National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 26, 2010 • Volume 7 / Number 2

NEWS

Pediatric Cancer Genome Project logoSt. Jude, Washington University Launch Genome Project for Childhood Cancers

Researchers at St. Jude Children's Research Hospital and the Washington University School of Medicine in St. Louis have launched the Pediatric Cancer Genome Project to sequence the genomes of at least 600 children with cancer over the next 3 years. The collaboration marks the first time that whole-genome sequencing will be used on a large scale to discover genetic changes driving pediatric cancers. Read more > >

COMMENTARY

Dr. Paulette GrayGuest Director's Update: Major Grant Application Changes Now in Effect

by Dr. Paulette Gray

The new year is beginning with a very important change for investigators intending to apply for grant dollars from NIH to support their research. As of January 25, the NIH grants application process will undergo the most significant changes to date with newly restructured and shortened application forms. Read more > >

A Conversation about Sequencing Cancer Genomes with Dr. Elaine Mardis

The co-director of the Genome Center at the Washington University School of Medicine in St. Louis discusses the cost, benefits, and technical challenges of sequencing cancer genomes. Read more > >

  
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IN DEPTH

UPDATES

  • Cancer.gov Update

    • Recovery Web Site Highlights the NCI Community Cancer Centers Program
    • NCI Launches Web Site for the Alliance of Glycobiologists
    • Online Resource on Menthol and Tobacco Now Available from NCI
    • NCI's Reagents Data Portal Features Added Content

    Notes

    • NCRR Hosts CTSA Industry Forum to Promote Collaboration, Drug Development
    • Registration Open for Cancer Drug Development Meeting
    • NCI Holds Annual Intramural Scientific Retreat
    • New NCI Spanish-language Resources Available

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

St. Jude, Washington University Launch Genome Project for Childhood Cancers

Pediatric Cancer Genome Project logo

Researchers at St. Jude Children’s Research Hospital and the Washington University School of Medicine in St. Louis have launched the Pediatric Cancer Genome Project to sequence the genomes of at least 600 children with cancer over the next 3 years. The collaboration marks the first time that whole-genome sequencing will be used on a large scale to discover genetic changes driving pediatric cancers.

“This is the largest and most powerful single initiative in the 50-year history of St. Jude,” the research hospital’s director, Dr. William E. Evans, said at a press briefing announcing the project yesterday. “DNA is being sequenced as we speak,” he added.

We view this as creating a resource not just for our efforts but for the world. - Dr. William Evans, director of St. Jude

St. Jude has a repository of biological samples and clinical information from children who have been treated there since the 1970s. The collection represents a treasure trove of information about cancer, and it can now be scrutinized using the latest genomic technologies at a cost that continues to decline substantially over time.

“This is a new era for pediatric cancers,” NIH Director Dr. Francis Collins said at the briefing. “The study represents an opportunity to discover all the ways that a good cell in an innocent child goes wrong.”

The project—estimated to cost $65 million and funded by St. Jude—aims to discover the genetic origins of pediatric cancers while creating knowledge that can be used to improve the care of young people with these rare diseases. Early results could reveal new uses for available drugs, and, over the long term, lead to targeted agents for these cancers, the researchers said.

New genetic signatures for classifying and treating patients are also anticipated. Knowing that a child has a subtype with a poor prognosis would allow physicians to select aggressive treatments early in the course of the disease. Similarly, doctors could safely withhold treatments from a patient who has a better prognosis, based on a genetic profile.

“These two great NCI-designated comprehensive cancer centers are demonstrating yet again their commitment to making a difference for kids with cancer,” said NCI Director Dr. John Niederhuber.

Dr. Larry J. Shapiro, dean of the Washington University School of Medicine and a pediatric geneticist, said at the briefing: “This project will provide a detailed and complete picture of the mutations in the cancer cells.”

In 2008, researchers at Washington University and their colleagues published the first genome sequence of a person with cancer—a woman with leukemia. They have since published the genome of a second person with leukemia, and they have also sequenced dozens of additional cancer genomes using the same whole-genome approach.

The new effort will focus on leukemias, brain tumors, and sarcomas (tumors of bone, muscle, and other connective tissues). To identify genetic changes associated with cancer, the researchers will sequence DNA from both the tumor cells and normal cells of each patient.

The project complements in every way the efforts of The Cancer Genome Atlas (TCGA) Research Network, which focuses on adult cancers, noted Dr. Collins. Just last week, TCGA investigators identified new subtypes of brain cancer using genomic and clinical data—an example of the kind of knowledge Dr. Collins expects to come from the pediatric project.

Another genome effort in pediatric cancer is the NCI-supported childhood cancer TARGET initiative, which includes St. Jude investigators as well as other childhood cancer researchers. The initial discoveries from this project are being translated to the clinic through an early stage clinical trial that is in development for a newly described type of acute lymphoblastic leukemia.

What distinguishes the new project from past efforts, said Dr. Richard Wilson, director of the Genome Center at Washington University, is that this one will be “all whole-genomes all the time.” Most genome studies have been limited to sets of genes or genetic markers because of the costs of sequencing DNA. Those costs have now fallen to below $100,000 for a tumor-normal combination, and the sequencing can be done in about a week, Dr. Wilson said. (See “A Conversation with Dr. Elaine Mardis” in this issue.)

“There is a sense of urgency to make progress here, and it has now become affordable,” said Dr. Evans. “We see this effort as a marathon, and the first 3 years are really just the beginning. I am certain there will be lots of unanswered questions at the end of this period, and there will be much more work to be done.”

He acknowledged the enormous challenge of managing and making sense of as much as 100 trillion pieces of data (600 cases, 2 genomes per case, and each genome will be sequenced 30 times to ensure that nothing is missed). To meet this challenge, Washington University is adding new instruments and computational power, and the researchers are confident that they are ready.

“The data storage, management, and analysis problems are substantial,” Dr. Wilson said in an interview. “But this project is coming along at just the right time in terms of our technical capabilities. We’ve really come a long way in just the last 6 months in terms of our data production technology.” 

St. Jude has, in effect, been preparing for this project for 45 years by creating the tissue repository and developing a capacity for preclinical research studies. The infrastructure and resources required for follow-up studies of the genomic data, such as mouse models, already exist at St. Jude, noted Dr. Elaine Mardis, co-director of the Genome Center at Washington University. “The genome project will fill these pipelines with new information to be analyzed.”

In the future, the project will include other types of alterations in cancer, such as those involving RNA and epigenetic changes, which alter the activity of genes without causing a change in DNA sequence, the researchers said.

They stressed that the results will be made publicly available through a Web site once the information has been validated. The hope is that other investigators will bring their own expertise and perspectives to the data and help move the science forward.

“We view this as creating a resource not just for our efforts but for the world,” said Dr. Evans. He quoted the founder of St. Jude, the entertainer Danny Thomas, who liked to say, “To cure one child in Memphis is to cure a thousand worldwide.”

“It is always a good thing if our discoveries can be amplified and leveraged elsewhere,” Dr. Evans added, “and that’s what has to happen.”

—Edward R. Winstead

Cancer Research Highlights

Adjuvant Chemotherapy May Benefit Older Patients with Colorectal Cancer

A new analysis of results from a large clinical trial indicates that some patients with colorectal cancer who are age 70 or older may have improved outcomes with post-surgical chemotherapy that includes newer agents. The finding, presented at the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium, runs counter to the results of a data analysis from another clinical trial, published last year, that found no such benefit.

