The evidence to support the idea that environmental exposures are associated with cancer risk comes from many types of studies. These include studies of migrant populations that often acquire the cancer patterns of their new countries; changes in cancer incidence over time; studies of twins; variation in cancer risk across geographic areas; increased cancer risk among certain occupational groups; and evidence from basic and toxicological research.
In perhaps the strongest epidemiologic research of its kind to date, a case-control study of invasive cutaneous melanoma, involving more than 2,200 participants, found that any use of indoor tanning devices increased melanoma risk, but the risk was highest among those who engaged in indoor tanning most frequently. The findings were published online May 27 in Cancer Epidemiology Biomarkers and Prevention. Read more > >
As the outgoing director of the National Cancer Institute, I would like you to know how honored I am to have been asked to serve in this wonderful position. Virtually every day brings a fresh reminder of the privilege and excitement that stem from being part of an extraordinary history of biomedical research. Since 1937, when it became the first disease-based institute of what would become the National Institutes of Health, thousands of women and men have devoted their professional lives to NCI and to alleviating the burden of cancer for all who suffer its pain. Read more > >
The deputy directors of NCI's Division of Cancer Control and Population Sciences and Division of Cancer Epidemiology and Genetics discuss environmental risk research. Read more > >
A MESSAGE TO READERS
Coverage of ASCO Annual Meeting
The American Society of Clinical Oncology Annual Meeting will take place June 4-8 in Chicago. Look for highlights from the meeting in the June 15 issue of the NCI Cancer Bulletin. Please also visit the Web site to learn about NCI events during the meeting.
- As Summer Begins, National Organization Helps Highlight Dangers of UV Overexposure
- Meet NCI Experts at ASCO (Updated)
Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.
The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.
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Tanning Bed Study Shows Strongest Evidence Yet of Increased Melanoma Risk
In perhaps the strongest epidemiologic research of its kind to date, a case-control study of invasive cutaneous melanoma, involving more than 2,200 participants, found that any use of indoor tanning devices increased melanoma risk, but the risk was highest among those who engaged in indoor tanning most frequently. The findings were published online May 27 in Cancer Epidemiology Biomarkers and Prevention.
The results—from the Skin Health Study, conducted between 2004 and 2009 in Minnesota, a state with documented high indoor tanning use—are the first to show a clear dose-response relationship, with melanoma risk increasing by as much as 200 percent when indoor tanning usage exceeded 50 hours, 100 sessions, or 10 years. Over the last decade or so, the commercial tanning industry has introduced a number of newer technologies, and these were found to further increase the melanoma risk. Compared with people who have never used indoor tanning devices, those who used high-speed/high-intensity devices experienced 2.9 times the risk, and using high-pressure devices led to 4.4 times the risk. High-speed/high-intensity devices emit mostly UVA radiation plus a small percentage of UVB radiation; high-pressure devices emit UVA radiation almost exclusively.
—Dr. Margaret Tucker
Dr. Margaret Tucker, director of NCI’s Human Genetics Program in the Division of Cancer Epidemiology and Genetics, lauded the study for its value to researchers and public health. “This study was designed to specifically investigate the role of tanning devices in melanoma risk. It is carefully done and analyzed. This is the most solid, substantive study to date to specifically address the tanning device issue and is an important contribution to the field,” said Dr. Tucker, who led research that established the first susceptibility genes for melanoma and the development of a melanoma risk assessment tool.
The design and quality of the research is significant because industry has used the limitations of earlier studies “to counter possible health concerns,” said lead author Dr. DeAnn Lazovich from the Masonic Cancer Center and the University of Minnesota. Using in-depth surveys and thorough follow-up phone interviews, the researchers were able to explore details of tanning bed use that had not been simultaneously examined in a study of this size and in a population with high use.
“The risk of melanoma was increased whether we looked at the age of diagnosis, gender, the body site of the tumor, time period of use, how we measured the amount, or the type of devices used,” explained Dr. Lazovich. “All of those pieces tell a very consistent story.”
While it may not be possible to definitively distinguish between the effects of UVA versus UVB radiation employed in different devices, “the evidence indicates that all of these approaches do harm: there is no such thing as a safe device,” she emphasized. “And you don’t have to actually get a burn to incur the higher risk from indoor tanning, though we know that often happens.”
In 2009, the International Agency for Research on Cancer classified tanning devices as carcinogenic, emphasizing the risk to those exposed to indoor tanning before age 36. The current study did not confirm increased susceptibility for younger ages, but did suggest that those who start younger would likely go on to a greater lifetime exposure and, thus, face higher risk.
A big part of putting these findings into action will come at the societal level, said Dr. Electra Paskett, associate director for population sciences at the Ohio State University Comprehensive Cancer Center. “We have to change the social norms, and there are ways to do that,” she said, citing the successful effort to reduce tobacco use.
Indoor tanning has indeed become a social norm. As the study authors noted in the paper, a recent analysis of policies and laws on indoor tanning in 116 large U.S. cities found that “the average number of tanning salons exceeded the average number of Starbucks or McDonald’s.” And Dr. Lazovich cited data from the American Cancer Society stating that, nationally, 35 percent of 17-year-old girls report indoor tanning use. An FDA advisory panel recommended in March that the agency consider age restrictions or parental consent requirements for children under 18.
“Given the findings on the 116 large U.S. cities, it will likely take stronger age restrictions rather than relying on parental consent,” said Anne Hartman, a biostatistician in NCI’s Risk Factors Monitoring and Methods Branch in the Division of Cancer Control and Population Sciences. “That study did not find an association between youth indoor tanning laws, which mainly consisted of various forms of parental consent, and lower indoor tanning use among teens.”
