National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 20, 2009 • Volume 6 / Number 20

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NEWS

Cancer cells found in the blood of a child with acute lymphoblastic leukemia. Better Options for Children with Difficult-to-Treat Leukemia

Some young patients with forms of acute lymphoblastic leukemia (ALL) that do not respond to current treatments may have new options, according to two clinical trials published online October 5 in the Journal of Clinical Oncology. Both trials were led by the NCI-supported Children's Oncology Group (COG), and each yielded impressive results for patients with difficult-to-treat cancers. Read more > >

COMMENTARY

Dr. James H. Doroshow

Guest Director's Update: The NExT Steps in Drug Development at NCI

by Dr. James H. Doroshow

The FDA's recent approval of the new agent pralatrexate (Folotyn) for the treatment of peripheral T-cell lymphoma (PTCL) was especially satisfying news for those of us at NCI who have been involved with this drug. Of course, we are always pleased to see a new, effective cancer treatment reach the clinic, especially one for patients with this rare form of lymphoma who have relapsed after or failed to respond to their initial treatment. Read more > >

IN DEPTH

UPDATES

  • Legislative Update

    • Experts Testify on Pending Breast Cancer Legislation
    • Congressional Delegation Visits NIH
  • FDA Update

    • FDA Approves Two HPV Vaccines: Cervarix for Girls, Gardasil for Boys
    • FDA Approves New Targeted Therapy for Kidney Cancer

    Notes

    • NIH Mourns Passing of Former Acting Director Dr. Ruth Kirschstein
    • NCI Cancer Bulletin Recognized with NIH Merit Award
    • International Palliative Care Resources Available Online

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 .

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

Featured Article

Better Options for Children with Difficult-to-Treat Leukemia

Cancer cells found in the blood of a child with acute lymphoblastic leukemia.Cancer cells found in the blood of a child with acute lymphoblastic leukemia.

Some young patients with forms of acute lymphoblastic leukemia (ALL) that do not respond to current treatments may have new options, according to two clinical trials published online October 5 in the Journal of Clinical Oncology. Both trials were led by the NCI-supported Children’s Oncology Group (COG), and each yielded impressive results for patients with difficult-to-treat cancers.

In the first study, children and young adults with an uncommon type of ALL linked to a genetic mutation known as the Philadelphia chromosome (Ph chromosome) lived longer without their disease coming back when the drug imatinib (Gleevec) was added to conventional intensive chemotherapy. The Ph chromosome causes leukemia cells to produce a fusion protein called Bcr-Abl, which is blocked by imatinib, a type of drug called a tyrosine kinase inhibitor (TKI). While less than 5 percent of childhood ALL cases are linked to the Ph chromosome, only about 40 percent of patients with this form of the disease are cured by conventional therapy.

COG researchers led by Dr. Kirk Schultz of British Columbia Children’s Hospital in Vancouver, Canada, treated 92 patients aged 1 to 21 with Ph-chromosome-positive ALL in five cohorts, with each successive cohort receiving a longer period of imatinib therapy. They compared patient outcomes with those for similar patients treated with standard chemotherapy in previous COG trials. Among patients who received the most imatinib (280 continuous days), 80.5 percent were alive and had not had a relapse after 3 years. Only about 35 percent of patients who received standard therapy in previous trials achieved this outcome.

“The remarkable improvement Dr. Schultz and his colleagues saw in early outcomes for children receiving imatinib plus chemotherapy provides strong evidence that children with Ph-chromosome-positive ALL should receive treatment that includes a TKI such as imatinib,” commented Dr. Malcolm Smith, a pediatric cancer specialist in NCI’s Cancer Therapy Evaluation Program.

Longer follow-up is needed to ensure that this outcome is sustained, and the results should be confirmed in a larger group of patients, said Dr. Smith. Further research is needed, he added, to determine whether imatinib or a “second generation” TKI, such as dasatinib, is more effective when added to chemotherapy for children with Ph-chromosome-positive ALL.