In the nearly 1,900-patient clinical trial, participants with stage III colorectal cancer who received capecitabine and oxaliplatin, a regimen called XELOX, lived longer after surgery without their tumors progressing than those who received an older regimen, the drugs 5-fluorouracil (5-FU) and leucovorin. Overall survival data aren’t yet available from the trial, explained the study leader, Dr. Daniel Haller, of the University of Pennsylvania’s Abramson Cancer Center, during a press briefing.

Disease-free survival after 3 years of follow up was 71 percent among patients who received XELOX compared with 67 percent among patients who received 5-FU and leucovorin. When disease-free survival was analyzed by age group (younger than 70 and 70 or older), XELOX led to improved disease-free survival for patients in both age groups, although the improvement was statistically significant only in patients younger than 70. The lack of statistical significance among those 70 or older, Dr. Haller said, was likely due to the smaller number of trial participants who fell into that age group—approximately 400 patients.

The finding that patients over age 70 may benefit from this adjuvant regimen is clinically important, Dr. Haller argued. Based on the recently published MOSAIC trial results and an analysis of six clinical trials of adjuvant therapy for colorectal cancer, which showed no benefit with the addition of oxaliplatin to adjuvant therapy in patients age 70 and older, some oncologists are not including such newer drugs as part of adjuvant chemotherapy offered to patients in this age group, regardless of their health status, he said.

The findings should help clinicians make more informed choices about adjuvant therapy with their patients who are older than age 70, said Dr. Jack Welch of NCI’s Division of Cancer Treatment and Diagnosis. The data show that some patients over age 70 can tolerate the XELOX regimen, he continued. “And capecitabine is an oral drug, which might make treatment more accessible for elderly patients with limited transportation options,” so the convenience of the regimen could contribute to patient compliance, he said.

Brain Cancer, Like Other Cancers, Has Distinct Subtypes

A survey of genomic changes in several hundred brain tumors revealed two new molecular subtypes of the disease and confirmed two previously known subtypes. The findings, from The Cancer Genome Atlas (TCGA) Research Network, indicate that glioblastoma, the most common malignant brain tumor in adults, includes at least four distinct forms that are recognizable by their genetic signatures. In additional work, the researchers found that the response to aggressive therapies for glioblastoma varied by subtype, according to their report in the January 19 Cancer Cell.

The ability to detect subtypes establishes a framework for future research and holds promise for matching patients with the most appropriate therapies. The findings could also lead to therapies directed at the molecular changes underlying each subtype, as has happened in some types of breast and other cancers. Similarly, experimental models could be developed for each subtype. The results may also help investigators identify the cells of origin for these cancers, which would have implications for treatment.

The work builds on a recent report by TCGA authors describing a core set of molecular pathways that are commonly deregulated in glioblastoma. In the current study, Dr. Neil Hayes of the Lineberger Comprehensive Cancer Center at the University of North Carolina and his TCGA colleagues integrated various types of genomic information for 200 tumors, including changes in the number of copies of genes and DNA mutations.

The four subtypes were characterized by alterations involving the genes PDGFRA, IDH1, EGFR, and NF1. In each tumor subtype, a series of molecular events occurred, often leading to changes in the activity of thousands of genes. This observation was validated in a second set of 260 tumors.

“This work is a powerful example of how data from TCGA can be used by research teams to better understand and treat complex diseases such as glioblastoma,” said NCI Deputy Director Dr. Anna Barker.

Dr. Hayes added, “These results give us a clear direction for how we’d like to proceed in this disease. Based on the patterns, we can divide patients up in a logical manner and eventually tailor therapies for more individualized care.” Noting that TCGA investigators will be analyzing a number of tumor types in the coming year, he continued, “This paper is a model for how we’d like to proceed. And it’s good to have a model, because we have a lot of data coming our way.”

Strategy May Enhance Umbilical Cord Blood Transplants

A new study offers a potential way to help restore blood cells and the immune systems of patients who have had treatments, such as chemotherapy, that deplete normal cells along with tumor cells. The method increases the numbers of hematopoietic stem cells that can be obtained from umbilical cord blood by stimulating the Notch signaling pathway of cord blood stem/progenitor cells in the laboratory (ex vivo). These cells can then be transplanted into patients, where they give rise to new blood cells, including the white blood cells of the immune system.

A team from the Fred Hutchinson Cancer Research Center (FHCRC) tested the method in a phase I trial of patients with acute leukemias. The modified transplanted cells repopulated certain immune cell types faster than normal umbilical cord blood did, in some cases by more than a week, the researchers reported online in Nature Medicine on January 17. The results, while preliminary, suggest that this method reduces the time it takes for the patient’s immune system to recover after a transplant. Speeding this recovery is important because the lack of an immune system leaves patients vulnerable to life-threatening infections.   

The Notch signaling pathway is an important regulator of development. A decade ago, Dr. Irwin D. Bernstein of FHCRC and his colleagues discovered that increased activity of the Notch1 gene was associated with expanded populations of hematopoietic stem/progenitor cells. Since then, he and others have been developing ways to translate this discovery into the clinic without having to alter the gene itself. Instead, their technique stimulates Notch signaling through molecules that interact with proteins in the pathway.

“This study demonstrates in principle that a well-known regulator of development can be used to self-renew a population of cells for therapeutic purposes without altering the genetic makeup of the cells,” said Dr. Bernstein. He collaborated on the trial with Dr. Colleen Delaney, who coordinates the cord blood transplant program at FHCRC. It is not yet known whether the strategy will improve the outcomes of patients, but the researchers plan to address that question in ongoing studies.

Acupuncture Reduces Joint Pain in Some Women with Breast Cancer

In a small randomized clinical trial, breast cancer patients experiencing joint pain and stiffness from aromatase inhibitor (AI) treatment reported an improvement in pain from acupuncture. Eighty percent of women receiving acupuncture reported at least a 2-point improvement on a 10-point pain scale, compared with 22 percent of women who received a sham treatment. These results were published January 25 in the Journal of Clinical Oncology.

Researchers led by Dr. Katherine D. Crew of Columbia University enrolled 51 women in the trial, 43 of who were randomly assigned and 38 of who completed the treatment. Scheduling difficulties accounted for most of the women who enrolled but did not begin or finish treatment.

All of the women were blinded to their treatment assignment, which consisted of either 12 acupuncture sessions or 12 sham treatments (in which needles were lightly inserted into the body at points thought to have no effect on pain) over the course of 6 weeks. The researchers used three different scales to measure changes in joint pain, stiffness, and knee and hand function.

At the beginning of the study, women in the acupuncture group reported a mean worst pain score of 6.7 (on a scale from 1 to 10), compared with a mean score of 5.6 in women in the sham group. After treatment, women in the acupuncture group reported a mean worst pain score of 3.0, compared to 5.5 in women in the sham group. These numbers corresponded to a 50 percent improvement in pain scores for the acupuncture group.

“To our knowledge,” concluded the authors, “this report is the first randomized, placebo-controlled trial establishing the use of an intervention to control AI-related joint symptoms, which should be confirmed in a larger randomized trial.”

Genome Scans for Pancreatic Cancer Yield Clues to Risk

A genome-wide association study for pancreatic cancer has, for the first time, identified regions on three chromosomes that may harbor risk factors for the disease. Researchers now have new leads for investigating genetic factors involved in this deadly disease. One of the regions, on chromosome 5, has been associated with multiple diseases and may have a role in various cancers, the study authors reported online in Nature Genetics on January 24.

“This is really the first large, comprehensive effort that has identified novel genomic regions associated with an increased risk of pancreatic cancer,” said lead author Dr. Gloria M. Petersen of the Mayo Clinic. The genetics of pancreatic cancer are challenging to study, she noted, because the disease is relatively rare and many patients do not live more than a year after diagnosis.

