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July 13, 2010 • Volume 7 / Number 14

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NEWS

Dr. Harold Varmus, accompanied by his wife Constance Casey, is sworn in as NCI director by Secretary of Health and Human Services Kathleen Sebelius on Monday, July 12.Harold Varmus Becomes Fourteenth Director of the National Cancer Institute

On July 12, Dr. Harold Varmus was sworn in by the U.S. Department of Health and Human Services Secretary Kathleen Sebelius to become the 14th director of NCI. Later that day, Dr. Varmus, who led NIH from 1993 to 1999, held a town hall meeting with NCI staff to lay out some of his objectives and "set the tone" for his time as NCI director.  Read more > >

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IN DEPTH

UPDATES

  • Legislative Update

    • The Congressional Biomedical Research Caucus: Highlighting Cancer Research
  • NIH Update

    • Videos Illustrate How to Navigate the NIH Funding Application Process
  • Cancer.gov Update

    • NCI Launches Comprehensive Biospecimen Resource Web Site
    • SEER Releases New U.S. Cancer Mortality Data
  • Notes

    • New Issue of CCR Connections Released
    • Winners of Smokefree Women Video Contest Announced

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.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

NCI Cancer Bulletin staff can be reached at ncicancerbulletin@mail.nih.gov.

Featured Article

Harold Varmus Becomes Fourteenth Director of the
National Cancer Institute

Dr. Harold Varmus, accompanied by his wife Constance Casey, is sworn in as NCI director by Secretary of Health and Human Services Kathleen Sebelius on Monday, July 12. Dr. Harold Varmus, accompanied by his wife Constance Casey (center), is sworn in as NCI director by Secretary of Health and Human Services Kathleen Sebelius on Monday, July 12. (Photo by Chris Smith)

On July 12, Dr. Harold Varmus was sworn in by the U.S. Department of Health and Human Services Secretary Kathleen Sebelius to become the 14th director of NCI. Later that day, Dr. Varmus, who led NIH from 1993 to 1999, held a town hall meeting with NCI staff to lay out some of his objectives and "set the tone" for his time as NCI director. (View the videocast online.)

“Everything we do and everything that we say will be based on evidence,” Dr. Varmus said. He stressed that the meeting was not intended to detail his full agenda as NCI director, but to preview some of his priorities.

“We need to pay attention to the repair of some things that are obviously dysfunctional in the system. First on the list is reforming the clinical trials system,” he said, referring to the recent report by an Institute of Medicine (IOM) committee that recommended substantial restructuring and increased funding of NCI’s Clinical Trials Cooperative Group Program. “This is a very important moment for us to get the clinical trials system into much better shape.”

Another priority: better use of the resources available at the Mark O. Hatfield Clinical Research Center, a facility that was planned and developed during Dr. Varmus’s tenure as NIH director. “The Clinical Center should be full of the most adventurous clinical research on cancer in the world,” he said. “We need to figure out how to pay for that and how to get patients and researchers from everywhere around the country to begin using it.”

Dr. Varmus also highlighted the cancer drug approval and regulation process as a priority area. “The methods that are currently being used need to be readjusted to a modern era in which there are genetically based therapies and new ways to monitor the responses to therapies,” he said. Doing so will require more productive partnerships, including those with the FDA, other Federal agencies, academic researchers, and industry. “I know NCI already has relationships with these organizations and individuals, but I’ll be doing a lot to make those relationships stronger,” he said.

Dr. Varmus acknowledged that there are other issues and NCI programs that may need to be addressed, and he will seek advice and input from many sources. For instance, a working group of NCI’s National Cancer Advisory Board is developing a report, expected to be completed in the fall, that will examine NCI’s roles and authorities and how the Institute can best lead the National Cancer Program in the years to come.  

A Nobel prize winner who served as president of Memorial Sloan-Kettering Cancer Center for the last 10 years, Dr. Varmus hopes to “change the ways we think about the scientific problems that we are trying to solve.” He told the town hall meeting audience, “We need to think a little more clearly about how we frame the questions that we’re trying to answer, so we know what we’re actually trying to achieve.” Rather than posing overly general, perhaps unanswerable questions, NCI needs to help researchers focus “with a new specificity, based on new developments in our science, and look at questions that are not pie in the sky, but have a substantial prospect of answerability in the foreseeable future.”

Dr. Harold Varmus addresses NCI staff and highlights some of his priorities for the Institute during a town hall meeting. Dr. Harold Varmus addresses NCI staff and highlights some of his priorities for the Institute during a town hall meeting. (Photo by Daniel Sone)

To achieve that vision, he continued, “Over the next year, I’m going to stage a series of meetings, inviting people who work in a variety of fields across the country, and try to establish a list of provocative, answerable questions that will help our scientists think about what the next steps ought to be.”

He also mentioned his keen interest in combating cancer on a global level in an organized way, especially in low-income regions of the world. That will entail “developing programs that are suitable for improving cancer control in poor countries, such as tobacco control and vaccination programs against oncogenic viruses,” he said.

“There is no better time, based on my view of working in cancer research for the last 40 years, to lead the nation’s cancer research efforts,” Dr. Varmus said.

—Bill Robinson

View a videocast of the town hall meeting and read a short biography on Dr. Varmus’s scientific career.