Changing behaviors, Dr. Paskett stressed, will also require action at the health care provider level, and not just among dermatologists. Providers should be “educating their patients about the risks of indoor tanning,” she said. Questions about tanning should be added to those about smoking, drinking, and other risk behaviors that clinicians commonly ask their patients, Dr. Paskett said.
Cancer Research Highlights
Some Older Women Can Forgo Radiation after Breast Cancer Surgery
Women 70 years of age or older with early-stage breast cancer did not benefit from the addition of radiation therapy to breast-conserving surgery and tamoxifen, according to the findings of a phase III randomized trial released last week. The study results, presented May 20 in advance of the American Society of Clinical Oncology (ASCO) annual meeting, indicate that “death from breast cancer is a very rare event among [older] women with these small cancers,” said lead author Dr. Kevin Hughes of Massachusetts General Hospital in Boston. The trial was conducted by three NCI clinical trials cooperative groups: the Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, and Radiation Therapy Oncology Group.
Between 1994 and 1999, the researchers enrolled 636 women in the trial; 319 received tamoxifen alone after surgery, and 317 received tamoxifen plus radiation therapy. All women had early-stage, estrogen receptor (ER)-positive disease that had not spread to the lymph nodes. The researchers followed the women for a median of 10.5 years after treatment.
Although adding radiation therapy to tamoxifen reduced the chance of cancer recurrence in the same breast by 6 percent, it did not affect overall survival, breast-cancer-specific survival, cancer spread, or the need for later mastectomy due to disease recurrence. The 10-year breast-cancer-specific survival was 98 percent for women receiving tamoxifen alone and 96 percent for women receiving tamoxifen plus radiation therapy.
“Older women often have small tumors that are ER-positive, without evidence of spread to the lymph nodes. This [study] is certainly practice-affirming and may be potentially practice changing,” said Dr. Douglas Blayney, president of ASCO. “Many [older] women…elect to defer radiation therapy. This gives us some comfort as physicians in supporting that decision…and maybe it will change the recommendations we make to our patients,” he concluded.
Sorafenib Kills Malignant Glioma Cells by Blocking Vital Cell Survival Pathway
Researchers have identified a cell-signaling pathway in malignant glioma (a type of brain cancer) controlled by a protein called ATF5 that promotes cancer-cell survival. Using cell-culture experiments and mouse models, the researchers, led by Dr. Zhi Sheng from the University of Massachusetts Medical School, determined that this pathway can be blocked by the drug sorafenib (Nexavar), leading to cancer cell death, and that the addition of temozolomide—a chemotherapy drug used to treat malignant glioma—sensitizes cancer cells to sorafenib treatment.
In a study published online May 23 in Nature Medicine, the researchers used RNA-interference techniques to identify genes required for the expression of ATF5 in mouse malignant glioma cells. Treatment of these cells with sorafenib, which blocks proteins controlled by one of the identified genes, reduced the expression of ATF5 and induced cell death. These results were confirmed in a mouse model of malignant glioma, in which mice injected with cancer cells developed tumors, but mice injected with sorafenib along with the cancer cells did not develop detectable tumors.
The researchers also showed that blocking ATF5 caused cell death in various human cancer cell lines, including lines established from melanoma and prostate, lung, and ovarian cancers, in addition to malignant glioma. This cell-killing effect was also seen in human glioma stem cells, the cells that have been proposed to give rise to malignant glioma and that are extremely resistant to chemotherapy and radiation therapy.
When the researchers examined ATF5 expression in tumor samples taken from 23 patients with malignant glioma, they found that patients whose tumors expressed ATF5 had significantly shorter survival times.
In a final set of experiments, the combination of sorafenib and temozolomide synergistically killed human glioblastoma cells that expressed high levels of ATF5 and another protein in the cell-survival pathway that controls the expression of ATF5. “When combined with temozolomide, the sorafenib concentration obtainable in patients may be well above that required for an effective response,” concluded the authors.
Genome Study Profiles Aggressive Form of Breast Cancer
Preliminary results from a genome study of triple-negative breast cancers suggest that uncommon genetic variants may distinguish these aggressive tumors from more treatable forms of the disease, researchers said last month during the Biology of Genomes meeting at Cold Spring Harbor Laboratory. If confirmed, the findings could be used to create genetic signatures associated with triple-negative cancers, which disproportionately affect younger women and African Americans.
Breast cancers that test negative for the estrogen, progesterone, and HER2 receptors are called triple negative. In an effort to learn more about the genetic basis of these tumors, Dr. Christopher D. Brown and his colleagues at the University of Chicago sequenced the protein-coding genes in 15 triple-negative tumors and 11 estrogen receptor (ER)-positive tumors. In all, the study found more than 35,000 genetic variants, including many that commonly occur in the human population.
The researchers went on to identify several thousand uncommon, or rare, variants that distinguished the triple-negative tumors from ER-positive tumors. Common variants, however, did not distinguish the tumor types.
By comparing tumor tissue with each patient’s corresponding normal tissue, the researchers found that many of the uncommon variants appear to have been inherited rather than having occurred during the development of cancer. This finding suggests that it may be possible to profile a woman to assess her risk of developing this form of the disease, though such tests could be years away, noted Dr. Brown.
“We think these initial results show promise for uncovering the genetic basis of tumor heterogeneity among these cancers, and we are validating the signature now,” he added. The work is part of a larger project to apply the tools of DNA sequencing to understudied cancers and to address clinically important questions.
Shark Cartilage Extract Ineffective Against Lung Cancer
A clinical trial to rigorously evaluate a shark cartilage extract as a cancer treatment found no benefit for patients with non-small cell lung cancer. Patients who took the extract, AE-941 or Neovastat, along with chemotherapy and radiation therapy lived no longer than patients who did not, according to a report published online May 26 in the Journal of the National Cancer Institute. Negative results from the study were first reported at the American Society of Clinical Oncology (ASCO) annual meeting in 2007.