In the team’s initial analysis reported last year, the researchers found that a variant in the gene ABO, which determines blood type, is associated with the risk of pancreatic cancer. For the current analysis, the team expanded their efforts and collected DNA from nearly 4,000 patients in 13 different studies around the world. They then tested 550,000 DNA markers (single-nucleotide polymorphisms) in both the patients and a comparison group. The top hits included segments on chromosomes 1, 13, and 5.

“The three regions are unequivocally associated with the risk of pancreatic cancer, and they point to biologically new and interesting places in the genome,” said senior author Dr. Stephen Chanock of NCI’s Division of Cancer Epidemiology and Genetics. The region on chromosome 5 appears to play a role in multiple cancers and in this respect may be comparable to a region on chromosome 8, known as 8q24, which is associated with at least five different cancers, he added.

Previous studies have linked the segment on chromosome 5 to cancers of the brain, lung, and bladder, as well as to melanoma, leukemia, and pulmonary fibrosis. This region includes two genes associated with cancer, including TERT, which is essential for maintaining the ends of chromosomes, called telomeres. Changes in the activity of this gene can cause cells to live longer and may lead to cancerous changes, the researchers noted.

Guest Director's Update

Major Grant Application Changes Now in Effect

Dr. Paulette Gray Dr. Paulette Gray

The new year is beginning with a very important change for investigators intending to apply for grant dollars from NIH to support their research. As of January 25, the NIH grants application process will undergo the most significant changes to date with newly restructured and shortened application forms.

These changes are the result of a comprehensive effort, the Enhancing Peer Review Initiative, which began in 2007 with an in-depth evaluation of the current peer review system. A year-long diagnostic phase and the publication of a final report preceded the release of a Peer Review Enhancements and Implementation Plan in June 2008. Recommendations that have already been phased in include: changes in new and early investigator policies; one resubmission limit; enhanced review criteria; and a new scoring system. The final major recommendations being implemented this month are changes in the NIH grant applications new instructions: significantly shorter page limits and restructured forms. The chief aim of these changes is to better align the structure and content of the grant applications with review criteria and to improve the efficiency and transparency of the review process.

Each of the key changes offers tangible benefits to all who have a stake in the applications process. Reducing page limits for competing applications, for example, will help to lower the administrative burden for applicants, reviewers, and staff. This change will focus applicants and reviewers on the essentials of the science that are needed for a fair and comprehensive review of the application. Shorter applications may have additional benefits for reviewers by avoiding information overload and enabling a larger number of reviewers to read each application and participate in review in a more informed manner. 

NIH is also restructuring the applications by aligning the structure and content with the new enhanced peer review criteria released in December 2008 (NOT-OD-09-025). For example, the new application format has a Research Strategy Section that includes defined subsections addressing significance, approach, and innovations, three of the five review criteria. In addition, the enhanced biographical sketch includes a personal statement describing the experience and qualifications that make the participants particularly suited for their role in the project. These changes will focus applicants and reviewers on the same elements and help ensure a more efficient and transparent review process.

Applications for due dates on or after January 25, 2010, require the restructured forms. Applicants should go to the reissued Program Announcements and updated Funding Opportunity Announcements (FOAs) to download new applications and instructions. Applicants must be careful to select the correct SF424 (R&R) electronic forms or PHS398 paper forms, if applicable. The changes apply to all competing applications: new, renewal, resubmission, and revision.

For submissions in January, a reminder in the electronic application submission process will trigger whenever an electronic application is submitted using the old application forms after the first week of January 2010. The warning will remind applicants of the new requirements.

NIH and NCI leadership are confident that this is a significant step forward in terms of the efficiency and transparency of the grant review process.

For more information, please see the Enhancing Peer Review site for the NIH Guide announcement NOT-OD-09-149, new Frequently Asked Questions, and a video overview of the changes, or visit the NCI Division of Extramural Activities (DEA) at http://deainfo.nci.nih.gov/funding.htm.

Dr. Paulette S. Gray
Director, NCI Division of Extramural Activities

A Conversation With

A Conversation about Sequencing Cancer Genomes with Dr. Elaine Mardis

Dr. Elaine Mardis Dr. Elaine Mardis

Dr. Elaine Mardis is co-director of The Genome Center at Washington University in St. Louis. As director of technology development, she leads the center’s efforts to explore progress in next-generation sequencing technologies. Dr. Mardis was part of the team that sequenced the genomes of two adults with leukemia, and she is now working on the Pediatric Cancer Genome Project, which is a partnership between Washington University and St. Jude Children’s Research Hospital.

How many tumors does one need to sequence to get results that benefit patients?

I don’t think anybody knows the answer to that question. While I’m hesitant to speculate on the number, I’m very hopeful, based on our own experience, that we’ll be able to achieve some really significant findings in a short period of time. We’ve already found key mutations that are recurrent throughout acute myeloid leukemia, that have prognostic value, and that in the long term may turn out to be drug targets.

A machine for analyzing DNA at the Genome Sequencing Center, Washington University School of Medicine in St. Louis A machine for analyzing DNA at the Genome Sequencing Center, Washington University School of Medicine in St. Louis

What happens after the sequencing?

Our sequencing activities will generate a list of clues, if you will. By clues, I mean key genes that are mutated in these tumors and germline (inherited) variations that likely play a role. We have to then take that set of clues and try to understand the implications of these mutations for the development of cancer. This work requires cell culture models, mouse models—all of those things are components of the research network and infrastructure that exist now at St. Jude.

I think it will be very exciting to work with that aspect of their operations and fill their pipelines, if you will, with all of these clues. This, in turn, will further our understanding of the basic impact of those mutations on cancer biology and the development of the disease. At the end of the day we need to have that infrastructure and expertise in place so that we can gain a better understanding of this disease, which is obviously what this is all about.

Do you have estimates for the costs of the sequencing?

It’s possible to do an estimate right now today and then the number will actually change dramatically over the upcoming months. But I can give you a sense of what the trajectory has been and probably will be.

Back in ‘07 and ’08 when we sequenced our first leukemia patient’s genome, we completed the project for around $1.5 million. We were really doing two genomes, because we were comparing the DNA of tumor cells and normal cells. It was quite an expensive project, but this was the first time that had ever been done. We had to build a lot of the infrastructure and the informatics to analyze the sequence data from the ground up, and that’s now in place. We now have a well-honed and, in many senses, an automated process for analyzing next-generation sequence data.

Our second tumor-normal genome comparison cost about $500,000, so already there was a dramatic drop in the price. That had to do with two things. We didn’t have to spend as much time generating the data, because the ability to sequence on the instruments we were using increased. The other reason was that many of the bioinformatic programs were already in place to analyze the data.

If you jump forward to today, it now takes just two runs of the instrument to generate the information for the tumor sample and another two runs to generate the data for the normal sample. We’re looking at a cost for that tumor-normal pair of about $90,000. So you can see a rather dramatic drop in cost in a reasonably truncated time frame, and the price keeps falling successively. So even though the St. Jude proposal specifies 600 tumor-normal pairs, it’s quite likely that with the same amount of money in this collaboration we’ll be able to do significantly more than that over the 3-year time period just because of that cost reduction.

Can you talk about your group’s ability to manage and make sense of the data?

One of the forward-looking things that the dean of the medical school, Dr. Larry Shapiro, did about 3 years ago was to allow us to build a state-of-the-art data center. We have filled the space with around 6,000 computing cores and over 5 petabytes of data storage capability. So this infrastructure is in place along with bioinformatic programs to do data analysis, which were largely developed for our work on adult cancers.