Cancer Research Highlights

Adherence Low among Women Taking Adjuvant Hormone Therapy for Early-stage Breast Cancer

Also in the Journals: ASCO Recommends Using an Aromatase Inhibitor in Adjuvant Breast Cancer Therapy

Updated guidelines from the American Society of Clinical Oncology (ASCO) recommend prescribing an aromatase inhibitor (AI) to women with hormone receptor-positive breast cancer at some point during their treatment. Treatment with an AI can last as long as 5 years, the guidelines explain, and AIs can be used in several ways: as initial adjuvant therapy, following 2 to 3 years of treatment with tamoxifen, or after 5 years of tamoxifen. The updated guidelines were published online July 12 in the Journal of Clinical Oncology

“Our panel carefully reviewed the explosion of research that has emerged in the past 5 years on anti-estrogen drugs, and filled in gaps in our understanding of how best to use these newer treatments, and what the trade-offs and side effects of therapy would be,” said Dr. Harold Burstein, chair of the expert committee assembled by ASCO to update the guidelines, in a news release.

Findings from one of the largest studies of its kind to date indicate that many women, particularly younger women, with early-stage breast cancer stop taking adjuvant hormone therapy before completing the 5-year regimen. The results were published online June 28 in the Journal of Clinical Oncology (JCO). In addition, an as-yet-unpublished analysis from the same study presented last month at the American Society of Clinical Oncology (ASCO) annual meeting indicates that failure to complete the treatment is associated with worse survival.

The findings published in JCO found that by 4.5 years after they began taking tamoxifen or one of three aromatase inhibitors, 32 percent of the nearly 8,800 women in the study had stopped taking their treatment. And among those who continued treatment, only 72 percent adhered to their prescribed regimen (that is, took most of their medication as prescribed) for the entire 4.5-year study period.

The study included women who are part of the Kaiser Permanente of Northern California (KPNC) health system, an integrated managed care program. The research team identified subjects via the KPNC cancer registry and tracked adjuvant therapy use via prescriptions filled through KPNC’s pharmacy information management system. Discontinuation was defined as going 180 days without filling a prescription, and nonadherence was defined as taking less than 80 percent of a given prescription.

Overall, only 49 percent of women completed the treatment regimen as prescribed. While women younger than 40 and older than 75 were the most likely to be nonadherent, the 202 women younger than 40 had the worst track record; they were 50 percent more likely to discontinue treatment and 40 percent more likely to be nonadherent than the rest of the study population.

Other studies have pointed to problems with discontinuation and adherence in women receiving adjuvant hormonal therapy. Nevertheless, given its “proven track record of reducing breast cancer recurrence,” the study authors were surprised by the extent of nonadherence, particularly in younger women. “Perhaps we need to do a better job of making patients aware that, to get the full benefit, they need to take their medications on time and for the full duration,” said lead author Dr. Dawn Hershman from Columbia University Medical Center, in a news release.

In the analysis presented at the ASCO meeting, early discontinuation and lack of adherence were associated with increases in mortality risk of 36 percent and 40 percent, respectively. The research team from Columbia University, led by Dr. Alfred Neugut, is conducting a prospective cohort study to learn why women discontinue treatment or do not adhere to the prescribed regimen, Dr. Hershman explained in an e-mail.

Drug that Inhibits DNA-repair Enzyme Shrinks Some Breast and Ovarian Tumors

In two small phase II clinical trials, the drug olaparib, which blocks a DNA-repair enzyme called PARP, shrank tumors or stopped the progression of advanced breast and ovarian cancer in some women with inherited BRCA1 or BRCA2 gene mutations. Cancer cells with BRCA mutations are thought to be especially sensitive to PARP inhibition because they have a defect in another DNA repair pathway and therefore rely on the pathway that involves PARP. The results of both studies were published online July 6 in The Lancet.

In the breast cancer trial, Dr. Andrew Tutt of King’s College London School of Medicine and his colleagues enrolled 54 women with locally advanced or metastatic breast cancer and verified BRCA1 or BRCA2 mutations. All of the women had undergone at least one prior chemotherapy regimen. Half of the women received 400 mg of olaparib twice daily—the maximum tolerated dose—and the other half received 100 mg of olaparib twice daily, which preliminary studies showed is the minimum amount to have antitumor effects. Preliminary results were presented at the 2009 ASCO annual meeting.

Tumors shrank in 11 of the 27 women in the 400 mg group and 6 of the 27 women in the 100 mg group. The median duration of this response was 144 days in the former group and 141 days in the latter. Twelve women who participated in the study experienced temporary stabilization of their disease.

The women who received 400 mg had a median survival without disease progression of 5.7 months compared with 3.8 months in the 100 mg group. Forty-one percent of patients in the 400 mg group and 33 percent of patients in the 100 mg group experienced a high-grade side effect, including fatigue, nausea, and vomiting.

Similar results were seen in a parallel phase II trial of olaparib for recurrent ovarian cancer in women with BRCA1 or BRCA2 mutations. In that trial, led by Dr. M. William Audeh of Cedars-Sinai Medical Center in Los Angeles, 33 women received 400 mg of olaparib twice daily and 24 received 100 mg twice daily. Tumors shrank in 11 women in the 400 mg group (with a median response duration of 290 days) and 3 women in the 100 mg group (a median response duration of 269 days).
 