The phase III randomized placebo-controlled clinical trial was cosponsored by NCI and the National Center for Complementary and Alternative Medicine. The study closed early because of slow patient accrual. Only 379 eligible patients were included in the final analysis. “It is, nevertheless, the largest phase III study ever conducted, to our knowledge, of a shark cartilage–derived agent, and the study outcome is unambiguous,” the researchers noted. The manufacturer of AE-941, Canadian pharmaceutical company Æterna Laboratories, worked closely with the investigators to ensure the purity of the extract used in the trial.
In a separate editorial about the study results, Dr. Jeffrey White, director of the NCI Office of Cancer Complementary and Alternative Medicine, noted, “This study was well designed and conducted and has generated important and useful findings with regard to one specific product, AE-941.” Dr. White cautioned against concluding that the study “completely disproved the efficacy of shark cartilage” or other natural materials for treating cancer. “The potential value of complex mixtures of natural materials in the anticancer armamentarium remains an open question for many and one that can only be answered one step at a time with high-quality research,” he wrote.
In a Time of Transition, a Strong Foundation for Success
As the outgoing director of the National Cancer Institute, I would like you to know how honored I am to have been asked to serve in this wonderful position. Virtually every day brings a fresh reminder of the privilege and excitement that stem from being part of an extraordinary history of biomedical research. Since 1937, when it became the first disease-based institute of what would become the National Institutes of Health, thousands of women and men have devoted their professional lives to NCI and to alleviating the burden of cancer for all who suffer its pain.
It is impossible to serve as NCI director without feeling every day the magnitude of this unique institute’s responsibilities, both nationally and internationally. In the 2009 fiscal year, for example, NCI responded to 63 formal Congressional letters and many more informal public queries. I received more than 250 requests to attend national and international conferences, and my office handled more than 12,000 pieces of correspondence. NCI routinely communicates with over 200 advocacy organizations in 34 states, and each year NCI responds to more than 5,000 media inquiries. Most important, all of these functions add up to a tremendous opportunity to represent groundbreaking cancer science and the new technologies impacting cancer care to our legislators, the public, and the scientific community. They are opportunities to show how NCI is continuing to make great strides toward early detection and improved strategies of decreasing cancer risk.
Today’s progress stands atop a proud history of drug development at NCI that has resulted in more than 50 novel compounds used in adjuvant therapies and in the treatment of advanced cancer. Together these advances have helped decrease the cancer death rate from 199 per 100,000 in 1973 (the year I accepted my first academic appointment) to an estimated 184 per 100,000 in 2009, despite a 44 percent increase in the U.S. population and an increase of approximately 25 percent in the population over age 65. Clearly this number is still far too high, but real progress is being made.
Two decades ago, the 5-year survival rate for women diagnosed with breast cancer was 84.3 percent. Because of NCI-supported research, the 5-year survival rate has risen by nearly 6 percent. Two decades ago, the 5-year survival rate for ovarian cancer was 40 percent. That rate today is 46 percent, and women diagnosed in the earliest stages have a 5-year survival rate of nearly 94 percent. Two decades ago, the 5-year survival rate for bladder and kidney cancers was about 58 percent. Today, because of NCI-supported research, that rate is approaching 69 percent.
Over the past 5 years, despite a series of below-inflation budgets, NCI has started no fewer than nine major new initiatives designed to hasten the pace of research and to get new therapies to patients faster and at lower cost, including the:
- Chemical Biology Consortium
- Functional Biology Consortium
- Physical Sciences-Oncology Centers
- NCI Community Cancer Centers Program
- Coordinating Center for Clinical Trials
- BIG Health Consortium
- Cancer Target Discovery and Development Network
- Cancer Human Biobank (caHUB)
- Enhanced nanotechnology and proteomics initiatives
Over the past 5 years, NCI has embraced the power of the genome. The Cancer Genome Atlas (TCGA), a joint project with the National Human Genome Research Institute, has moved from a pilot project striving to sequence the genomes of three cancers to an established program that has set an ambitious goal of sequencing the genomes of 20 more tumors and potentially, in time, all major cancers.
Over the past 5 years, NCI has begun to take the mountains of data emanating from TCGA to the laboratory, where sequencing and genomic characterization information are turned into knowledge of protein structure and biologic function. This work contributes to a new understanding of cellular processes, which makes it possible to establish new targets for enhanced, individualized therapies. Building on its rich history in drug development, NCI, through the newly expanded NeXT program, is poised to be a singular national resource for the public, academic, and private sectors to work together in the continuum from discovery through first-in-human studies. The result, we firmly believe, will significantly reduce the time and cost of bringing new, safe, effective drugs to patients. The commissioning of the Dilts study on clinical trial efficiency provides NCI, for the first time, with real data concerning the much-too-burdensome series of steps required to start a clinical trial. These data will clearly empower change.
Recently, NCI has led an effort to develop electronic health records for cancer, to help make our oncology care system ready for a time when patients will be, as a matter of course, genomically profiled at various life stages. This idea of characterized, electronically linked patients will be the basis for an entirely new system of clinical trials, in which we will much more quickly—and far more precisely—match patients with newly developed drugs, molecularly based methods of cancer prevention, and enhanced techniques for the very earliest detection of small numbers of transformed cells. Detecting cancer as it begins, and when it is most curable, would certainly change outcomes.
Over the past 5 years, the NCI Community Cancer Centers Program has come into existence, with a network that now numbers 30 hospitals in 22 states working together to find better ways to bring the latest benefits of cancer science to all patients in their home communities, whether in a city center or a distant rural area.