The St. Jude opportunity builds upon this existing infrastructure and bioinformatic capability. Working closely with our collaborators at St. Jude, we now need to figure out which of the samples and which of the clinical questions in the near term will be most relevant to some of the weightier questions in pediatric cancer we’d like to explore. We will then get those samples up here and start on DNA sequencing.

How will you integrate the genomic and the clinical data?

All of the samples are from patients treated at St. Jude, and the samples come to us with extensive clinical records, so we know how the patients did, how they were treated, what the outcomes were. It is really invaluable to have that kind of rich clinical data available to us. And in many cases we will be dealing directly with the oncologists who acquired these samples and treated these patients. These oncologists, of course, have an intimate knowledge of the disease.

Once we have the data sets in hand and the preliminary analyses completed, this, in my mind, is where the enterprise succeeds or fails. The challenge will be to roll up our sleeves with those pediatric oncologists and begin to discuss what the data might mean—and how to interpret these results in the context of that clinical information. This project really involves building a strong collaborative relationship with those key players at St. Jude. We already have that with Dr. James Downing and some of his leukemia colleagues, and we’ll continue to build that out as we look at the other major tumor types that occur in children.
 
What might you learn about normal genomes from this project?

For starters, I don’t think that we know enough about normal genomes. In some ways, the beauty of sequencing the normal genome along with sequencing a tumor is that, over time, we accrue so much information about normal genomes and the variation that lies therein. In fact, we have an active effort in our existing cancer-sequencing program to build a database of normal genome variation. To look at the big picture, cancer, regardless of whether it is pediatric or adult, is an interplay between the mutations you are born with—your germline (inherited) mutations—and whatever happens downstream of that—your somatic (naturally occurring) mutations.

Now, in pediatric cancer this is a particularly interesting question. Obviously, adult cancers make more sense in that the disease happens to people who are older. Their bodies have experienced many cell divisions, and there have been many opportunities for mutations to creep in. But for children, that logic does not apply. So I think there is likely to be a story here looking at normal variation. We are very keen to generate lots of data on normal genome variants and see what we can come up with in terms of that interplay between the germline and the somatic mutations.

Special Report

UPDATE

The ATTRACT-1 trial testing the drug ASA404, also called vadimezan, in patients with previously untreated, advanced non-small cell lung cancer was halted after a planned interim analysis showed that there was little or no prospect of demonstrating a survival benefit. Read the full article about the trial’s termination in the April 6, 2010 NCI Cancer Bulletin.

Trials Point to Potential Advances in Lung Cancer Treatment

These FLT-PET scans show a 43-year-old nonsmoker, whose lung tumor was positive for an ALK gene rearrangement. The image on the left shows the primary tumor in the left lung, as well as disease in regional lymph nodes (green areas). The image on the right, taken after 4 weeks of treatment with PF-02341066, reveals marked tumor shrinkage. These FLT-PET scans show a 43-year-old nonsmoker, whose lung tumor was positive for an ALK gene rearrangement. The image on the left shows the primary tumor in the left lung, as well as disease in regional lymph nodes (green areas). The image on the right, taken after 4 weeks of treatment with PF-02341066, reveals marked tumor shrinkage. [Enlarge]

Results from two early phase clinical trials suggest that patients with advanced lung cancer may have new treatment options that improve their survival. The results were reported recently at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer in Coronado, CA.

The findings, said Dr. Paul Bunn of the University of Colorado and a leading expert on lung cancer treatment, are part of an encouraging trend. “Almost every year now we’re getting new drugs that improve survival in lung cancer patients,” he said during a press briefing. “But we have a long way to go.”

The larger of the trials, dubbed ATTRACT-1, was a phase II study with more than 100 patients who had advanced non-small cell lung cancer (NSCLC) and had not yet received treatment. Patients were randomly assigned to receive one of two doses of the investigational targeted therapy vadimezan, also called ASA404, along with standard chemotherapy or chemotherapy alone. Patients who received the combination therapy had improved overall survival compared with those who received only chemotherapy. Those patients whose tumors had a squamous histology, which are typically more difficult to treat than tumors with nonsquamous histology, had a median survival of 10.2 months if they were treated with the combination therapy compared with 5.5 months if they were treated with chemotherapy only.

Serious side effects in patients who received vadimezan and chemotherapy were not significantly different from those seen in patients who received chemotherapy only, reported the trial’s lead investigator, Dr. Mark McKeage of the University of Auckland in New Zealand.

Vadimezan works by attacking the tumor vasculature but in a different way than angiogenesis inhibitors. Drugs like bevacizumab (Avastin) work predominantly by halting the growth of new blood vessels to a tumor. Vadimezan, on the other hand, is referred to as a “vasculature disrupting agent” because it causes established blood vessels that feed tumors to collapse, prompting cells to die within the tumor.

The phase II findings “are quite promising” and justify the two ongoing phase III trials of vadimezan in patients with advanced NSCLC being conducted by the drug’s manufacturer, Novartis, said Dr. Neal Ready of the Duke University Comprehensive Cancer Center, who was not involved in the study. But, he added, there is no guarantee that the phase II results will be duplicated in the larger trials, particularly with regard to serious toxicities, which are a common challenge when treating patients with squamous cell lung cancer.

Often in smaller trials done at academic medical centers “you get younger and healthier patients than those who find their way into larger, phase III trials,” Dr. Ready said. “So sometimes you start to see toxicities that were not appreciated in phase II trials. Certainly we would like to have better treatment options, particularly in patients with squamous cell histology. But we’ll have to wait to see what the phase III trials show.”

The other trial, a phase I study that began nearly 3 years ago, involved the experimental agent PF-02341066, which targets two genes, ALK and cMET. The trial initially included patients with a wide range of tumors to determine the highest tolerable dose. However, based on laboratory studies suggesting that certain molecular markers were associated with greater sensitivity to the drug, the investigators added an “expansion cohort” of patients whose lung tumors had specific molecular characteristics, including the fusion, or rearrangement, of ALK with other genes. In 2007, one study described the rearrangement of ALK with the gene EML4 in a small percentage of NSCLC tumors, and further investigation showed that the genetic abnormality itself could fuel tumor growth.

At the AACR-IASLC conference, Dr. Ross Camidge of the University of Colorado reported data on 31 patients whose tumors had the EML4-ALK rearrangement and were treated with PF-02341066. There was a 65 percent response rate (tumor shrinkage), including complete tumor eradication in some patients. Nearly two-thirds of patients in the trial had already received at least two different treatment regimens.

In some NSCLC tumors, Dr. Camidge explained, fusion of ALK with another gene—most often EML4, but other fusions have been identified—is required to ramp up its activity and drive tumor growth. Rearrangements involving ALK are seen in 3 to 6 percent of patients with NSCLC, particularly in nonsmokers or light smokers, and in those with the adenocarcinoma type of lung cancer.

The trial is “a nice story,” said Dr. Camidge, “of flexible and rapidly responsive clinical investigators in close partnership with the pharmaceutical industry.” Because it was a smaller trial, the researchers could “react quickly to the emerging data” about the gene rearrangement, he said.

The adaptations made during the trial (which is ongoing and also includes an expansion cohort, planned from the trial’s initiation, of patients whose tumors overexpress the cMET gene) are representative of an important shift in the conduct of clinical trials, said Dr. Ravi Salgia, a trial co-investigator from the University of Chicago.

“This sets up a new paradigm, where early on we have a molecular signature of a tumor that defines the best population for a drug, and we have rapid translation into the clinic,” Dr. Salgia said. “It’s an imatinib type of story, where we are making advances in the lab and quickly translating them into the clinic and vice versa.”

