school students and 3 million high school students currently smoke. Ninety percent of smokers begin before the age of 18, she added, and one-third of 18- to 26-year-olds smoke.
"That's a higher rate than any other age group," Dr. Benjamin said. "So this is a serious public health issue."
The last Surgeon General's report on youth and tobacco was issued in 1994.
"Since then we've learned a lot about the science of nicotine addiction, the health consequences of tobacco use among youth, patterns of youth tobacco use, how addiction develops, and determinants of addiction," said Dr. Yvonne Hunt of NCI's Tobacco Control Research Branch.
For example, there is sufficient evidence to conclude that smoking reduces lung function and impairs lung growth in children and adolescents, the report stated, and that it can lead to abdominal aortic atherosclerosis—the thickening of the portion of the aorta that runs through the abdomen—increasing the risk of heart disease and aortic aneurysms in young adults.
The new report is also the first to comprehensively analyze tobacco use behaviors among young adults. "That's important because this age group hasn't been a major focus of prevention efforts in the past," Dr. Hunt continued. "And yet it's a group where we see a significant amount of tobacco initiation, as well as escalation to nicotine dependence."
The portrayal of smoking in movies and other popular culture is a substantial cause of youth tobacco use, the report found, and tobacco industry marketing plays a large role in encouraging young people to smoke.
Despite legal limitations on tobacco marketing to youth, the tobacco industry still spends $29 million a day to market tobacco products, much of it aimed at counteracting taxes on cigarettes. As young smokers are more price-sensitive than older smokers, the report found, this kind of marketing tactic has a larger impact on youth.
In a major racketeering case, for example, a federal court found in 2006 that the country's biggest cigarette companies had known for decades that recruiting new, teenage smokers was essential for their continued profitability, and for that reason, they designed their marketing campaigns to target young people and to entice them to become lifelong smokers.
The marketing works, particularly on adolescents, stressed Assistant Secretary of Health Dr. Howard Koh. And, the report showed, adolescents are more susceptible to the addictive effects of nicotine.
"It's not an accident" when a teenager starts smoking, Dr. Koh said during the briefing.
Packaging all of the findings into a Surgeon General's report is important, noted Dr. Jean Forster of the University of Minnesota, whose research focuses on health policy and adolescent smoking. "It really highlights the weight of the evidence about the factors that influence tobacco use," Dr. Forster said. "And it emphasizes that we have not solved the problem."
The report comes at a time when many U.S. states have slashed spending on tobacco control, said Matthew Myers, president of the Campaign for Tobacco-Free Kids.
"Recent studies show that these programs not only reduce smoking and save lives, but also save money by reducing tobacco-related health care costs," Myers said in a statement.
Future gains will require a mix of proven tools and more research, Dr. Hunt said. "We know that there are important policy measures that can have an impact when implemented as part of a broad, coordinated strategy," she said. "But we also need research that will help us better understand how to intervene, especially during those early stages, to prevent experimental use of tobacco from escalating to more regular use.
Mapping the Evolution of Cancer Cells in Leukemia
Using whole-genome sequencing, researchers have uncovered new clues to the genetic alterations underlying acute myeloid leukemia (AML) that arises in patients who were previously diagnosed with a myelodysplastic syndrome. Myelodysplastic syndromes develop when the bone marrow stops producing enough healthy cells, and some cases progress to what is known as secondary AML.
To identify genetic mutations driving this type of AML, researchers at the Washington University School of Medicine in St. Louis sequenced the genomes of abnormal cells (obtained from bone marrow) and normal cells (obtained from skin biopsies) from seven patients whose myelodysplastic syndrome had progressed to AML. Each patient had provided samples when they were diagnosed with a myelodysplastic syndrome and later when they were diagnosed with secondary AML.
By comparing the alterations in each sample, the researchers could track the genetic evolution of the cancer cells over time. They could also identify the cluster of cells that initially caused each cancer to develop—known as the founding clone. Then, they observed new clusters of cells, or daughter clones, that emerged.
The findings, published online March 14 in the New England Journal of Medicine, suggest that the secondary AMLs were derived from bone marrow cells carrying mutations that were present during the myelodysplastic phase of disease.
The collection of proteins within a tumor may be just as diverse as the collection of altered genes. A recent clinical study of samples from patient tumors found "a surprising degree of heterogeneity in protein expression both across the different patient samples and even within the same tumor."
"The reality is that tumors within a single patient can have different genetic changes, and we have observed this heterogeneity at the protein level as well," said Dr. Cesar Castro of Massachusetts General Hospital, who co-led the study. His team profiled the cells using a technology developed to diagnose cancer rapidly.