The authors of the breast cancer paper noted that women in both the breast and ovarian trials had received a median of three previous chemotherapy regimens, meaning their disease was highly resistant to treatment. Future trials should compare the efficacy and toxicity of olaparib with traditional cytotoxic chemotherapy, they said.

Colorectal Cancer Screening Rates Rise, Mammography Rates Dip Slightly in the U.S.

Between 2006 and 2008, the percentage of adults age 50 to 75 who had undergone screening for colorectal cancer with a method recommended by the U.S. Preventive Services Task Force rose from 51.9 percent to 62.9 percent. During the same time period, the percentage of women age 50 to 74 who had received a mammogram in the previous 2 years declined slightly, from 81.5 percent to 81.1 percent.

These findings come from the ongoing Behavioral Risk Factor Surveillance System (BRFSS), run by the CDC, and were published online July 9 in the Morbidity and Mortality Weekly Report.

Adults age 50 to 59 years, Hispanics, and persons with lower income, less than a high school education, and without health insurance were least likely to have been screened for colorectal cancer. Women age 50 to 59 years, women with less than a high school education, American Indians and Alaskan Natives, women without health insurance, and those with an annual income of less than $15,000 were least likely to have received a mammogram.

The report highlights the need for evidence-based interventions to increase community cancer screening rates, such as those recently recommended in the CDC’s Guide to Community Preventive Services, concluded the authors. They also stressed the importance of physicians recommending screening services to their patients. “The most common reason women give for not having a mammogram is that no one recommended the test,” they wrote. “Therefore, health care providers have the most important role in increasing the prevalence of up-to-date mammography among women in the United States.”

Length of Telomeres Linked to Risk for Some Cancers

In one of the first prospective studies of its kind, European researchers have found an association between the length of DNA-protein complexes, known as telomeres, that are at the ends of chromosomes and the risk of incident cancer and cancer mortality. Dr. Peter Willeit of the Innsbruck Medical University in Austria and his colleagues published their findings July 7 in the Journal of the American Medical Association.

Telomeres are biological markers for aging; each time a cell divides, telomeres lose a small amount of DNA and become shorter. These structures help protect the genome, and shortened or damaged telomeres may lead to the chromosome instability that is associated with cancer.

To prospectively test for associations between telomere length and cancer incidence or death, the researchers measured telomere length in white blood cells, or leukocytes, from 787 men and women in the Bruneck Study, a cross-sectional population-based survey of atherosclerosis carried out in the small town of Bruneck, Italy. This baseline testing was done in 1995, when participants were free of cancer. After 10 years of follow-up, 92 of 787 participants (11.7 percent) had developed cancer and 44 had died of the disease.

As had been seen in previous studies, individuals with shorter telomeres at baseline had higher risks of cancer. The risk was highest in the group with shortest telomeres and lowest in the group with longest telomeres. An association was also seen with cancer mortality overall.
 
The authors noted that the sample size was too small to precisely assess associations between telomere length and specific types of cancer. Future studies would need to include participants of other races and ethnicities, as well as geographic regions. These studies could also test telomere length in a variety of tissues rather than in the easily accessible leukocytes, the authors said.

Study Estimates Cancer Cases Due to Radiation Exposure in the Marshall Islands

NCI researchers have estimated the risk of radiation-related cancers in the Marshall Islands caused by fallout from U.S. nuclear weapons testing over a 12-year period in the 1940s and 1950s. They concluded that as many as 1.6 percent of all cancers among Marshall Islands residents alive between 1948 and 1970 may be attributable to radiation exposure, and they projected that 170 radiation-related cancers will occur among more than 25,000 Marshallese. This result is based on a sophisticated analysis of available information about the weapons testing, weather patterns, population demographics, and other factors.

The estimates were released as part of a series of eight papers published online July 7 in Health Physics that describe in detail the methods and findings from the research. The studies determined the deposition of the radioactive fallout from the 66 nuclear tests conducted from 1946 to 1958, of which 20 were associated with measureable fallout in the islands. They also analyzed the internal (e.g., via ingestion of contaminated food) and external (e.g., via irradiation from radioactive fallout) radiation doses experienced by island residents.

The findings will be of benefit to Congress and health officials in the Marshall Islands, wrote lead author Dr. Steven L. Simon of NCI’s Division of Cancer Epidemiology and Genetics (DCEG) and colleagues. The methods used to study the nuclear tests’ impact “are also illustrative of methods that may be useful in broader circumstances,” they continued, such as nuclear detonations “due to accidents or intentional actions in wartime or by terrorists.”

In 2004, members of Congress asked DCEG researchers to estimate cancer risk in this population using the data that were immediately available. Those initial “unrefined estimates” were not peer reviewed, the research team explained, and “were generally conservative and purposely intended to not underestimate the actual number of cancers that might occur.”

Of the 170 estimated excess cancer cases, all but 65 are likely to have already occurred, the researchers reported. The most common radiation-related cancer was thyroid cancer, followed by colon cancer and leukemia. Residents of the northeastern atolls, or islands, who were closest to the two primary testing sites (the Bikini and Enewetak atolls) experienced the highest exposures (hundreds to more than 2,000 mGy on average) and developed about 30 percent of the estimated excess cancer cases. Prior to the tests, Bikini and Enewetak residents were relocated. Radiation exposures were likely lowest (between 5 and 12 mGy on average) among residents from the southern part of the island chain, which is farthest away from the testing sites.