Dr. Crystal Mackall, chief of NCI’s Pediatric Oncology Branch, noted that “of five dosing cohorts in this study, only patients receiving the highest exposure to imatinib experienced a benefit––yet, remarkably, this was not associated with any detectable increase in toxicity. It is an unusual occurrence in oncology to see benefit with no increase in toxicity, but this is exactly the type of outcome that is to be expected when effective targeted therapies are incorporated into treatment regimens.”

In the second study, adolescents and young adults aged 16 to 21 with ALL who were treated with an intensive multi-drug pediatric chemotherapy regimen lived longer and remained cancer-free longer than patients treated with adult therapies. Patients in this age group tend to have poorer outcomes than younger children with ALL. 

Dr. James B. Nachman of the University of Chicago Children’s Hospital and his COG colleagues randomly assigned 164 adolescents and young adults with ALL who responded rapidly to induction therapy to receive a further course of either standard or intensified chemotherapy with multiple drugs, including vincristine, pegylated asparaginase, and intravenous methotrexate.

Among rapid responders to induction therapy who went on to receive intensified chemotherapy, 83 percent were alive after 5 years and 82 percent had not had a relapse. Among rapid responders treated with standard-intensity chemotherapy, 76 percent were alive after 5 years and 67 percent had not had a relapse.

These findings add to data from previous studies showing that relapse-free survival is 20 percent to 30 percent better for young adults with ALL who are treated using pediatric regimens rather than adult regimens, the authors wrote. The reason for this difference is unknown. Potential explanations include the distinctive way in which pediatric-type regimens combine specific types of leukemia agents, said Dr. Smith. An ongoing trial in which young adult patients with ALL are being treated with this COG pediatric-type regimen by medical oncologists may shed further light on this question.

Dr. Nachman and colleagues further noted that when a pediatric-type regimen is used for this patient population, routine use of stem-cell transplantation in first remission seems unwarranted.

This study, Dr. Smith said, offers convincing evidence that patients in the 16 to 21 year age range with ALL should be treated with a pediatric-type ALL regimen. “Several studies from across the world comparing outcomes for patients in this age group who are treated with adult versus pediatric regimens have uniformly shown that the pediatric ALL regimens perform better,” he added.

—Eleanor Mayfield

Cancer Research Highlights

Minimally Invasive Prostate Cancer Surgery Shows Benefits, Shortcomings

Minimally invasive surgeries to remove the prostate in men with prostate cancer, including procedures performed with a surgical robot, are superior to standard “open” prostate removal surgeries by some measures but fall short on several other important outcomes, including risk of incontinence and erectile dysfunction. The study was published October 14 in the Journal of the American Medical Association.

From 2003 to 2007, the number of minimally invasive radical prostatectomy (MIRP) procedures increased from 1 percent to more than 40 percent of all prostatectomies, an increase that the researchers believe has been largely driven by the rapid proliferation of robotic surgery. Currently, robotic prostatectomy accounts for 70 percent of all MIRP procedures, said the study’s lead author Dr. Jim C. Hu of Brigham and Women’s Hospital in Boston.

The study was not a randomized clinical trial. Rather, the researchers used billing and diagnostic data from NCI’s SEER Medicare database, identifying 1,938 men who underwent MIRP and 6,899 men who underwent open surgery. After accounting for differences in physician and patient characteristics in men receiving MIRP versus open procedures, the researchers found that men who underwent MIRP had shorter hospital stays (2 days versus 3 days), far fewer blood transfusions, and a lower risk of respiratory and other surgical complications. But they also had more than twice the risk of genitourinary complications, a 30 percent increased risk of incontinence, and a 40 percent increased risk of erectile dysfunction 18 months after the procedure.

The need for additional cancer therapies was roughly equivalent between the groups, Dr. Hu explained, suggesting that neither procedure is superior in terms of cancer control. The study also revealed several disparities related to MIRP, including less frequent use by African American and Hispanic men.