The drug’s manufacturer, Pfizer, has already launched a phase III trial that will include only patients with NSCLC whose tumors have the EML4-ALK rearrangement.

Pointing to the new data on the ALK rearrangements and to previous findings showing that EGFR gene mutations predict response to erlotinib (Tarceva) in NSCLC patients, Dr. David Carbone of the Vanderbilt-Ingram Cancer Center said that testing for these mutations should now become “part of standard therapy” for lung cancer patients.

“It’s clear that most patients with adenocarcinoma of the lung should now have genetic testing of their tumors performed on a routine basis,” he said at the press briefing. “None of these patients can be identified by clinical parameters. It’s the mutations that identify these patients, and more and more of these drugs are going to become available.”

Abbott is collaborating with Pfizer to develop a “companion diagnostic” test that would be used to screen patients for gene rearrangements that make them more likely to benefit from treatment with PF-02341066.

Carmen Phillips

Spotlight

Helping Breast Cancer Gene Mutation Carriers Weigh Prevention Choices

Individual women make widely disparate choices about how to manage their cancer risks, depending on their family history, access to health care, reproductive concerns, and concurrent diagnoses and personal preferences. Preventive choices show small differences in survival but potentially large differences in physical and emotional effects. -Dr. Allison W. Kurian

More than 300,000 women in the United States have defects in one of two DNA repair genes known as breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2). Since the mid-1990s, when work by Dr. Mary-Claire King and others helped to uncover the significance of harmful mutations in genes located on chromosomes 17 and 13, dozens of studies in the United States and abroad have confirmed that women who carry specific BRCA1 and BRCA2 mutations face a much higher risk of some cancers, including an approximately 60 percent lifetime risk of breast cancer and a 15 to 40 percent lifetime risk of ovarian cancer.

“The real question becomes: What can women do about it, and how can we best help them understand and cope with their elevated risk?” said Dr. Beth Karlan, director of the Women’s Cancer Research Institute and Division of Gynecologic Oncology at Cedars-Sinai Medical Center and professor of obstetrics and gynecology at UCLA’s David Geffen School of Medicine. “In many cases, women feel as if they have to act, but they may not fully understand the potential impact of the preventive measures that we know will lower that risk.”

It has generally been shown that prophylactic mastectomy reduces breast cancer risk in mutation carriers by 90 percent. Prophylactic salpingo-oophorectomy reduces the risk of ovarian cancer by approximately 80 percent and also cuts breast cancer risk in half. And, in a study led by Drs. Sylvia K. Plevritis, Allison W. Kurian, and Bronislava M. Sigal of Stanford University, supplementing mammography with annual magnetic resonance imaging (MRI) of the breast in this high-risk population helped women manage their risk even further, at an acceptable cost relative to the benefit. (The American Cancer Society revised its screening guidelines in 2007 to include annual MRI for BRCA mutation carriers, citing this study.)

Despite having these risk-reducing and surveillance options, women who carry BRCA mutations are still faced with difficult decisions about the timing and acceptance of what amounts to highly invasive strategies that do not completely eliminate cancer risks and that carry long-term physical consequences. And because it is not possible to randomly assign women to drastic interventions like prophylactic mastectomy or prophylactic oophorectomy, no definitive evidence exists to help them decide whether to have either procedure.

Modeling Earns Its Place

One approach is to develop decision aids based on computer simulations that are firmly rooted in evidence from a range of sources, such as clinical trials, observational studies, and clinical expertise. “The goal is to bridge the evidence gap by using models to integrate the best available data,” said Dr. Plevritis.

In December 2009, she and Drs. Kurian and Sigal built on their previous study by analyzing the outcomes of prophylactic mastectomy and prophylactic oophorectomy in combination with intensive screening, reporting their results in the Journal of Clinical Oncology. Their earlier MRI study provided a tool for policy-level decision making, whereas the current model was designed to support individual-level decision making.

Among the general population, 84 percent of 25-year-old women will survive to age 70. Risk of death from any cause is greater for women with BRCA2 mutations, however; 71 percent will survive to age 70 with no risk-reducing intervention, and only 53 percent of women with BRCA1 mutations will survive to that age.

The model shows how specific risk-reducing strategies used alone or in combination improve the chances of survival to age 70. The most aggressive combination of risk-reducing strategies—prophylactic BRCA2 mastectomy at age 25 plus prophylactic oophorectomy at age 40—can increase survival for a BRCA2 mutation carrier to 83 percent, only 1 percentage point less than estimates for the general population. Those same strategies, the model predicts, will bring the survival probability to 79 percent for BRCA1 mutation carriers.

Probability of Survival to Age 70 among BRCA1/2 Mutation Carriers

Interventions used singly:

 

BRCA1
mutation carriers

BRCA2
mutation carriers

No intervention
Prophylactic salpingo-oophorectomy (PO) at age 40
Prophylactic mastectomy (PM) at age 25
PM at age 40
PO at age 50
Mammography and breast MRI from age 25 to 69

53 percent
68
66
64
61
59

71 percent
77
79
78
75
75

Interventions used in combination:

PM at age 25 + PO at age 40
PM + PO at age 40 + mammography and MRI from age 25 to 39
PO at age 40 + mammography and MRI from age 25 to 39
PO at age 50 + mammography and MRI from age 25 to 49

79 percent
77
74
69

83 percent
82
80
79

Helping Women Make Tough Choices

Weighing the projections from a computer model is only part of the equation for women who carry BRCA mutations and want to reduce their cancer risk. “Discussing cancer risk with BRCA1/2 mutation carriers can be complicated for all sorts of individual, cultural, and emotional reasons,” explained Dr. Karlan.

“Individual women make widely disparate choices about how to manage their cancer risks, depending on their family history, access to health care, reproductive concerns, and concurrent diagnoses and personal preferences,” agreed Dr. Kurian. “These preventive choices show small differences in survival but potentially large differences in physical and emotional effects.”

Memorial Sloan-Kettering Cancer Center in New York City is one of the few hospitals offering genetic testing services for BRCA mutations that refers women having difficulty with these decisionsthose who are either highly stressed or very ambivalentto an on-staff clinical psychologist, Dr. Karen Hurley.

“People are hungry for data, and decision aids like the one in this model can be very helpful,” she explained. “On the other hand, there are things that can’t be captured in numbers.”

Dr. Hurley sometimes sees patients who use risk numbers to obsess about small differences in survival. “As professionals, we deal with survival numbers all the time in pragmatic and matter-of-fact terms. But we have to be sensitive to the fact that these numbers put mortality on the table, with all the feelings that entails.” Not many people in their 20s, 30s, and 40s find it easy to grapple with their mortality, she said, but “the BRCA mutation can fast-forward them in time in relation to their peers.

“I tell people that their decisions about these dramatic risk-reducing strategies should make both medical and emotional sense,” Dr. Hurley continued. “Most people are resilient. They may need help in understanding the numbers, and they may have unresolved issues to deal with that affect their decision making, such as past bereavements or other life stressors. We try to work through those things together. As a clinician, I’m listening for one clear statement to emerge: What they expect the specific risk-reducing intervention to do specifically for them.”

Ultimately, each woman must make her own personal decision about the best strategy for managing the high cancer risks conveyed by a BRCA1 or BRCA2 mutation. “Our model aims to anchor women’s choices quantitatively,” said Dr. Kurian, “guiding women with BRCA1/2 mutations toward better-informed decisions between prophylactic surgery and screening alternatives.”