“For the first time, NCI scientists have completed a comprehensive dose and cancer risk assessment for Marshallese exposed to fallout from all nuclear weapons tested in their country,” said Dr. Simon. “It was a difficult technical achievement that will be of benefit to the radiation epidemiology and dosimetry communities.”

Spotlight

Synthetic Biology and Cancer: Exploring the Possibilities

A dye marker on agarose gel being used to separate DNA Synthetic biologists are using techniques in chemistry, bioengineering, and biology to synthesize new and redesigned biological components to better understand and treat diseases like cancer.

Ten years ago, researchers created the first devices (here and here) widely viewed as launching the field of synthetic biology. In the decade since, advances in genomics and the chemical synthesis of DNA, among other fields, have created new tools for investigating and understanding the behavior of biological systems. Some researchers now believe that the time is right to harness these tools in new efforts against cancer and other diseases.

To explore how these tools might be used, NCI and the National Institute of General Medical Sciences convened a workshop in April called “Synthetic Biology and Biomedicine: Progress, Outlook, and Challenges.” The meeting brought leaders in the field to Bethesda, MD, to discuss everything from state-of-the-art technologies and their potential applications in cancer research to ethical questions raised by new discoveries. (See the sidebar below.)

“The goal was to see where the field of synthetic biology is, in terms of cutting-edge research, and to learn from experts about what the current hurdles are, especially hurdles involved in translating basic synthetic biology research into cancer research,” said Dr. Jerry Li, a program director in NCI’s Division of Cancer Biology (DCB).

Dr. Drew Endy of the Department of Bioengineering at Stanford University and Dr. Aristides Patrinos, president of Synthetic Genomics, Inc., chaired the workshop. (The workshop agenda is available online.)

While there are many definitions of synthetic biology, one of the central ideas is the belief that to truly understand how something works, one has to build it. In this sense, synthetic biology refers to the design and creation of the components of biological systems that are not found in the natural world, as well as to the redesign and fabrication of existing biological systems.

“Synthetic biology brings together knowledge learned from a number of fields—biology, engineering, physics, chemistry—and uses this information to try to redesign and engineer biological components,” said Dr. Daniel Gallahan, deputy director of DCB. For cancer research, these approaches could both reveal new insights into the disease and potentially lead to new treatments, he added.

“Coming of Age”

The Department of Energy and the National Science Foundation have funded research using synthetic biology approaches to address environmental and energy issues, but NCI does not yet have a program in synthetic biology. Dr. Dinah Singer, the director of DCB, told meeting participants that NCI was interested in integrating synthetic biology approaches into its research programs. DCB’s mission, along with supporting and coordinating research projects in cancer biology, is to facilitate the emergence of new ideas, concepts, and technologies.

“In our efforts to understand and treat cancer, NCI wants to be prepared to exploit any advance in technology that emerges from this field,” said Dr. Gallahan. “The technology has reached a point where we can not only begin to understand cancer in new ways,” he continued, “but we may also be able to intervene in the disease at different levels.”

In a recent article titled “Synthetic Biology: Applications Come of Age,” Dr. James Collins, a professor of biomedical engineering at Boston University, and Dr. Ahmad Khalil, a postdoctoral fellow in his laboratory, wrote that engineered biomolecular networks are starting to move into “the application stage,” including for cancer.

Although more work is needed “to elucidate the biological design principles, this foray into practical applications signals an exciting coming-of-age time for the field,” the authors continued. They cited as examples synthetically engineered viruses and organisms that are able to sense cues in the local environment as the basis for therapeutic activity. 

Preliminary Efforts

At the workshop, Dr. Chris Anderson of the University of California, Berkeley, described his group’s efforts to engineer bacterial cells that selectively target and then invade cancer cells. The engineered bacteria are designed to release toxic enzymes to kill the host cells once they have entered the cells. While this work is not yet ready for testing in humans, it demonstrates what might be possible with synthetic biology approaches.

Presidential Bioethics Panel Considers Synthetic Biology

On May 20, the day that Science published a study describing the first synthetic bacterial genome, President Barack Obama asked his advisory panel on bioethics to focus on synthetic biology as its first assignment. The commission will provide, within 6 months, recommendations on how to maximize the benefits of this emerging field while minimizing the risks and respecting ethical concerns. The commission held its first public meeting July 8–9. More information, transcripts, and the agenda are available online.

In another example, Drs. Ron Weiss at the Massachusetts Institute of Technology and Christina Smolke of Stanford University have been independently designing molecular switches that could be used to construct new signaling networks inside a cell. They have used these new devices experimentally to detect and react to abnormal cellular signaling events that may be associated with the development of cancer.

Although the work is still in preliminary stages, “One could envision that these approaches, if developed further, could be used in the early detection and treatment of cancer,” said Dr. Li.

Also at the workshop, Dr. Daniel Gibson of the J. Craig Venter Institute described his group’s efforts to synthesize the genome of a bacterium and transplant it into the cell of a closely related species. The results of this work were published a month later in Science. Transplanting the synthetic genome into the new host cell had essentially “rebooted” the cell, causing it to behave like bacteria with the same genome, the researchers said.