Given the available data on standard open surgery compared to MIRP, said Dr. Hu, open surgery should remain the “gold standard” for men who opt for surgery to treat localized prostate cancer.

Liver Cancer Study Finds Potential Marker for Treatment

A small RNA molecule in liver tumors could be a biological marker for assessing a patient’s prognosis and might also be used to select candidates for treatment with the biological therapy interferon, according to a study in the October 8 New England Journal of Medicine. The molecule is one of approximately 1,000 microRNAs in the human genome. Each microRNA is thought to regulate the activitiy of several hundred genes.

The researchers found that patients whose tumors had reduced levels of a microRNA called miR-26 tended to have a poor prognosis but were more likely to benefit from interferon than other patients. MicroRNAs are thought to regulate the activity of hundreds of genes, and some have been linked to cancer.

“We think this microRNA could be quite useful for helping clinicians determine how aggressive a tumor will be and also to identify patients who will benefit from interferon to prevent relapse,” said lead investigator Dr. Xin Wei Wang, head of NCI’s Liver Carcinogenesis Section. The study was done with investigators at Fudan University, Shanghai; the University of Hong Kong in China; and Ohio State University.

The study’s original aim was to see whether differences in microRNA levels, or expression, could help explain the different outcomes seen in males and females with a form of liver cancer called hepatocellular carcinoma. The analysis found clear differences in the expression of miR-26 between males and females and also between patients with more or less aggressive tumors.

Overall, both male and female patients with low levels of miR-26 did not live as long as patients with higher levels of the microRNA. The difference in survival was about 4 years between the groups. But while patients with low levels of miR-26 had a poor prognosis, these patients were more likely to benefit from interferon as an adjuvant therapy. This group survived at least 7.7 years longer than patients with low tumor levels of miR-26 who did not receive interferon therapy. Patients with normal levels of miR-26 in their tumors did not benefit from interferon.

The association between miR-26 and prognosis or treatment response does not imply cause and effect, but a recent study in mice provided evidence that miR-26 may act as a tumor suppressor, noted Dr. Wang. Future studies will assess the microRNA in additional populations and explore its potential use as a therapeutic target in the disease, he added.

Gene Mutation Linked to Aggressive Childhood Cancer

Rhabdomyosarcoma (RMS), an aggressive childhood cancer caused by mutations in genes that control the development of skeletal muscle tissue, has often spread (metastasized) by the time it is diagnosed in children, leading to poor survival rates. Researchers have now identified mutations in the fibroblast growth factor receptor 4 (FGFR4) gene that are associated with metastasis and poor outcomes in patients with RMS. The FGFR4 protein belongs to a family of proteins known as receptor tyrosine kinases, which are involved in cellular signaling processes that help regulate cell growth, maturation, and survival. The gene, the researchers believe, may provide a target for therapy. The results appeared online October 5 in the Journal of Clinical Investigation.

Researchers from NCI; the National Heart, Lung, and Blood Institute; The Children’s Hospital at Westmead, Australia; and the Nationwide Children’s Hospital in Columbus, OH, were involved in the project. Their previous research, and that of others, has shown that FGFR4 is highly expressed in RMS. Because the gene is active during muscle development and not in mature muscle, the team investigated whether expression of FGFR4 might contribute to RMS. Using mouse models, the researchers showed that the growth and spread of human RMS cells to the lungs was inhibited by suppressing FGFR4 expression. After sequencing the FGFR4 gene in human RMS tumor samples, they found that more than 7 percent of the tumors had mutations in the tyrosine kinase portion of the protein. Some of these mutations caused the protein to become overly active. Mutations that increase receptor tyrosine kinase activity have been found in other cancers, but the researchers note that this is the first time that mutations in a receptor tyrosine kinase have been found in RMS.