The long list of NCI’s accomplishments over these years includes efforts to attract outstanding young scientists to the study of cancer and to adequately support their development. We have instituted programs that are drawing established scientists from disciplines not traditionally involved in the study of cancer, including the more theoretical branches of physics, mathematics, and physical chemistry, for example. NCI is leading in exciting efforts to create new, genetically engineered mouse models of cancer and to develop new methods of diagnostics and treatments based on nanoparticles. We have come a long way, through our extramural programs in systems biology and our work in stem cell biology, to understand the dynamic nature of the relationship between host and tumor (the tumor microenvironment) and the potential of targeting the components that support growth and invasion.
NCI is proving a vital ally to the Food and Drug Administration in its efforts to regulate tobacco in the United States. NCI’s science also extends to those who have concluded cancer treatment, as we work to distinguish why some fare better than others—and why certain patients are more prone to second, third, and even fourth malignancies. Our survivorship program has changed how we conceive of life after cancer and how we work to support cancer survivors and their loved ones, too.
As I have said many times during these 5 years, what we invest in, through some 5,500 extramural and 345 intramural principal investigators, is not only about cancer; our work benefits all chronic disease, by increasing the knowledge of the very basic foundations of abnormal cellular and host biology.
Every effort NCI puts forward has the goal of benefitting all people and reducing the inequities of race, ethnicity, age, income, language, and education that keep Americans from receiving equal cancer care. Our programs have also recognized that cancer is a global issue for NCI. We have established very successful programs in the Middle East, Ireland, China, and more recently in Latin America, which benefit patients in those countries, while providing vital research links for NCI.
These examples are just a small sampling of the unparalleled research infrastructure and power of the National Cancer Institute and its outstanding community. It gives me great pride to see everything NCI has accomplished in my time here, to witness the extraordinary commitment of every researcher and clinician, nurse and technician, manager and office worker.
I am particularly mindful of NCI’s accomplishments and its commitment—to the unprecedented scientific opportunities that continually push the institute to the forefront of science and medicine—as I prepare to step aside from my position.
As we hand over the responsibility for leading NCI to Dr. Harold Varmus, who will become its 14th director on July 12, we do so recognizing that there is much to be done on the frontiers of science, and we need important new structures to maximally take advantage of the new era of genomic-driven medicine—the new era of translational science.
Dr. Varmus is a stellar scientist and a recognized scientific leader—at both the NIH, where he was director from 1993 to 1999, and at the Memorial Sloan-Kettering Cancer Center, which he led for the past decade. Perhaps it is because I know Harold so well that I can assure you he will, from his first day at NCI, intimately feel the power of its history and work diligently to create a vision for its future.
Dr. John E. Niederhuber
Director, National Cancer Institute
A Conversation With
A Conversation with Drs. Deborah Winn and Shelia Zahm about Environmental Cancer Risks
A report on environmental cancer risks was issued last month by the President’s Cancer Panel, an independent advisory board that monitors the development and execution of activities of the National Cancer Program, and reports directly to the President. To learn more about research in environmental cancer risks, the NCI Cancer Bulletin sat down with Drs. Deborah Winn and Shelia Zahm, who are, respectively, the deputy directors of NCI’s Division of Cancer Control and Population Sciences and Division of Cancer Epidemiology and Genetics.
What is meant by environmental exposures?
Dr. Zahm: The environment can be defined broadly as anything other than genetics, but the recently released President’s Cancer Panel report focused on chemical agents and physical agents, such as environmental contaminants and radiation. Tobacco, diet, and viruses, for example, might also be considered environmental exposures, but these were not a focus of this year’s report. The President’s Cancer Panel addressed these exposures in previous reports.
What is the evidence linking environmental exposures and cancer?
Dr. Zahm: Many lines of evidence support the idea that environmental exposures are associated with cancer risk. (See sidebar) But, while there is no doubt that some environmental exposures cause cancer, there’s also a lot we don’t know. We have more to learn about the effects of low doses of environmental exposures, about interactions among multiple exposures, and about newly introduced exposures, for example. We also need more research on the periods of time over a lifetime when a person may be most susceptible to the effects of environmental exposures.
What are some of the challenges in studying these questions?
Dr. Winn: One of the challenges is that people do not always know what their environmental exposures have been. For instance, people are much less likely to be able to report the levels of radon in their homes than their smoking habits or medical conditions. In addition, because of the long time it takes most cancers to develop, we need information about exposures in the distant past.
Are researchers working on this problem?
Dr. Winn: Yes, and we’re having success in several areas. NCI is a partner in the NIH Genes, Health and the Environment Initiative that includes research to develop new methods for monitoring personal environmental exposures and exposures where people live and work. The research has led to the development of new sensors that people could wear on a lapel, say, to measure environmental exposures during daily activities. This could capture exposures in real time and over time. Meanwhile, some groups are using geographic information systems, mapping data on exposures to maps of cancer cases, which could give us clues about hazards.
Does a person’s age play a role in the risk from exposure?
Dr. Zahm: Studies have shown that there are windows of susceptibility. For example, women exposed to radiation below age 20 are at higher risk of radiation-associated breast cancer than those exposed at older ages. This finding came from studying women with scoliosis or tuberculosis who were monitored by X-ray or fluoroscopy, a procedure that involves radiation exposure.
Thyroid cancer is another example. Studies of atomic bomb survivors in Japan and the population near the Chernobyl nuclear accident have shown that persons exposed as children are at higher increased risk of thyroid cancer later in life than persons exposed as adults.
What can you learn by studying people in high-exposure areas?
Dr. Winn: Studying people with high exposures, either in the United States or internationally, has led to important discoveries about cancer risk factors. These high-exposure areas have been extremely important for discovering cancer-causing agents in the environment and for understanding mechanisms of action. NCI has for many years partnered with international investigators in places where air pollution is extremely high or heavy occupational exposures occur in relation to mining or manufacturing.