“By changing the chromosome in the cell, it completely changes the cell from one form to another,” said Dr. J. Craig Venter, the study’s senior author. Both Drs. Gibson and Venter emphasized that their experiments sometimes did not go as planned, leading them to revise their approaches based on the new information they uncovered.

This idea of “learning as you go” was a theme of the workshop, as others shared similar stories from their own projects. Even so, many participants expressed optimism about the future of the field.

“It’s a very exciting time,” said Dr. Li. “More people are becoming interested in learning how to apply their knowledge and skills in synthetic biology to biomedicine. This field is ready to take off.”

—Edward R. Winstead

A Closer Look

PSA Screening and Cancer Mortality: Swedish Study Adds to the Debate

Over the last 2 years, findings from several studies, including two large randomized clinical trials, have fueled debate about the value of screening men for prostate cancer with the prostate-specific antigen (PSA) test. The larger of the two trials, the European Randomized Study for Prostate Cancer (ERSPC), conducted in seven countries, showed a 20 percent reduction in cancer mortality in men who underwent routine screening. But that mortality reduction came at a steep price: many men whose lives would likely never have been threatened by the disease were diagnosed with and treated for cancer.

Now, results from a trial that is part of the larger ERSPC study suggest that PSA screening for prostate cancer may—under certain circumstances, at least—substantially improve cancer-specific survival without the extent of overdiagnosis and overtreatment seen in the ERSPC and the other large prostate cancer screening trial, the NCI-led Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Unlike the ERSPC, the PLCO reported no mortality benefit, but it also had a significant amount of “contamination,” that is, men in the trial who had already undergone screening with a PSA test, which a number of researchers have said may preclude the trial from ever demonstrating a cancer-specific survival improvement.

After 14 years of follow-up, the study, conducted in Sweden’s second-largest city, Göteborg (pronounced “Yotaborg”), showed an approximate 50-percent reduction in prostate cancer mortality among men age 50 to 64 (at the time of study entry) who were offered routine PSA screening compared with men not offered routine screening. The results were published online July 1 in Lancet Oncology.

Screening with PSA is an investment in future health, but as with all investments there is a cost.

—Dr. Jonas Hugosson

The findings, while suggesting promise, also brought calls for caution from researchers in the field, including the team that led the Göteborg trial.

“There are still uncertainties about the risks with PSA screening, especially the risk of overdiagnosis and overtreatment and how many years a man needs to live with possible side effects from treatment before he gains the benefits of screening,” said the trial’s lead investigator, Dr. Jonas Hugosson from Sahlgrenska University Hospital in Göteborg, in an e-mail. “Screening with PSA is an investment in future health, but as with all investments there is a cost.”

Digging into the Discrepant Results

So how are the results of the PLCO, ERSPC, and the Göteborg studies at odds? In the case of ERSPC, for example, the study authors concluded that 1,410 men would need to be screened with a PSA test and 48 cases of prostate cancer treated to prevent a single prostate cancer death. In the Göteborg study, those numbers were much smaller: 293 men screened and 12 diagnosed or treated to prevent one death from prostate cancer.

In an accompanying editorial in Lancet Oncology, Dr. David Neal of the University of Cambridge in the United Kingdom sorted through some of the key differences that could have led to these results, including the Göteborg trial’s much smaller size (20,000 men compared with 77,000 in PLCO and 182,000 in ERSPC), different screening schedules, and longer follow-up (14 years compared with 11 and 9 years, respectively). The median age of the men in the Göteborg trial was also more than 4 years younger (56 compared with over age 60), he wrote, “which is important because younger men are likely to benefit more from early diagnosis than older men.”

More than half of the participants in the Göteborg study are part of the ERSPC trial, which also complicates how the results are interpreted. In effect, the Swedish trial is a subgroup analysis of the larger European trial, explained Dr. Chris Berg of NCI’s Division of Cancer Prevention and the principal investigator of the PLCO trial.

“The Göteborg cohort provided the longest follow-up and the highest mortality benefit from PSA screening in the ERSPC trial. That means that the other groups reported in ERSPC had less than a 20 percent mortality reduction from screening,” Dr. Berg said. So the Göteborg results do not constitute “an independent confirmatory study,” she continued, but instead represent “extended follow-up on an already reported cohort with new information on an additional 8,048 individuals.”

There are other key differences, as well. Few men in the Göteborg trial had ever had a PSA screening test before enrolling in the study, Dr. Neal noted, including men in the control arm, meaning there was very little contamination. This is an important difference compared with the PLCO trial, he pointed out, in which 40 percent of participants had already been screened with a PSA test at study entry.

During the course of the trial, the state of prostate cancer screening in Sweden was “very different from the situation in the United States right now,” explained Dr. Eric Klein, chair of the Glickman Urological and Kidney Institute at the Cleveland Clinic. “It’s comparable to when PSA was introduced in the United States in the late ’80s. Now we have a heavily screened population, which is why it makes sense to build on the results of this trial to further refine our screening efforts to identify men at risk for potentially lethal cancers.” 

Dr. Klein pointed, for example, to data suggesting that a baseline PSA in men in their 40s and subsequent PSA velocity (the rate of increase in PSA levels) can predict both lifetime risk of developing cancer and of potentially lethal cancers. Such an approach, he continued, could help identify men at high risk who may benefit from chemoprevention or men diagnosed with biologically significant cancer who would benefit from early intervention.