To better understand the heterogeneity in cancer cells, Dr. Castro continued, researchers will need minimally invasive techniques that can collect serial specimens, as well as new ways to extract as much information as possible from these samples.
"These diseases are combinations of multiple clones, and the clones have a relationship," said Dr. Timothy Graubert, the study's senior author. "In every case, the daughter cells of the founding clone carried forward mutations from the cluster of cells that caused the cancer in the first place."
Implications for Treatment
The finding that suspicious mutations in secondary AMLs were always derived from clusters of cells in myelodysplastic syndromes suggests that targeting these early mutations may be the most effective way to prevent the progression of the mutant cells, the researchers predicted. Drugs that target mutations found only in later-evolving cancer cells may be effective only against those cells, they noted.
To develop the most promising targets, "researchers need to determine whether a particular mutation is part of the founding structure of the [cancer] or whether it occurred at a later time," Dr. Graubert explained.
The researchers identified 11 mutations in the patients' cancer cells that were later found in other patients with AML, which is an indication that they may play a role in the disease. Four of the mutations had not been implicated previously in either myelodysplastic syndromes or leukemia.
In addition to sequencing DNA, the researchers profiled changes in the numbers of copies of genes, as well as in patterns of gene expression. Each cancer cell had hundreds of mutations, but the researchers predict that only a small percentage of these may drive the disease.
The additional mutations, however, provided the statistical power the researchers needed to track the evolution of clones over time.
"The deep sequencing allowed us to confirm that a mutation was present, and it gave us a sense of how many cells in a given sample carry the mutation," Dr. Graubert said. "We could then describe the heterogeneity of the [cancers] and construct a picture of clonal evolution."
A Model of Cancer
The study provides evidence to support a model of cancer that has been hard to test experimentally, noted Dr. Lucy Godley of the University of Chicago Medical Center in an accompanying editorial.
The model describes cancer as a series of acquired mutations and epigenetic alterations that start with a single mutated cell and accumulate in a progressive manner. As the process unfolds, "subclones" of cells acquire new properties that give the cells advantages, such as the ability to resist chemotherapy or to metastasize.
This theory has been around for years, Dr. Godley said in an interview. "But new technologies allow you to ask questions that you couldn't ask before. That's what's so exciting about these kinds of genome studies."
Another recent sequencing study—this one led by Dr. Charles Swanton of the London Research Institute—described the genetic variability within different regions of the same kidney tumor. Instead of sequencing the entire genome, the researchers analyzed the protein-coding regions, or exomes.
"We know that cancer can be heterogeneous, and there's probably an evolutionary relationship between different parts of a tumor mass or different cancer cells in leukemia," said Dr. Elaine Mardis, co-director of the Genome Institute at Washington University and a co-author of the AML study.
The new findings on tumor heterogeneity are consistent with previous work in breast cancer, she noted. For instance, her group conducted an analysis of four DNA samples from the same patient whereas another group compared tumors collected from a patient 9 years apart. Similarly, her group recently reported that, in de novo AML, when patients relapse after receiving chemotherapy, the clone that emerges is derived from a clone that was present at initial diagnosis.
Sequencing the genomes of individual cancer cells could reveal additional layers of genetic complexity, as Dr. Graubert and his colleagues noted in their study. This technology is in its infancy, but a recent pilot study suggests how this could work.
—Dr. Lucy Godley
Researchers at BGI (formerly the Beijing Genomics Institute) sequenced the exomes of 25 cells donated by an Asian man with a form of kidney cancer. Among other findings, the researchers discovered that the man did not have alterations in a gene closely associated with that disease in Western populations.
This study, published in Cell, produced interesting findings, but single-cell sequencing is not ready for clinical studies, noted Dr. Michael Dean, an investigator in NCI's Center for Cancer Research and a co-author of the study.
He added: "It is clear that, for at least some [cancer] types, we will need to use multiple samples and multiple methods of genomic analysis to develop a complete picture of a cancer that can be used to guide therapies."
Dr. Mardis agreed. "These studies are all very exciting because we're now getting to the point of being able to approach [cancer] in different ways."
Featured Clinical Trial
Combining Systemic Therapies for Patients with Advanced Liver Cancer
Name of the Trial
Phase III Randomized Study of Sorafenib Tosylate with Versus without Doxorubicin Hydrochloride in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma (CALGB-80802). See the protocol summary.