Dr. Zahm: In another example, DCEG has collaborated with the Chinese Center for Disease Control and Prevention on studies of occupational exposure to benzene. This work has greatly increased our understanding of the carcinogenic risks of benzene and helped set standards for benzene exposure in the United States and abroad. Because the exposure levels in China included a broad range, investigators were able to evaluate whether risks increase with increasing exposure—which supports a cause-and-effect relationship—and also to study effects at levels relevant to the regulatory standard targets in this country.
How are you studying exposures in this country?
Dr. Zahm: Using the Atlas of Cancer Mortality in the U.S., we can identify geographic areas with elevated rates for certain cancers and target epidemiologic studies to investigate the risk factors responsible. For example, with respect to the high rates for bladder cancer in New England, the exposures of interest include arsenic, which is present naturally at relatively high levels in the groundwater. We are also studying occupational groups that have unusual cancer patterns, such as the farmers in the Agricultural Health Study, miners exposed to diesel exhaust, and workers exposed to formaldehyde. Another important area of research underway in DCEG is determining the long-term risks associated with the recent dramatic increase in medical radiation.
Is it ever possible to determine the cause of an individual cancer?
Dr. Zahm: It is not usually possible to determine on an individual basis whether a particular tumor is caused by a specific exposure based on histologic or molecular genetic markers. There are a few exceptions, such as mesothelioma associated with asbestos fibers that persist in the lung, but generally we can only talk about increased risk on a population level.
How do you study multiple exposures?
Dr. Winn: We have techniques for human population studies that can help us unravel the effects of different exposures people experience. Each person may behave in ways that increase or decrease his or her health risk, for instance, through diet or smoking behavior, and genetic or other predisposing factors may also influence cancer risk. The goals in population studies are to capture and understand all of the risk factors, and, once the other known factors are accounted for, to identify the environmental exposures that might be responsible.
What proportion of cancer is due to environmental exposures?
Dr. Zahm: The exact proportion is not known and, in fact, varies from country to country and as exposures change over time. Our understanding of the proportion also changes as we do more research. Tobacco is undoubtedly the most significant cause of cancer, but other environmental exposures are important and avoidable causes of cancer as well.
What is your view of the future of environmental cancer research?
Dr. Winn: The more research we do, the more we learn. Along with the research, the development of improved methods for capturing data on environmental exposures is critically important. Training the next generation of environmental scientists is also key.Dr. Zahm: As the excitement surrounding research on genetics continues to grow, it will be important to continue to focus attention on the role of environmental exposures. The way we will learn the most about carcinogenesis, I believe, is by looking at genes and environment together and how they interact.
—Edward R. Winstead
The Test and the Target: Diagnostics’ Critical Role in Individualized Cancer Care
In what are still the early days of personalized cancer medicine, much of the focus has been on the use of molecularly targeted therapies, such as imatinib (Gleevec) or trastuzumab (Herceptin). But this is beginning to change as cancer researchers and pharmaceutical and biotechnology companies devote greater attention to an integral part of the therapeutic equation: the tests—or “companion diagnostics,” as they are often called—needed to determine not only whether a patient’s tumor expresses the molecule being targeted, but also whether that expression correlates with the patient’s response to the treatment.
Based on a 2007 workshop sponsored by NCI and the FDA, a recent commentary published in the Journal of the National Cancer Institute, for which Dr. Taube was the lead author, laid out the challenges for biomarker development, including developing companion diagnostics in concert with a molecularly targeted agent.
Building on that earlier conference, as part of the PACCT initiative, NCI is launching a clinical assay development program that will establish a network of laboratories, including an NCI laboratory, to help both industry and academic researchers develop validated, clinical-grade companion diagnostics, Dr. Taube explained. This will complement and build upon the efforts that NCI initiated a number of years ago to develop standard operating practice (SOP)-driven assays to measure pharmacodynamic biomarkers in Phase 0 and I clinical trials.
“Our initial focus will be on tests that are proposed as integral assays that must be done in order for a trial to proceed,” she said. That would include, for example, an assay to determine patient eligibility for the trial or to assign patients to a specific treatment arm.
The effort, which is just beginning and being supported with funds from the American Recovery and Reinvestment Act, will initially focus on assays for phase III trials and large phase II trials. More information on the program will be available in the coming months.
It’s all part of the move away from “nonselective therapeutics,” explained Dr. Paul Mischel, a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “If we’re dealing with therapies that target specific enzymes, the alterations in those enzymes and the pathways that they regulate are often different in patients with the same types of cancers, so having companion diagnostics is essential” to individualizing patient care, he said.
Companion diagnostics are intimately tied to the development of diagnostic and prognostic biomarkers; novel clinical trial designs, such as so-called adaptive design trials; and initiatives like NCI’s Cancer Human Biobank to standardize and centralize tissue sample procurement and storage—all part of a collective effort to spur more rapid advances in personalized cancer treatment.
All of these approaches, argued Drs. Richard Schilsky, Anil Potti, and Joseph Nevins in a recent commentary in Science Translational Medicine, are “critical for a renewed war on cancer: Without a robust mechanism for selecting the right treatment for the right patient at the right time, we will continue to see only incremental improvements and have little hope for substantial survival gains.”
Complexity Fueling Collaboration
The difficulty and expense of developing a successful cancer treatment have been well documented. But the challenge of developing diagnostics that are, in effect, therapeutic partners for a given treatment, “can’t be understated,” stressed Dr. Mischel, whose laboratory, in collaboration with Dr. James Heath from the California Institute of Technology, is focused on using nanotechnology and other platforms to develop diagnostics that can predict response to therapy and be used to noninvasively monitor response after treatment has begun. “Creating the tests, getting them into [Clinical Laboratory Improvement Amendment]-certified labs, creating testing kits, and being able to do these things in a way that is highly standardized and highly reproducible is just a very difficult thing to do,” he said.