The substantial mortality reduction in the Göteborg study was achieved even though men in both arms diagnosed with low- to moderate-risk disease received comparable treatments and even though a significant portion of the men in the screening arm who were diagnosed with prostate cancer underwent active surveillance (approximately 40 percent versus approximately 30 percent in the control arm); that is, they chose to forgo definitive treatment, such as surgery or radiation, until there was evidence that their disease was progressing. At the time of the last data analysis, more than one-quarter of those men were still under an active surveillance regimen.

“The weight of the data clearly shows a benefit to screening” in men under 70, Dr. Klein said, “but there are still opportunities to further improve our screening paradigm to focus on identifying men at risk for biologically significant disease.”

While Dr. Berg agrees that screening with PSA likely can reduce prostate cancer mortality, she was less enthusiastic about the state of knowledge surrounding its use and the Göteborg results’ contribution to it.

“I think we still have the same issues, including potential overdiagnosis and overtreatment” she said. “Furthermore, the precise magnitude of the benefit from PSA screening and the precise schedule for screening have not been further defined.”

Carmen Phillips

Featured Clinical Trial

Targeting HER2 in the Treatment of Ductal Carcinoma In Situ

Name of the Trial
Phase III Randomized Study of Radiotherapy with Versus without Trastuzumab (Herceptin) in Women with HER2-Positive Ductal Carcinoma In Situ Who Underwent Lumpectomy (NSABP-B-43). See the protocol summary.

Dr. Melody Cobleigh Dr. Melody Cobleigh

Principal Investigators
Dr. Melody Cobleigh, Dr. Douglas Arthur, and Dr. Thomas Julian, National Surgical Adjuvant Breast and Bowel Project

Why This Trial Is Important
Ductal carcinoma in situ (DCIS), a condition in which abnormal cells are confined entirely to the milk duct of the breast, is a risk factor for the development of invasive breast cancer. The standard treatment for DCIS is surgery, which produces excellent long-term disease-free results. Although most patients can be treated with lumpectomy (breast-conserving surgery, in which only part of the breast is removed) and radiation therapy, patients with larger tumors or tumors with high-grade features may undergo mastectomy (removal of as much of the breast as possible).

One high-grade feature seen in some DCIS tumors is overexpression of the HER2 protein. When there is too much of this human epidermal growth factor receptor, tumors tend to grow faster and are also more likely to recur after initial treatment. Trastuzumab (Herceptin) is a monoclonal antibody that binds to the HER2 receptor and interferes with the growth of HER2-expressing tumors. It is approved by the FDA to be used with chemotherapy to treat HER2-positive invasive breast cancer. In addition, laboratory and animal studies have suggested that trastuzumab can increase the effectiveness of radiation therapy.

In this clinical trial, women with HER2-positive DCIS will be treated with lumpectomy followed by whole-breast radiation therapy; half of the women will also receive two doses of trastuzumab during their radiation treatment. The researchers will then monitor the women in both groups to see whether trastuzumab prevents or delays the development of invasive breast cancer or the recurrence of DCIS in the breast, among other outcomes, such as breast cancer in the opposite breast. Trastuzumab is administered for a short period of time with radiation and without chemotherapy, so the side effects from trastuzumab are expected to be minimal.

“We are looking for ways to extend the option of breast-conserving surgery to women whose more aggressive or advanced DCIS would normally indicate a mastectomy,” said Dr. Cobleigh. “We have seen that radiation therapy can significantly improve protection after lumpectomy.

“Trastuzumab has been proven safe and effective in the treatment of both early and metastatic breast cancer, and we want to see if it can make HER2-expressing tumor cells more sensitive to radiation. These women are more likely to have aggressive DCIS, and they should have an alternative to mastectomy,” she said. “This is a targeted approach that could make a real difference for women in that group.”

For More Information
See the lists of entry criteria and trial contact information or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/ft-all-featured-trials.

Community Update

Survivorship
This is the fourth article in a series of stories related to cancer survivorship. Look for the symbol on the left in an upcoming issue for the next article in the series.

Cancer Survivors Discover the Power of Blogging

Ann Silberman was diagnosed with cancer in August 2009. Two weeks later, she started writing Breast Cancer? But Doctor...I Hate Pink, a blog that puts a lighter spin on her struggle with breast cancer.

A cartoon by cancer blogger Amy Marash Amy Marash uploads cartoons to her blog, Cancer Is So Funny, to share information with other cancer patients.

“I am able to take myself out of treatment and uncomfortable situations by thinking about how I’m going to write about it, or by looking for the humor in a situation for my readers,” Silberman said. “By being able to write about cancer for other people, I find that I am able to focus on the positives rather than the negatives, because that is what I want my readers to do.”

Nancy Morgan, director of the Arts and Humanities Program at the Lombardi Comprehensive Cancer Center at Georgetown University, affirmed the power of blogging for patients.

“The people I encounter at Lombardi who blog about their cancer are very much empowered by their ability to articulate thoughts and feelings about cancer and to link with others,” Morgan said. “One person’s courage to write inspires another to express their feelings. The relief that comes from self expression is palpable.”