—Addison Greenwood

Also in the Journals

A study published in the January 2010 Radiology by the American College of Radiology Imaging Network (ACRIN) looked at both diagnostic performance and consequences of breast MRI. The results point to some challenges that could affect how many women with BRCA1/2 mutations will follow the American Cancer Society’s guidelines and actually use breast MRI.

More than 1,200 women who had already completed 2 years of screening with mammography and ultrasound were offered a no-cost MRI breast exam. Only 52 percent of the women actually completed this screening exam, and 42 percent declined to participate. A quarter of those who declined said they were claustrophobic, another 18 percent cited inconvenience due to time or travel, and 12 percent declined citing financial concerns.

The authors wrote that “for a screening test to be practical, it must be widespread, well-tolerated, and cost-effective,” and these results suggest that “there may be a large group of women at elevated risk of breast cancer for whom MRI imaging would not be acceptable.”

A Closer Look

The Downside of Diagnostic Imaging

A CT scan machine CT scan machines, like the one pictured here, deliver doses of ionizing radiation from 50 to over 500 times that of a standard x-ray. Increasing use of these diagnostic procedures may pose a cancer risk in the general population.

Modern diagnostic imaging has revolutionized medicine. In a matter of seconds, a computed tomography (CT) machine can produce extremely detailed images of any part of the body. Nuclear medicine tests, such as positron emission tomography (PET) or the technetium-based stress tests used widely in cardiovascular medicine, let doctors observe the inner workings of cells and tissues.

CT and nuclear medicine tests do have a downside, however: they deliver doses of ionizing radiation from 50 to over 500 times that of a standard x-ray, such as a chest x-ray or mammogram. Scientists have raised concerns that such large doses of radiation plus the widespread and increasing use these diagnostic procedures may, in a small but significant way, pose a cancer risk in the general population.

Data from several studies released in the second half of 2009 have helped to quantify this risk and the pace at which it is growing.

Unacceptable On the Job, but Not in the Clinic?

In the United States, people exposed to radiation at their jobs are monitored and limited to an effective dose of 100 millisieverts (mSv) every 5 years (an average of 20 mSv per year, with a maximum of 50 mSv in any single year). The concept of effective dose and the mSv measurement estimate the potential future risk of cancer from radiation exposure.

However, the available evidence indicates that most patients exposed to radiation from diagnostic imaging are not subject to similar monitoring or exposure limits. In a study published in the New England Journal of Medicine in August 2009, researchers led by Dr. Reza Fazel of the Emory University School of Medicine examined the medical records of 952,420 people in four states from 2005 through 2007 to estimate the number of people who might receive radiation doses from diagnostic imaging at a level that would cause concern in an occupational health setting.

Between 1980 and 2006, the annual per-capita effective radiation dose in the United States nearly doubled. Almost all of this increased dose came from exposure through medical imaging, which increased by about 600 percent. Note: This graphic uses the United Nations Scientific Committee on Effects of Atomic Radiation value of 2.4 mSv for natural background radiation. (Figure adapted from Mettler et al., Radiology 253(2), 2009) Between 1980 and 2006, the annual per-capita effective radiation dose in the United States nearly doubled. Almost all of this increased dose came from exposure through medical imaging, which increased by about 600 percent. Note: This graphic uses the United Nations Scientific Committee on Effects of Atomic Radiation value of 2.4 mSv for natural background radiation. (Figure adapted from Mettler et al., Radiology 253(2), 2009)
[Enlarge]

In that 3-year period, their patient sample underwent more than 3 million imaging procedures delivering radiation exposure. Almost 194 per 1,000 people each year received moderate radiation doses (between 3 and 20 mSv). Almost 19 per 1,000 received high doses (between 20 and 50 mSv), and almost 2 per 1,000 received very high doses (over 50 mSv) each year. Using this data, the authors estimated that about 4 million Americans each year receive radiation doses higher than 20 mSv from medical imaging.

Worldwide Exposure

These data are particularly concerning, experts say, given the recent and continuing increase in the use of imaging procedures using ionizing radiation both in the United States and worldwide. A report published November 2009 in Radiology using data from the U.S. National Council on Radiation Protection and Measurements and the United Nations Scientific Committee on the Effects of Atomic Radiation concluded that, worldwide, the annual effective radiation dose per capita from medical imaging has doubled in the past 10 to 15 years. The increase in the United States was much greater than anywhere else in the world.

The authors, led by Dr. Fred A. Mettler of the New Mexico Veterans Administration Health Care System reported that, in the United States, this dose increased by about sixfold between 1980 and 2006. Over the past 56 years, the estimated number of annual radiologic and nuclear medicine procedures increased by about 15-fold.

“The use of CT in particular has gone up dramatically, and we’ve drastically lowered the threshold for using it,” said Dr. Rebecca Smith-Bindman, a visiting research scientist with NCI’s Radiation Epidemiology Branch (REB). “There’s a general belief that if you get a CT scan, you must be reasonably sick and must really need it. This is no longer true, and we are increasingly using CT scans in patients who are not that sick. There’s been drift not only in how often we use it but in how we use it.”

“We’ve only talked about the benefits of CT for the past 20 years, without considering any potential harm” she continued. “I’m hoping the medical community can start a dialogue about when it should be used. CT is a fabulous test, but we have to use it prudently and only when there is clear evidence of benefit that outweighs its potential harm.”

Considering Benefit, Reducing Harm

Epidemiological Studies Underway

Performing epidemiological studies of cancer risk from diagnostic imaging requires researchers to follow hundreds of thousands of patients for decades. That is why, to date, estimates on cancer risk from diagnostic imaging have relied on modeling studies.

Researchers are now performing the first epidemiological studies of this kind. One study, being led by Dr. Elaine Ron of NCI’s Radiation Epidemiology Branch (REB) in collaboration with Dr. Mark Pearce from Newcastle University in the United Kingdom, is following over 250,000 people who were less than 22 years old at the time of their first CT scan. The researchers are tracking cancer incidence and mortality in this population and expect to have preliminary data available in approximately 2 years.

A second REB study is following a similar population in Israel (50,000 people who were less than 18 years old at the time of their first CT scan), in collaboration with Dr. Gabriel Chodick of Maccabi Healthcare Services. There are plans to pool the data from these two studies with data from additional studies planned in Europe, Australia, and Canada “to provide a reasonable picture of the risk from childhood CT scans,” said Dr. Berrington de González.

The medical community has proposed numerous ways to reduce radiation exposure from diagnostic medicine without negatively impacting the quality of patient care. (See the box at the end of the article.)

The failure to optimize and standardize diagnostic protocols and techniques was highlighted recently in a study led by Dr. Smith-Bindman, published in the December 2009 Archives of Internal Medicine. She and her colleagues gathered data on radiation dose from CT scanning at four hospitals, all of which used equipment from the same manufacturer.

Even with this homogeneity in CT equipment, the researchers observed a mean 13-fold variation between the lowest and highest radiation doses seen in each type of CT study measured, both within and across the four institutions. This variation is due to different institutions and individual physicians choosing different technical parameters on the machines when running similar types of CT scans done for similar indications, explained the authors.

“There are no standards set for what’s an acceptable radiation dose for different types of scans, and no group is monitoring the radiation doses patients receive,” said Dr. Smith-Bindman. “Thus, the variation in dose is high and unacceptable. With available technology we could lower the doses by 30 to 50 percent immediately, but there’s currently no mandate to do this.”

The Coming Storm?