With a series of lab and animal studies, they confirmed that two of the FGFR4 mutations caused increased tumor growth, reduced RMS cell death, and enhanced the ability of RMS cells to metastasize.

The mutations, which were found in both types of RMS, alveolar and embryonal, appeared to act via the STAT3 pathway. Mouse RMS cells harboring these mutations were also more sensitive to treatment with drugs that inhibit FGFR4, which has “direct implications for personalized therapy and for patients with metastatic RMS, for whom long-term prognosis remains poor,” said lead author Dr. Javed Khan of NCI’s Pediatric Oncology Branch.

Primary and Metastatic Tumors from Same Patient Sequenced

Using next-generation DNA sequencing technology, researchers in Canada have compared the genetic changes in two breast tumors collected from the same patient 9 years apart. The secondary tumor (metastasis) included genetic changes not present in the tumor sample collected at diagnosis, suggesting that “significant evolution can occur with disease progression,” the researchers reported in the October 8 Nature.

“The cancer evolved significantly in terms of its genome content, but moreover, the primary cancer was heterogeneous from the start,” said lead investigator Dr. Samuel Aparicio of the BC Cancer Research Center in Vancouver. “We’ve known that cancer cells must be heterogeneous for many decades, but now we’re seeing it up close.”

The researchers found 32 genetic mutations in the secondary tumor, 19 of which were not in the primary tumor. (It was not known whether these 19 mutations were a consequence of radiation therapy or of innate tumor progression.) Knowing which alterations are present in a primary tumor prior to therapy and to metastasis could make it easier to uncover the genetic factors responsible for the initial cancer, the researchers said.

When asked about the findings, Dr. Joan Massagué of Memorial Sloan-Kettering Cancer Center said that because cancers essentially happen by accident and evolve in the body any way they can, one would expect to see many different paths of evolution. Studies like the current one show how tumor evolution “may happen in one situation or another,” but he cautioned against drawing broader conclusions from any particular report.

Dr. Massagué made his comments at a recent press briefing on metastasis hosted by the American Association for Cancer Research.

Prostate Tumor Microenvironment Found to Change Immune Cell's Function

Much remains unknown about the process tumors undergo to evade attack by the immune system. Now a team including researchers from NCI’s Center for Cancer Research and the Fred Hutchinson Cancer Research Center has shown that tumor-specific immune cells that have migrated to the mouse prostate tumor microenvironment can switch from their normal antitumor activity to an immune suppressor function. Their report appeared in the October 15 Journal of Immunology.

The researchers found that, once within the microenvironment of mouse prostate tumors, tumor-specific CD8+ T cells actually began to block the normal immune response: a call for nonspecific T cells to multiply and attack the tumor.

This immune-suppressive activity appeared to be caused, in part, by substances secreted by the CD8+ T cells in the tumor microenvironment. One of these substances, TGF-β, is a protein that controls cell proliferation and differentiation and plays a role in cancer and other diseases. When the researchers used an antibody to block TGF-β, the CD8+ cells were prevented from switching to a suppressor role.

While it’s not clear whether TGF-β is required for this process, the researchers did note that CD8+ T cells only suppressed other immune cells after they had infiltrated the tumor microenvironment. In contrast, CD8+ T cells isolated from elsewhere (in this case from the lymph nodes of the same mice) were unable to suppress the growth of nonspecific T cells. The research team also found that they could disrupt suppressive immune signaling within the tumor microenvironment by introducing CD4+ T cells into the region. When CD4+ T cells were added, CD8+ T cells isolated from the prostate tumors no longer suppressed the proliferation of other T cells, and they produced less TGF-β.

With these findings, the authors concluded that “new approaches to block these pathways will enhance our ability to generate more sustained and effective antitumor T cell responses.”