The technological and logistical aspects are not the only difficulty. An additional challenge comes in trying to measure the right thing, said Dr. Sheila Taube from NCI’s Program for the Assessment of Clinical Cancer Tests (PACCT) initiative. (See sidebar.)
“Cancer biology is very complex, and there are numerous interconnected pathways in a cancer cell,” she said. “If you cut off one pathway, there may be another pathway the cell uses to accomplish the same end. So if you measure only one piece of a pathway that may be involved, that may not be sufficient to know whether the patient will respond to the drug.”
Both the increased understanding of cancer’s complexity and the complexity of developing companion diagnostics are driving many pharmaceutical companies’ activities in the area of personalized medicine, said Dr. Cecilia Schott, AstraZeneca’s business development director for personalized healthcare. Part of that change is the growing number of companies that are establishing partnerships with diagnostics firms, as AstraZeneca did earlier this year in inking a deal with Dako Denmark.
“It’s challenging to find the biomarker, determine whether it is meaningful, and then to identify the right technology to measure it,” Dr. Schott said. So, at earlier stages in the drug development process, there is a greater emphasis on understanding the biological importance of a biomarker in certain tumor types, as well as identifying the best way to measure that marker. As for the testing platforms, she continued, “You may have to try several in parallel until you find the one that is best to use.”
Although all of these efforts may make the drug development process more complicated early on, the long-term pay-off, in terms of success of a drug and impact on patients, will likely be greater, Dr. Schott said.
Developing a Drug and a Test in Unison
“We were thinking about it from the beginning,” explained Dr. Peter Hirth, CEO of Plexxikon—the “it” referring to a companion test to identify the best candidates for the company’s investigational drug PLX4032. The agent targets a specific mutation in the BRAF gene, which is present in approximately 70 percent of patients with melanoma. In a phase I clinical trial, the response rate to treatment with PLX4032 (at least a 30 percent reduction in tumor size) was 70 percent in patients with the mutation, including the complete eradication of tumors in some patients.
Although the phase I dose-escalation trial was open to any patient with metastatic melanoma, an “extension cohort” was later opened, enrolling only patients whose tumors had the BRAF mutation, assessed using a PCR-based test developed by Roche, which is an official collaborator with Plexxikon in the development of PLX4032. This test is also being used to enroll patients in a phase II trial, as well as a recently launched phase III trial meant to establish PLX4032 as a first-line treatment for patients with advanced melanoma who have the BRAF mutation.
Should the phase III trial yield positive results, the specifics on how to perform the test and analyze the results, based on work done as part of the clinical trials, will be part of the overall submission package to the FDA for approval to market the drug, Dr. Hirth noted.
—Dr. Elizabeth Mansfield,
Food and Drug Administration
Pfizer has taken a similar route with several of the cancer drugs in its development pipeline, including crizotinib (formerly known as PF-02341066), which targets the ALK gene and has shown promising results in a phase I trial in patients with advanced lung cancer. The phase I trial was enriched with individuals whose tumor cells had a fusion of two genes, including ALK. The patients were identified using a FISH-based assay developed by Abbott, under an agreement between the two companies. According to a Pfizer spokesperson, the assay will be used to enroll patients in a recently launched phase III trial of the drug.
This start-early approach is highly advisable, said Dr. Elizabeth Mansfield from the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health (CDRH). “To the degree that your drug program allows it, it’s never too early to start thinking about developing a companion diagnostic,” she said.
And the FDA is doing what it can to help researchers and companies move things in that direction. “If there is even an inkling that there is a potential for targeting a specific population [with an investigational drug], even if hasn’t been tested in humans yet…we encourage them to get in contact with CDRH,” said Dr. Issam Zineh, from the Office of Clinical Pharmacology in the agency’s Center for Drug Evaluation and Research.
There’s been little doubt or confusion about the need for companion diagnostics to individualize cancer therapy, said Dr. Mischel. “But what’s different now,” he continued, “is that the business models are catching up” with that understanding.
Profiles in Cancer Research
Dr. Sholom Wacholder
Senior Investigator, Biostatistics Branch
NCI’s Division of Cancer Epidemiology and Genetics
Dr. Sholom Wacholder has used three criteria in guiding his career choices: “Are you good at it? Are you having fun? Are you making a difference?”
A talented biostatistician who is revered by colleagues, he is credited with contributing to numerous seminal epidemiologic studies, so he’s hit on the first and third marks.
But it may be surprising to learn that an area he has found to be difficult and therefore not always fun—communication—is central to the work that he does.
“I’m not a natural writer, and I have to work hard to communicate effectively,” he admitted. “But, really, communication is critical for this job. I always paraphrase Robert Hoover [the NCI epidemiologist], who said that good science that nobody understands or nobody can learn from isn’t doing the job.”
Points of Interest
“Like most every kid, I had no idea what I wanted to do with my life,” said Dr. Wacholder. “I just knew that I didn’t want a career that would require me to write papers.” He said that his excitement about math first emerged during a sophomore-year honors math course at the University of Cincinnati, where he enjoyed the practice of proving abstract theorems.
He turned his attention to the more practical applications of his skills when a friend of the family, a radiologist, suggested that he contact a colleague in the University of Cincinnati’s department of epidemiology and biostatistics. From there, Dr. Wacholder went to graduate school to study biostatistics at the University of Washington in Seattle, and he joined the Biostatistics Branch at NCI in 1986.
“What I try to do in much of my work is think about the clinical impact,” Dr. Wacholder said.
“The point is to improve public health.” Means to that end often begin with an observation from his own research.