In addition to measuring variability in dose, Dr. Smith-Bindman and her colleagues used data from the National Research Council to estimate the number of excess cancers expected to develop from exposure to high-dose diagnostic imaging. Their results suggested that 1 in 270 women and 1 in 600 men undergoing CT heart scans (a potentially high-dose procedure) at the age of 40 will develop cancer related to that CT scan.

Lower-dose imaging procedures carried lower risks, but increased risks nonetheless. When these tests were performed in younger patients, the risks were higher.

In the same issue of Archives, Dr. Amy Berrington de González, also of REB, and her colleagues used National Research Council data to estimate the number of excess cancers expected to be caused by CT scans performed in the United States in 2007.

Their research estimated that approximately 29,000 future cancers could be related to CT scans performed in the United States in that year alone, with women being at higher risk than men. About 35 percent of these cancers were projected to be related to scans performed in patients 35 to 54 years old, and 15 percent related to scans performed in children younger than 18.

“It’s becoming more widely accepted that this is a potential problem and a growing problem,” said Dr. Berrington de González.

“The three cornerstones of radiological protection are justification of all tests, optimization of how the tests are performed, and having some sort of diagnostic reference level so that we know if a test is done at too high a dose,” said Dr. Andrew Einstein from the departments of medicine and radiology at Columbia University. “I think we can make advances on all three of those fronts in terms of the amount of radiation that our patients receive and decrease the collective doses to [patients in] the United States and worldwide.”

The medical community has proposed many ways to reduce radiation exposure from diagnostic medicine without negatively impacting the quality of patient care:
  • Reduce the number of CT exams by using other technologies (such as ultrasound or MRI) in cases where they would provide equal diagnostic quality.
  • Limit the use of CT in healthy patients who would obtain little benefit (such as whole-body CT screening).
  • Limit the use of repeat CT surveillance of patients in whom a diagnosis has already been made, when repeat scanning would lead to little change in their treatment.
  • Tailor the radiation dose carefully to a patient’s individual size. This point, which is particularly important for children, has recently been addressed by The Alliance for Radiation Safety in Pediatric Imaging’s national Image Gently campaign.
  • Educate both doctors and patients about radiation exposure from diagnostic imaging. In a recent survey, nearly all physicians polled significantly underestimated radiation doses from a CT scan.
  • Track and collect information on radiation exposure for individual patients through a system such as the International Atomic Energy Agency’s proposed Smart Card digital record system.
  • Improve communication between doctors as a patient moves through the diagnostic process to avoid unnecessary imaging and repeated imaging in different departments or hospitals.
  • Optimize and standardize diagnostic protocols and techniques to limit exposure from any individual procedure.

Sharon Reynolds

Featured Clinical Trial

Adjuvant Bevacizumab and Chemotherapy for High-risk Breast Cancer

Name of the Trial
Phase III Randomized Study of Adjuvant Therapy Comprising Doxorubicin Hydrochloride, Cyclophosphamide, and Paclitaxel with Versus without Bevacizumab in Patients with Lymph Node-Positive or High-Risk, Lymph Node-Negative Breast Cancer (ECOG-E5103).  See the protocol summary.

Dr. Kathy Miller Dr. Kathy Miller

Principal Investigators
Dr. Kathy Miller and Dr. Ramona Swaby, Eastern Cooperative Oncology Group; Dr. Donald Northfelt, North Central Cancer Treatment Group; and Dr. Chau Dang, Cancer and Leukemia Group B

Why This Trial Is Important
Women with breast cancer that is removed by surgery often receive postsurgical (adjuvant) chemotherapy and radiation therapy if they are deemed to have a high risk for recurrence. High-risk breast cancers are those that have spread to nearby axillary lymph nodes (lymph node-positive cancer) or those that have not spread but have other characteristics (such as large tumor size, absence of hormone receptors, or high tumor grade) that make them more likely to recur (high-risk, lymph node-negative cancer).

Adjuvant chemotherapy has greatly improved the survival of patients with high-risk breast cancer and has contributed to increasing cure rates. However, many patients still experience recurrence of their cancer. Doctors want to find new ways to prevent or delay the recurrence of breast cancer.

One approach to improving treatment for several types of cancer has been to target the growth of new blood vessels (angiogenesis) to tumors. The antibody bevacizumab (Avastin) inhibits angiogenesis by blocking the activity of VEGF, a protein secreted by many cancer cells that spurs the growth of blood vessels to tumors.

In this trial, patients with lymph node-positive or high-risk, lymph node-negative breast cancer who have received radiation therapy or plan to do so following chemotherapy will be treated with adjuvant chemotherapy and randomly assigned to receive short-term treatment with bevacizumab, long-term treatment with bevacizumab, or treatment with an intravenous placebo. The researchers want to see if either bevacizumab regimen prevents or delays the recurrence of high-risk breast cancer better than adjuvant chemotherapy and radiation therapy alone.

“In women with metastatic breast cancer, adding bevacizumab to chemotherapy doubled responses and also led to longer durations of response,” said Dr. Miller. “We think that antiangiogenesis therapy should be more effective in earlier stages of cancer, and this trial is designed to directly test that hypothesis,” she added.

For More Information
See the lists of entry criteria and trial contact information or call the 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

Chinese and American Scientists Meet to Discuss Environmental Causes of Cancer

Earlier this month, researchers from science and public health organizations in China and the United States, including NCI, met in Guangzhou, China, to discuss specific research goals and possibilities for collaboration in cancer epidemiology, environmental monitoring, and tobacco control, and how to foster translational research in these areas.

View from the Great Wall obscured by smog View from the Great Wall obscured by smog

“The meeting focused on adult lung and childhood cancers,” explained Dr. Gary Ellison, an epidemiologist in NCI’s Division of Cancer Control and Population Sciences (DCCPS), who led the development of the scientific meeting agenda for NCI. He noted that in addition to the scientific presentations, representatives from Chinese and U.S. funding agencies presented existing mechanisms to support new collaboration in the scientific areas addressed at the meeting. While NCI has supported several China-related research projects, he explained, this workshop will help define scientific priorities related to environmental pollution and cancer with the goal of expanding and creating additional opportunities for mutual scientific cooperation.

The Chinese Academy of Sciences (CAS), which hosted the meeting January 5–8, is a basic research organization that includes more than 90 institutions across China that are engaged in physical, computational, engineering, and life sciences research. In addition to members of CAS, Chinese speakers at the meeting represented the national and local centers for disease control, the Chinese Academy of Medical Sciences, the National Natural Science Foundation of China, and several top universities.

Participants from the United States included representatives from several institutes at NIH, including NCI, the National Institute of Environmental Health Sciences, Fogarty International Center, National Institute of Child Health and Human Development, and extramural NIH-funded researchers.

Dr. Ellison noted that workshop participants represented a wide variety of scientific disciplines capable of addressing the many scientific issues associated with environmental pollution and cancer.

The Ministry of Health of the P.R. China has observed that pollutants such as toxic occupational hazards may be contributing to increasing rates of certain cancers in China. Dr. Julie Schneider, who leads NCI’s Office of China Cancer Research Programs in Beijing, noted that rising environmental challenges and increasing capacity in science and technology make it an opportune time to establish new cooperation with Chinese researchers in the area of environment and cancer.

Lung cancer is now the most common type of cancer in China. Although smoking incidence is low among Chinese women, lung cancer rates are still high in this group. Tobacco control experts at the meeting emphasized the importance of continuing to support research addressing strategies to keep the rates of smoking low among Chinese women, as tobacco companies may increase marketing efforts that target them. Other delegates suggested initiating new efforts to understand how indoor pollution, such as that created from cooking oils, might help explain the relatively high rates of lung cancer in Chinese women.