Guest Director's Update

The NExT Steps in Drug Development at NCI

Dr. James H. Doroshow

The FDA’s recent approval of the new agent pralatrexate (Folotyn) for the treatment of peripheral T-cell lymphoma (PTCL) was especially satisfying news for those of us at NCI who have been involved with this drug. Of course, we are always pleased to see a new, effective cancer treatment reach the clinic, especially one for patients with this rare form of lymphoma who have relapsed after or failed to respond to their initial treatment.

NCI has a particular interest in this drug because it is the first agent from NCI’s Rapid Access to Intervention Development (RAID) program to receive FDA approval for a cancer indication. For a program that was in existence for a decade, the fact that this is the first approval demonstrates how difficult it can be to bring a new treatment to patients. Now that RAID has been incorporated into NCI’s Experimental Therapeutics (NExT) program, we believe that efficiencies and improvements in NCI’s drug development efforts are achievable and real.

There is a great deal of excitement about NExT, which is a collaboration between NCI’s Division of Cancer Treatment and Diagnosis and Center for Cancer Research (CCR). The program’s goal is to speed up the drug development process by getting promising drugs—particularly those for pediatric and rare cancers—into human trials more quickly and to prune agents from the development pipeline that are unlikely to be effective, saving valuable resources.

NExT was designed to bring NCI’s diverse drug development efforts into a single pipeline and to follow a formalized, business-like approach to the development of potentially promising therapeutics. At the same time, the broad array of services and resources such as toxicology testing and drug manufacturing that was available to researchers via RAID is still available with NExT.

Where RAID was more focused on aiding researchers with highly specific tasks, drugs accepted into NExT can provide a more comprehensive approach to advancing agents through the development pipeline, including established milestones that drive “go/no-go” decisions about whether to continue NCI’s role in the development of a given agent. The objective is to move drug candidates through preclinical work into first-in-human studies, including phase 0 trials in which nontoxic doses of the agent are tested in a small number of patients. Using advanced imaging and other techniques, in these trials we can determine in a matter of months whether the drug is reaching its intended target and having the intended biologic effects. This will give us more confidence in the decision to move the agent further along in human trials and help to shave at least a year off of the time it typically takes to develop a drug, while also limiting the resources spent developing treatments that will likely never benefit patients.

A number of agents are already in the NExT pipeline, including agents being investigated by researchers from CCR, large academic medical centers, and private industry. (See the box below.) And we’ve already seen an example of how NExT will function. NCI worked with Abbott Laboratories in the early clinical development of its PARP inhibitor, ABT-888, and in testing it in the first-ever phase 0 trial of only 13 patients. The trial demonstrated that the drug, which interferes with a cell’s ability to repair DNA damage, was in fact hitting its biologic target. Now we are working with Abbott to test this agent in phase I and II clinical trials in patients with a variety of tumors.

Although many of the agents in NExT will be supported from preclinical testing through first-in-human studies, the program is open for applicants to enter and exit at any stage in the process. There may be cases, for example, where a research team or private company is already testing an agent in early stage trials in adults, but they may be interested in using NExT to develop the agent for use in a pediatric population, an area in which NCI has unique expertise and resources.

So whether it is serving as a bridge at critical points in the development path, as was the case for pralatrexate, or as a more comprehensive driver of an agent’s development from the earliest stages of preclinical research, we are confident that with NExT we can have many more successes in the coming decade.

Dr. James H. Doroshow
Director, NCI Division of Cancer Treatment and Diagnosis

In the NExT Pipeline

Dr. Yves Pommier, chief of CCR’s Laboratory of Molecular Pharmacology, has two compounds in the NExT program on the verge of being tested in phase I trials. In both laboratory tests and animal model studies, the two compounds, known as indenoisoquinolines, or indenos, have demonstrated an impressive ability to kill cancer cells with little evidence of toxicity.

Like a class of compounds known as camptothecins, the indenos target topoisomerase 1, which plays a critical role in DNA replication during cell division. But the indenos have some advantages over camptothecins, Dr. Pommier said, including more chemical stability and the ability to remain active in the blood for longer periods.