In a study published in The Oncologist in 2008, Morgan and her colleagues found that patients reported feeling better after completing an expressive writing exercise.

“Post surveys and subsequent interviews identified a significant correlation between those who felt the writing changed the way they thought about cancer and improved physical quality of life,” Morgan said.

Amy Marash was referred to Morgan after telling her onocologist she wanted to draw cartoons to share information with other cancer patients. Morgan gave her a sketchbook, and Marash began drawing the cartoons with ballpoint pens, adding color with markers, and then uploading her work to her blog, Cancer Is So Funny, after perfecting the sketches in Photoshop.

“People love my cartoons,” Marash said. “They say my stuff is ‘wicked funny’ and that they laugh out loud. Some of these people lost someone they love to cancer. One of my biggest fans lost his father and his brother to the same disease. Others are fighting cancer and share my comic strip with their cancer buddies. So far, no one has said that my strip upset a cancer patient, and I hope it never does.”

Daria Maluta, who was diagnosed with breast cancer in 2000, writes the blog Living with Cancer. She had recurrences in 2004 and 2008 and is currently receiving chemotherapy.

“The blogging community offers a place for people with cancer to connect, share stories, and offer each other encouragement,” Maluta said. “Through blogging, I have learned an enormous amount, not only about cancer and its treatment, but also about how others deal with their illness. I believe it’s made me a stronger person.”

Carolyn Langlie-Lesnik, a registered nurse from Indiana, was diagnosed with appendix cancer in March 2001 and was once told her cancer was untreatable. Her blog, Appendix Cancer Survivor’s Blog, “is devoted to sharing what has been the more difficult part of the journey for me,” she said. “The emotional and spiritual road I’ve traveled as a rare cancer survivor.”

Langlie-Lesnik hopes her blog provides appendix cancer patients a place to vent and gives them information via useful links and other survivor stories.

“I truly needed to find purpose in my survival, to find a way to ‘pay forward’ all of the help I received,” Langlie-Lesnick said. “I hope my blog serves a purpose of helping others know they are not alone in their struggle; ours is a rare and lonely cancer. I’ve met several people I’ve come to admire via my blog, though many have lost their battle.”

Silberman has a large group of followers and is linked to her hometown newspaper’s Web site, The Sacramento Bee.

“I do see that a lot of people find my blog using a Google search term and then read it from start to finish, which is amazing,” Silberman said. “It tells me people really want to know what may happen to them.”

Both Silberman and Langlie-Lesnick were familiar with blogging before starting their cancer blogs. Langlie-Lesnick started an educational Web site, Appendix Cancer Connection, 5 or 6 years ago prior to publishing her blog. Silberman said she had previously blogged on other topics and was familiar with the tools. Maluta follows over 200 other cancer blogs. Marash blogged for The Digital Journalist before starting her own blog.

Each of the women has developed a community with her readers. “There are times the disease or treatment gets me down,” Maluta said. “I blog about how I’m feeling and/or what I am experiencing, and before you know it, someone is sending me an encouraging comment or e-mail. These few words of encouragement really lift my spirits. To be honest, I don’t know where I’d be without my blogging family.”

—Elizabeth Goers

Legislative Update

The Congressional Biomedical Research Caucus: Highlighting Cancer Research

Cancer research is featured prominently in this year’s Congressional Biomedical Research Caucus (CBRC) biweekly briefing series. Each year, the CBRC hosts the series to educate Congressional staff and members of Congress, particularly those who serve on committees with jurisdiction over science and health issues, to build support for basic and clinical biomedical research. In general, the briefing series focuses on health care advances made possible by investments in biomedical research and future advances that could be achieved through additional research.

The CBRC is a bipartisan caucus with members from both the House and the Senate, co-chaired by Representatives Rush Holt (D-NJ), Brian Bilbray (R-CA), Michael Castle (R-DE), and Jackie Speier (D-CA). Rep. Holt, who earned a Ph.D. in physics from New York University, was a researcher before taking office. “I am proud to be a co-chair of the Congressional Biomedical Research Caucus, which strives to educate legislators on the importance of adequate biomedical research funding as well as highlight the research results that are generated with that investment,” Rep. Holt said. “Biomedical research plays a critical role in improving the quality of health care in our country and improving our economy. In addition, we need to remember that basic science research leads to the new tools and techniques that make important biomedical research possible.”

Several of the 10 briefings in the 2010 series, including three that have been held already, directly address cancer research:

  • A May 26 briefing featured Dr. Mina Bissell of the Lawrence Berkeley National Laboratory, with a presentation titled “Cancer Cells and Their Neighborhoods.” She discussed her research on how cancer cells interact with surrounding tissue, focusing on the idea that these cells depend on the cooperation of other cells nearby in order to spread.
  • Dr. Daniel Silver of the Dana-Farber Cancer Institute presented “PARP Inhibitors: A Breakthrough in Cancer Therapy?” on June 9. In his overview of the successes and inherent challenges of developing PARP inhibitors for use in the treatment of breast cancer, Dr. Silver stressed the importance of translational research—connecting basic science to clinical practice and bringing discoveries to patients.  “We are making progress,” he noted.  “It’s incremental, but it’s steady.”
  • On June 23, Dr. John Coffin of Tufts University presented “Viruses in our Genomes: Unending Surprises,” highlighting several proviruses and their roles in human and animal cancer. Dr. Coffin, who is also director of NCI’s HIV Drug Resistance Program, described how NIH research over the past few decades has led to the basic groundwork for understanding cancer causation.  “Without the research on retroviruses supported by NIH,” he said, “I can’t imagine where we would be in the field right now.”