For example, the March 27 issue of the British Medical Journal (BMJ) published a study that Dr. Wacholder led on HPV vaccine safety. The analysis used data on pregnancy loss pooled from two randomized controlled trials of the HPV vaccine Cervarix. “Overall, vaccinated women did not appear to have a higher risk of miscarriage,” explained Dr. Wacholder, “but concern remains for a possible effect in women who conceived within 90 days after vaccination.” Based in part on the data in the BMJ publication, the FDA asked the manufacturer for post-licensure studies on risk of miscarriage, because “even a tiny effect in a small subset of women adds up to a large number of possible miscarriages in tens of millions of women to be vaccinated,” explained Dr. Wacholder.
In the mid-1990s, Dr. Wacholder conducted a study on the risk of breast cancer among women of Ashkenazi Jewish descent who had BRCA mutations. Previous studies reported an 85 percent risk of breast cancer for these women before the age of 70. Dr. Wacholder and his colleagues surveyed more than 5,000 Ashkenazi Jewish women and men in the Washington, DC, area using the “kin-cohort” method—an approach that Wacholder developed in which risk is estimated from the cancer history of family members. Using this new approach, he found the risk of breast cancer in BRCA carriers to be closer to 50 percent.
“All of the previous data had come from families with a number of breast cancer cases,” he said. “Our population-based study found many carriers had no or minimal family history, and, hence, our estimates of rates in carriers are much lower than most earlier estimates. Subsequent studies confirmed our results. I told the Wall Street Journal that this was the difference between a sure thing and a coin flip.”
Teaching to Learn
Dr. Wacholder smiles often as he speaks about his work. At times he sounds philosophical. Echoing Einstein, Wacholder believes: If I can’t explain it simply, I don’t understand it well enough.
“I never feel I truly understand something if I can’t explain it to someone else, orally or in writing,” he said. “The teaching part of what I do is essential to my work.” The biggest challenge, he explained, is boiling down the extraordinary range of details to those few essential points. “To communicate, you have to think of the audience, and not just what excites you.”
Collaboration is key to his work, he said. “I spend a lot of time in person-to-person and group settings,” he said. “A big part of my job is to make sure my collaborators understand and appreciate the statistical and methodological issues.” Dr. Wacholder also spends a lot of time mentoring other scientists. One mentee stands out in his mind.
“Nilanjan Chatterjee was a graduate student when we first met. When he came here as a post-doc, everyone recognized him as extremely talented. And now he’s my boss,” said Dr. Wacholder, laughing.
Dr. Chatterjee remembers the generosity of his former mentor. “Sholom allowed me to work independently and gave me advice,” he said. He also described Dr. Wacholder as a visionary when it comes to thinking about the big picture of a research question and all the elements—study design, false positives, and genetic applications, for example—that will come along with it.
“The way he thinks about selecting a problem, the criteria that he uses, is something you can’t learn from books,” said Dr. Chatterjee. “You can only learn it from seeing someone else do it. So I was really fortunate to be one of his mentees because, even now, when I think about taking on a project and I have to prioritize, what I learned from him helps me.”
Looking back at the three criteria he uses to guide his career, Dr. Wacholder’s résumé speaks to both his professional success and his impact on public health: the Chinese benzene workers study and other occupational hazard research; more than 20 years working on HPV and cervical cancer research; and recently, a report on the impact of inherited genetic variation on breast cancer risk in clinical settings. His teaching and communication skills have continued to develop through his work as a statistics editor for the Journal of the National Cancer Institute and in editorial positions at Epidemiology, Cancer Epidemiology Biomarkers and Prevention, and the American Journal of Epidemiology.
The “fun” element is clearly present as evidenced by his total absorption in his subject matter. Dr. Wacholder talks about his research with visible joy and awe. It’s also clear that he is always learning and teaching and that, for him, the two are one and the same.
Cancer Center Profile
UCLA Jonsson Comprehensive Cancer Center
Director: Dr. Judith Gasson • 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781
Phone: 310-825-5268 • Web site: http://www.cancer.ucla.edu/
In the late 1960s, a group of scientists and volunteers at UCLA came together to develop a cancer center they hoped would become renowned for excellence in research, education, and patient care.
Today, UCLA’s Jonsson Comprehensive Cancer Center (JCCC) has established an international reputation for developing new cancer therapies, providing the best in experimental and traditional treatments, and expertly guiding and training the next generation of medical researchers. With a membership of more than 240 physicians and scientists, JCCC handles more than 20,000 patient visits per year and offers hundreds of clinical trials. The center was designated a comprehensive cancer center by NCI in 1976.
JCCC researchers lead the way in research focused on cancer prevention, detection, treatment, and survivorship. JCCC physician-scientists have played key roles in the development and/or testing of trastuzumab (Herceptin) for breast cancer; bevacizumab (Avastin) for colon and lung cancer; rituximab (Rituxan) for lymphoma; erlotinib (Tarceva) and gefitinib (Iressa) for lung cancer; imatinib (Gleevec) for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST); sunitinib (Sutent) for kidney cancer; dasatinib (Sprycel) for CML and breast cancer; panitumumab (Vectibix) for colorectal cancer; and lapatinib (Tykerb) for breast cancer.
The cancer center has partnered with outstanding scientists at UCLA to form a molecular imaging program that has resulted in compelling insights into cancer both in patients and animal models. Cancer center researchers have been able to track gene therapy at work in animal models and watch, in real time, the immune system’s first response to cancer.
JCCC leaders have also developed a focus on stem cell biology, including the study of cancer stem cells, which are thought to be the driving force behind the development and persistence of cancers. This effort also includes the UCLA Human Gene Medicine Program, which is developing and testing novel cell-based therapeutics to treat cancer.
Cancer center researchers also have been using nanotechnology to develop a localized and controlled drug delivery method that is invisible to the immune system, which could lead to newer and more effective treatments for cancer and other diseases. Nanotechnology is additionally providing novel ways to detect the presence of cancer cells and biomarkers in patient samples.