Dr. Ghassan Abou-Alfa, Cancer and Leukemia Group B
Why This Trial Is Important
Primary liver cancer (hepatocellular carcinoma) is one of the leading causes of cancer death worldwide. Although it is still relatively uncommon in the United States, liver cancer incidence in this country nearly tripled between 1975 and 2008 and continues to rise. Much of the increase in the U.S. population can be traced to rising rates of infection with hepatitis C virus. Other risk factors include alcohol-related cirrhosis of the liver, which accounts for about one-third of U.S. liver cancers, as well as a condition called nonalcoholic steatohepatitis (NASH), which can develop among diabetic and morbidly obese people. As the incidence of diabetes and obesity increases, liver cancer related to NASH is likely to increase.
Localized liver cancer that can be surgically removed (resected) is potentially curable, but most patients are not diagnosed until the cancer has become advanced. Until recently, patients with advanced unresectable liver cancer were often treated with the drug doxorubicin, despite little evidence of a survival benefit. In 2007, however, a large randomized phase III trial found that patients with advanced liver cancer who were treated with the targeted drug sorafenib survived nearly 3 months longer than those treated with a placebo.
At the same time, Dr. Abou-Alfa and other researchers were conducting a randomized phase II trial to evaluate the addition of sorafenib to doxorubicin. The analysis of data from the trial showed that patients who received sorafenib plus doxorubicin experienced longer overall survival and progression-free survival than those who received doxorubicin plus a placebo. On the basis of these findings, together with preclinical data that suggest a possible synergistic effect between doxorubicin and sorafenib, researchers decided to compare the combination treatment with sorafenib alone.
In this phase III trial, patients with unresectable, locally advanced or metastatic primary liver cancer who have good liver function (Child-Pugh score A) will receive sorafenib and be randomly assigned to also receive either doxorubicin or no additional therapy. Doctors will compare overall survival between the groups, as well as progression-free survival and tumor responses.
"Doxorubicin was historically accepted based on the experience of individual doctors, but it was not a proven standard of care," said Dr. Abou-Alfa. "In this context, and before sorafenib became recognized as a standard of care, we carried out our phase II study comparing doxorubicin and sorafenib to doxorubicin alone. We noticed improved survival but we cannot say if that improvement was entirely due to sorafenib or if doxorubicin also contributed to the benefit. The current study should answer that question."
Federal Campaign Seeks to Shrink Smoking Rates Further
A series of "hard-hitting" ads designed to encourage adult smokers to quit began hitting airwaves, billboards, and print publications nationwide yesterday, in the first-ever Federal antismoking campaign. Funded by the Centers for Disease Control and Prevention (CDC), the ads feature real people who have suffered serious, often disfiguring health problems caused by smoking, as well as former smokers offering guidance on how to quit.
The campaign, called "Tips from Former Smokers," will run for 3 months and will include ads in Spanish and English. The campaign "tells the real story of how tobacco can change your life," said Health and Human Services Secretary Kathleen Sebelius during a briefing to announce the campaign's launch.
Although great gains have been made in reducing smoking rates, progress has stalled during the last decade. Approximately 20 percent of Americans still smoke.
The campaign builds on an effort launched by President Barack Obama's administration to reverse that trend, Sebelius explained, including provisions in the Affordable Care Act that require coverage of smoking cessation services and the Family Smoking Prevention and Tobacco Control Act, which greatly expanded the Food and Drug Administration's regulatory authority over tobacco products.
The administration's efforts are intended "to help the 70 percent of smokers who want to quit to make that leap," Sebelius said. The ads direct people to 1-800-QUIT-NOW and www.smokefree.gov.
One of the ads features Terrie Hall from North Carolina, who started smoking when she was 17 and eventually smoked two packs a day. Diagnosed with laryngeal cancer at the age of 40, Hall had to have her voice box removed. In the ad, Hall demonstrates how she gets ready for her day: putting in false teeth, placing a blond wig onto her mostly bald head, and inserting a filter into her stoma, a surgically created opening in her windpipe.
In 2008, NCI analyzed research literature about the impact of media on tobacco use. Results from this detailed analysis found that ads such as those being used in CDC's current campaign effectively reduce smoking.
"The ads only work if they're done right," CDC Director Dr. Thomas Frieden said during the briefing. "And the evidence is clear that hard-hitting ads work."
The agency predicts that the campaign will help 50,000 smokers quit. Its cost, $54 million, is equivalent to what the tobacco industry spends in 2 days on marketing its products, Dr. Frieden said.
Many states have been criticized for cutting back on their tobacco control programs, and most states currently spend far less than the CDC recommends. But the new campaign is not meant to replace states' tobacco control efforts, only augment them, Dr. Frieden cautioned.