The briefings are organized by the Coalition for the Life Sciences, an alliance of nonprofit professional organizations that serve as the Advisory Committee to the CBRC. (NCI Director Dr. Harold Varmus is a former scientific advisor to the CBRC.) The briefings do not pose a specific call to action, but instead provide a forum for the audience and presenters to discuss key questions. An emerging theme common to these cancer-focused briefings was the complexity of cancer research. Dr. Bissell offered her view of this challenge, saying: “The problem of cancer is a problem of evolutionary biology and is a problem of developmental biology. There’s not a single answer to these things.”

Four briefings are scheduled for the remainder of the 2010 series, including one on July 21 that will feature Dr. Ann Partridge of the Dana-Farber Cancer Institute. Dr. Partridge will speak about mammography and the evolution of breast cancer screening guidelines, as well as the most recent updated guidelines from the U.S. Preventive Services Task Force.

More information about the CBRC is available on the Coalition for the Life Sciences Web site, including the full 2010 briefing schedule.

NIH Update

Videos Illustrate How to Navigate the NIH Funding Application Process

Screenshot of Youtube video, NIH Peer Review Revealed

NIH’s Center for Scientific Review (CSR) has released two videos to aid new and established researchers in the grant application process. The first, NIH Peer Review Revealed, is a 15-minute video that simulates a peer-review meeting and “provides an inside look at the dynamic way reviewers evaluate grant applications,” said CSR Director Dr. Toni Scarpa. A second video, NIH Tips for Applicants, is a 5-minute production in which reviewers and NIH staff members provide insights and advice to new applicants about what to do and what to avoid when applying for research funding from NIH.

The largest portion of NIH’s annual $31 billion budget supports grants to researchers; more than 80,000 grant applications are received each year. For more than 60 years, CSR has managed the review and distribution of these grants using the expertise of scientists from around the country who have themselves received major peer-reviewed grants. “NIH prides itself on using a process that is fair, independent, expert, and timely,” said Dr. Scarpa.

Cancer.gov Update

NCI Launches Comprehensive Biospecimen Resource Web Site

Screen shot of caHUB Web site

NCI’s Office of Biorepositories and Biospecimen Research has developed a new Web site to help advance the mission of its cancer Human Biobank (caHUB) initiative. The recently launched site hosts a variety of resources for the general public, professionals who work with biospecimens, potential partners, health care professionals, and patients. These include:

  • Videos from thought leaders in the field of biospecimens
  • Information about funding and partnership opportunities
  • Reports for the scientific, policy, and advocacy communities
  • Progress updates on this initiative to improve cancer research

caHUB was created in response to the critical shortage of high-quality, clinically annotated biospecimens, which are essential resources to accelerate the development of molecular-based diagnostics and therapeutics for personalized medicine. caHUB will contribute to medical advances by providing high-quality human specimens and data, as well as analyses, scientific tools, and services to the cancer research community and product development industries.

SEER Releases New U.S. Cancer Mortality Data

NCI’s Surveillance Research Program updated the 2010 SEER Cancer Statistics Review, 1975-2007 (CSR) to include U.S. cancer mortality data. This update is in addition to previously posted materials, which were released on April 15. Other materials available online include:

The updated CSR presents the most recent statistics on cancer incidence, survival, mortality, prevalence, and lifetime risk. All material in the SEER CSR report is in the public domain and may be reproduced or copied without permission. Citation of the original source is appreciated.

The latest SEER data were also released through SEER*Stat, statistical software that provides a mechanism for analyzing data in SEER and other cancer-related databases.

Notes

New Issue of CCR Connections Released

Cover of CCR Connections

The newest issue of the NCI’s Center for Cancer Research (CCR) news magazine, CCR Connections, is available online. Volume 4, issue 1, features articles about how genomic profiling can be used to exclude ineffective treatments for pediatric tumors, how synthetic silencing RNAs can identify which genes need to be targeted to make glioblastoma cells more vulnerable to radiation, and how therapeutic synergy can be achieved by combining new treatment strategies with standard modalities. This issue also includes a commentary from former NCI Director Dr. Samuel Broder, a clinical highlight on detecting multiple myeloma at a precancerous stage, and summaries of several recent CCR scientific publications and staff awards.

CCR Connections is published semiannually. Please send requests for print or online subscriptions to tellccr@mail.nih.gov.

Winners of Smokefree Women Video Contest Announced

Screen shot of smokefree.gov Web site

Smokefree Women, the campaign associated with NCI’s smoking cessation Web site developed for women, recently hosted a video contest called “Celebrating Smokefree Voices,” in which people from across the United States developed and submitted videos in two categories: “Why I’m a Smokefree Woman” and “Why I Want You to Be a Smokefree Woman.” Visitors to the site cast more than 14,000 votes for their favorites. The winning videos capture the variety of quitting experiences and reasons for quitting smoking among women, their friends, and their families. To watch the top three videos in each category, visit the contest page.