JCCC researchers have a long history of disparities research and outreach to the Los Angeles community. To aid the underserved, JCCC created the UCLA-Avon Cares for Life program at Los Angeles County’s Olive View-UCLA Medical Center. This program helps low-income, underinsured, and uninsured women, many of them from minority populations, to navigate their way through breast cancer treatment. The women are guided by bilingual case workers from diagnosis through treatment and beyond. Cares for Life also includes a program designed to follow patients at high risk for developing breast cancer, to provide survivorship services, and to offer clinical trials for breast cancer.
Featured Clinical Trial
Targeting the Hedgehog Pathway in Stomach Cancer
Name of the Trial
Phase II Randomized Study of FOLFOX Chemotherapy With Versus Without Hedgehog Antagonist GDC-0449 in Patients With Advanced Gastric or Gastroesophageal Junction Carcinoma (NYCC-09-0356). See the protocol summary.
Dr. Deirdre Cohen, New York University Cancer Center
Why This Trial Is Important
Stomach cancer is one of the leading causes of cancer-related deaths worldwide. Although the overall incidence of stomach cancer has been declining in the United States, the rates of cancers of the upper stomach (called the proximal stomach) and gastroesophageal junction (where the esophagus enters the stomach) have been increasing over the past 20 years, especially in people younger than age 40. Surgical resection can be potentially curative, but most patients are not diagnosed until after the cancer has spread and can no longer be removed surgically.
Clinical trials have shown that patients who have advanced stomach cancer that cannot be removed surgically live longer if they are treated with chemotherapy compared to best supportive care. However, substantial improvements in long-term survival have not been obtained using standard chemotherapy agents alone.
Doctors are currently exploring the use of a new drug, called GDC-0449, in patients with advanced, inoperable stomach cancer. GDC-0449 targets a signaling pathway called the Hedgehog pathway, which is active in developing embryos and helps regulate cell proliferation and maintenance in many adult tissues. Abnormal activation of the Hedgehog pathway has been observed in a number of human cancers, including stomach cancer. Adding GDC-0449 to standard chemotherapy may be more effective than standard chemotherapy alone in prolonging the survival of patients with advanced stomach cancer.
This phase II trial will recruit patients with inoperable cancer of the stomach or gastroesophageal junction who have not been previously treated for advanced disease. The patients will be randomly assigned to receive either the combination chemotherapy regimen FOLFOX plus GDC-0449 or FOLFOX plus a placebo. Doctors want to see if adding GDC-0449 to FOLFOX will improve progression-free survival. They will also assess the relationship between several biological characteristics of the patients and their clinical outcomes.
“The Hedgehog pathway is thought to be one of the driving forces leading to cancer growth in gastric and gastroesophageal junction cancer,” said Dr. Cohen. “The premise, based on solid preclinical research, is that inhibiting this pathway will lead to increased cancer cell death.
“FOLFOX chemotherapy is one of the accepted standards for this cancer, so patients will receive either the standard of care, or the standard of care plus this experimental drug,” Dr. Cohen explained. “In phase I testing, GDC-0449 was very well tolerated and had no dose-limiting toxicities, so we’re hopeful that it won’t add toxicity to the FOLFOX regimen.”
As Summer Begins, National Organization Helps Highlight Dangers of UV Overexposure
On Friday, May 28, the National Council on Skin Cancer Prevention sponsored the second annual “Don’t Fry Day,” a nationwide event held in advance of the Memorial Day weekend to encourage sun safety awareness and to remind people to protect their skin while enjoying the outdoors.
NCI is an advisory member of the Council, which is dedicated to reducing skin cancer morbidity and mortality in the United States by minimizing exposure to intense ultraviolet radiation.
To learn more about skin cancer prevention and other related research, please visit NCI’s Skin Cancer home page.
Meet NCI Experts at ASCO (Updated)
Learn about NCI’s programs and Web sites by visiting booth #2033 in the exhibit hall during the 2010 American Society of Clinical Oncology Annual Meeting, taking place June 4-8 in Chicago, Illinois. NCI experts will be available to talk about a wide range of topics (see schedule below). Also visit the NCI @ ASCO Web site for information about other NCI educational and special sessions taking place at the meeting.
Saturday, June 5
Ellen Richmond and Linda Parreco
|12:00 p.m.||Funding for Biomarker, Imaging, & QOL Studies Associated with NCI’s Clinical Trials|
|1:00 p.m.||NCI Online Course: Including Clinical Trials in Your Practice|
Rose Mary Padberg
|2:00 p.m.||Using TNF-alpha Antagonists to Treat Primary Tumor and Tumor Metastases|
Holly Massett and Rose Mary Padberg
|4:00 p.m.||Cancer Training Branch|
Sunday, June 6
|10:00 a.m.||NCI Online Course: Including Clinical Trials in Your Practice|
|11:00 a.m.||NCI’s Office of Cancer Complementary and Alternative Medicine|
|12:00 p.m.||Overview of Specialized Programs of Research Excellence (SPOREs)|
|1:00 p.m.||NCI SBIR Funding for Small Startup Businesses to Bring Science to the Market|
|2:00 p.m.||Using TNF-alpha Antagonists to Treat Primary Tumor and Tumor Metastases|
|3:00 p.m.||Funding for Biomarker, Imaging, & QOL Studies Associated with NCI’s Clinical Trials|
|4:00 p.m.||Funding Opportunities to Promote Workplace Diversity|
John O. Ojeifo
Monday, June 7
|9:00 a.m.||Translations Research Program (SPOREs)|
|11:00 a.m.||Funding for Biomarker, Imaging, & QOL Studies Associated with NCI’s Clinical Trials|