"I understand that states are under considerable pressure economically. But tobacco control is a good buy," he continued, noting that it can significantly reduce Medicaid costs and other health care spending and improve productivity.
Some people have argued that the current 20 percent smoking rate is "some sort of irreducible minimum," he said. But a number of states that have consistently invested in tobacco control have reduced smoking rates to well below 20 percent, he stressed. "More progress is possible."
NCI and CICAMS Sign Statement of Intent
Dr. Jie He, president of the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences (CICAMS), and NCI Director Dr. Harold Varmus signed a statement of intent to share an interest in fostering collaborative biomedical research in oncology and a common goal in educating and training the next generation of cancer research scientists and clinicians. The signing took place March 14 during the Setting Priorities for Global Cancer Research meeting, hosted by NCI's Center for Global Health.
NCI and CICAMS aim to improve the discovery and development of new anticancer agents and prevention strategies to enhance the design, implementation, and analysis of cancer treatment and prevention trials, basic science research, and epidemiologic studies.
NCI and CICAMS intend to collaborate on the following activities:
- Basic and translational research
- Preclinical research and clinical trials and associated translational research
- Cancer prevention and early detection trials and epidemiologic studies
- Joint meetings, conferences, workshops, and informational exchanges
NCI-supported researchers and CICAMS researchers have collaborated on scientific projects for more than 30 years. CICAMS was recently designated China's National Cancer Center and will have an expanded role in China's cancer prevention and control efforts.
NCI Advisory Committee on Clinical Trials Holds First Meeting of 2012
The Clinical Trials and Translational Research Advisory Committee (CTAC) held its first meeting of 2012 on March 7 on the NIH main campus in Bethesda, MD.
The meeting highlighted NCI-supported early-phase prevention and treatment clinical trials programs, including the Division of Cancer Prevention's Consortia for Early Phase Prevention Trials, and the Early Experimental Therapeutics Program and the Cancer Diagnosis Program's biomarker resources, both in the Division of Cancer Treatment and Diagnosis.
The agenda, presentations, and a link to the archived videocast are available online. The next two CTAC meetings are scheduled for July 11 and November 30, 2012.
NCI at American Association of Cancer Research Annual Meeting
NCI staff will be participating at the American Association for Cancer Research's 103rd Annual Meeting from March 31–April 4 in Chicago, IL. Learn about sessions with NCI staff and activities at the NCI exhibit booth online.
Look for highlights from the meeting in the April 3 issue of the NCI Cancer Bulletin.
Dr. John Potter to Deliver First Schatzkin Lecture in Nutritional Epidemiology
The inaugural Arthur Schatzkin Distinguished Lecture in Nutritional Epidemiology will be held at 3:00 p.m. on April 16 in Lipsett Amphitheater on the NIH main campus in Bethesda, MD. NCI established this annual lecture to honor the memory of Dr. Arthur Schatzkin, a visionary scientist, mentor, and leader in the field of nutrition and cancer.
Dr. Schatzkin joined NCI in 1984 and served as the chief of the Nutritional Epidemiology Branch from 1995 to 2011. He was committed to understanding the role of nutrition in cancer etiology and prevention and was instrumental in addressing major methodological issues of research in nutritional epidemiology. Dr. Schatzkin passed away in January 2011.
This year's lecturer is Dr. John Potter, member and senior advisor of the Division of Public Health Sciences at Fred Hutchinson Cancer Research Center and professor of epidemiology at the University of Washington. Dr. Potter's research focuses on the role of diet and physical activity in the development of cancer, with a particular emphasis on the epidemiology, biology, early detection, and prevention of colon cancer. The title of his talk is "Nutrition, Environment, Development, and Cancer: Casting a Wider Net."
New Complementary and Alternative Medicine Report and Information Posted Online
In fiscal year 2010, NCI funded more than 400 projects related to complementary and alternative medicine (CAM), and the American Recovery and Reinvestment Act supported 27 other CAM grants, according to NCI's Annual Report on Complementary and Alternative Medicine.
Projects highlighted in the report include studies on exercise and cancer prevention, curcumin's role in preventing the spread of prostate cancer, and the effect of altering cellular fats on cancer risk. Researchers are also examining whether various foods can prevent or fight cancer. For instance, blackberries are being studied to determine whether they interfere with the growth of tumors in the oral cavity, esophagus, and colon.
In addition, NCI's Physician Data Query (PDQ®) webpage on Prostate Cancer, Nutrition, and Dietary Supplements has been updated with new information on modified citrus pectin, soy, and pomegranates.