“International studies are instrumental in moving the science of environmental epidemiology forward,” noted Dr. Robert Croyle, director of DCCPS, who delivered opening remarks at the meeting. “These collaborative efforts can provide unique opportunities to study populations and exposures that do not exist in the United States to generate discoveries that help cancer patients both domestically and abroad.”

Cancer.gov Update

Recovery Web Site Highlights the NCI Community Cancer Centers Program

The NCI Recovery Act Web site has added new content that highlights the NCI Community Cancer Centers Program (NCCCP) and describes how the program is moving cancer care forward. The site features “Better Cancer Care, Close to Home,” a 5-minute video about the bond between a cancer patient and his cancer team at St. Joseph Cancer Institute in Towson, MD, one of the 16 community cancer centers in the NCCCP pilot. ARRA funds are being used to sustain jobs, including additional patient navigators, at existing NCCCP hospitals and to expand the entire program to more communities in 2010. An accompanying article looks at community cancer care at three NCCCP centers and how patient navigators are helping cancer patients access the medical, social, and financial services they need throughout treatment and follow up.

NCI Launches Web Site for the Alliance of Glycobiologists

NCI’s Division of Cancer Prevention has launched a Web site for the trans-NIH Alliance of Glycobiologists for Detection of Cancer and Cancer Risk. The alliance is a consortium that is working to reveal the cancer-related dynamics of complex carbohydrates and to develop biomarkers for early cancer detection and risk assessment.

Glycomic biomarkers based on the sugar part of a glycoprotein are a new target area for early cancer detection due to emerging technologies. The Web site details the alliance’s findings, publications, resources, and organizational structure. There is a dedicated page for each of the seven NCI-supported Tumor Glycomics Laboratories, which make up the primary component of the alliance, and links to the alliance’s NIH research partners: the Consortium for Functional Glycomics, funded by the National Institute of General Medical Sciences; the Glycomics and Glycotechnology Resource Centers, supported by the National Center for Research Resources; and NCI’s Early Detection Research Network.

Online Resource on Menthol and Tobacco Now Available from NCI

NCI’s Division of Cancer Control and Population Sciences has launched a new menthol and tobacco Web page that provides background information on the pharmacological properties of menthol and its use in tobacco products as a cigarette additive and flavoring. The page also highlights research on the tobacco industry’s targeted marketing practices to promote the use of menthol tobacco products, and it includes updated information on menthol cigarette use among current smokers by sociodemographic characteristics, based on national data from the 2006–07 Tobacco Use Supplement to the U.S. Census Bureau's Current Population Survey. Other resources, including information on the 2002 First Conference on Menthol Cigarettes, related publications, and links to national and state-level surveys that include questions on menthol, are also available.

Most recently, NCI posted a comprehensive bibliography that includes 343 peer-reviewed research articles related to menthol and tobacco and the final report from the recent Second Conference on Menthol Cigarettes, held in October 2009.

NCI's Reagents Data Portal Features Added Content

Reagents Data Portal banner

NCI recently expanded the Proteomic Reagents and Resources Portal, a community site made available by NCI’s Clinical Proteomic Technologies for Cancer initiative. The portal was created in response to input by the research community on the need for high-quality proteomic reagents and resources.

Added content that is publicly accessible now includes:

  • Data sets to a landmark clinical performance study published in Nature Biotechnology on the reproducibility and transferability of MRM-mass spectrometry across multiple sites
  • Mass spectrometry analytical performance mixtures
  • Standard operating procedures for reagent development and platform usage
  • Computational science (software) tools that enhance instrumentation accuracy and data mining
  • Highly characterized monoclonal antibodies and hybridomas with side-by-side feature comparisons

NCI is transforming clinical proteomics by developing workflows that use metrics and standards with open access to data and reagents, providing researchers with the necessary tools to accurately and quantitatively study cancer etiology at the protein level.

Notes

NCRR Hosts CTSA Industry Forum to Promote Collaboration, Drug Development

On February 17 and 18, the National Center for Research Resources (NCRR) will present the Clinical and Translational Science Award (CTSA) Industry Forum: “Promoting Efficient and Effective Collaborations among Academia, Government, and Industry.” Designed to explore ways to streamline the development of new drugs, devices, and diagnostics, the forum will focus on current practices and successful management models to improve this process.

NIH Director Dr. Francis Collins will deliver the opening address entitled, “Why Industry and Academia Should Work Together: An NIH Perspective,” and NCI Deputy Director Anna Barker will serve on a panel to discuss opportunities and unmet needs in translational research. Sessions will focus on translational research topics, challenges, and potential solutions; issues and barriers to intervention development; innovative new models, and international perspectives.

The forum will take place on the NIH main campus and will be videocast online. The event is free and open to the public. Posters are due by February 1, and registration is requested by February 5. To register or submit a poster, visit the forum Web site.

Registration Open for Cancer Drug Development Meeting

TAT 2010

On March 4–6, NDDO Education Foundation, NCI, and the European Society for Medical Oncology will co-sponsor “TAT 2010: 8th International Symposium on Targeted Anticancer Therapies” in Bethesda, MD.

The all-plenary program will include keynote presentations, reviews, and original papers on emerging targeted agents for cancer therapy, with updates on early phase clinical studies, preclinical studies, and translational research. 

Program topics include:

  • Insulin-like growth factor receptor inhibitors
  • RNA-based approaches to cancer treatment
  • Targeting the cancer stem cell
  • DNA repair mechanisms as drug targets
  • Other drug targets in clinical development
  • Drug development methodology and regulatory affairs

The program is designed to offer ample opportunity for interaction and discussion with leading experts, and participants may earn continuing medical education credits.

View the final program and register online by February 28.

NCI Holds Annual Intramural Scientific Retreat

On January 7, NCI’s Annual Intramural Scientific Retreat brought together investigators from NCI’s Center for Cancer Research (CCR) and Division of Cancer Epidemiology and Genetics (DCEG), as well as members of NCI’s Board of Scientific Counselors, Board of Scientific Advisors, and the National Cancer Advisory Board. The event provided an opportunity for colleagues from different disciplines to interact and learn about the work being done across the institute.

Over the course of the day, three award lectures were presented. Dr. Michael Gottesman presented on “New Ways to Think about Multidrug Resistance in Cancer” for the Alan S. Rabson Award Lecture for Intramural Research, Dr. Leslie Bernstein delivered the NCI Rosalind E. Franklin Award Lecture for Women in Cancer Research on “Reducing Breast Cancer Risk through Biology, Epidemiology, and Serendipity,” and Dr. Stephen Baylin spoke about “Dissecting the Cancer Epigenome—From Biology to the Patient” for the Alfred G. Knudson Award Lecture in Cancer Genetics.

The Women Scientists’ Association (WSA) hosted a lunchtime discussion on topics related to career development in science. The first WSA Mentoring and Leadership Awards were presented to DCEG’s Dr. Joseph Fraumeni and CCR’s Dr. Maria Merino.

Finally, a number of NCI scientists received NCI Director’s Intramural Innovation Awards, which are designed to support the development of highly innovative approaches and technologies that could unravel cancer-related problems.

Recipients of NCI Director's Intramural Innovation Awards Recipients of NCI Director's Intramural Innovation Awards

New NCI Spanish-language Resources Available

NCI Spanish-language booklets from the What You Need to Know About Cancer series

NCI has released three new Spanish-language materials that are part of the popular What You Need To Know (WYNTK) About Cancer series: 

WYNTK booklets are intended for recently diagnosed cancer patients to help them prepare for treatment.  Nine WYNTK topics are now available in Spanish on Cancer.gov/espanol.