“It takes time to realize that you have something worthy of pursuing in human trials,” Dr. Pommier stressed. The compounds have been under development for more than a decade, he noted, so the researchers involvement in NExT is a bridging step before likely working with industry to conduct large-scale human trials.

At Ohio State University (OSU) Medical Center, Dr. Michael Grever and his colleagues, Drs. Doug Kinghorn and David Lucas, are pursuing the development of an agent called silvestrol, a natural product derived from a plant found in Sarawak, on the island of Borneo. Their research is focused on developing new treatments for chronic lymphocytic leukemia and acute lymphoblastic leukemia, both of which involve the overproduction of malignant B cells.

In very low concentrations, silvestrol induced selective killing of leukemic cells taken from patients. And in an animal model of a highly aggressive leukemia, treatment with silvestrol appeared to completely eradicate the disease in some cases. The compound causes little if any apparent damage to normal immune system cells, Dr. Grever said—a common problem with current treatments for these cancers.

As part of its involvement in NExT, silvestrol is undergoing intensive safety analyses at NCI, and the OSU researchers are working in close collaboration with scientists in Sarawak. His goal with NExT, Dr. Grever said, is to help move silvestrol into phase I clinical trials.

Special Report

Duplicated Gene May Explain Rare Cancer in Some Families

A circular map representing chromosomal rearrangements. The chromosomes are color-coded in the outermost circle. Inside are lines connecting the origin and the new location of 58 out of 75 interchromosomal duplications. (Image courtesy of Jan Aerts, Wellcome Trust Sanger Institute) A circular map representing chromosomal rearrangements. The chromosomes are color-coded in the outermost circle. Inside are lines connecting the origin and the new location of 58 out of 75 interchromosomal duplications. (Image courtesy of Jan Aerts, Wellcome Trust Sanger Institute) [Enlarge]

For more than a decade, researchers at NCI and their collaborators have collected DNA from seven families with an inherited form of chordoma, a type of bone cancer. The researchers have now identified a genetic change that may lead to the disease in four of the families.

The change was not a mutation in the DNA sequence of a gene, as the researchers had expected, but rather the duplication of an entire gene. In each family, an extra copy of the gene was created by a large structural change in the genome—a rearrangement—that occurred once and was passed down to future generations.

While the type of the genetic change was perhaps unexpected, the identity of the gene was not. As the researchers reported online in Nature Genetics on October 4, the gene is active in the chordoma tumor cells of people with the noninherited form of the disease. The gene is called T, or brachyury (for the protein it encodes).

“We have found the gene for a subset of families with an inherited predisposition to chordoma,” said lead investigator Dr. Rose Yang of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “We had thought this gene may be important in predisposing to the disease, and for the first time we have direct evidence from a study of high-risk families.”

Broader Implications

About 300 cases of the noninherited form of chordoma are diagnosed in the United States each year. The disease causes a tumor to develop anywhere along the spinal column, from the base of the skull to the tailbone, and the tumor can be fatal. Researchers believe the tumors arise from remnants of the notochord, an embryonic precursor to the spinal cord.

The discovery provides a new clue to the biology of chordoma and could have broader implications. It suggests an alternate strategy for finding susceptibility genes when traditional methods fail, the researchers said. In this case, genetic mapping studies had linked a region of chromosome 6 to the disease, but sequencing DNA in the region, including the T gene, revealed no suspicious changes.

“Sequencing DNA doesn’t find everything, and it won’t tell you if a whole gene is deleted or duplicated,” said co-author Dr. David Ng of the National Human Genome Research Institute (NHGRI). “So if a gene appears to play a role in a disease but you don’t find any mutations by sequencing, looking for genomic rearrangements, including duplications or deletions in the gene, is a reasonable next step.” 

To survey the structural changes in the genome, the researchers used a technique called array comparative genomic hybridization (CGH), which revealed a different genomic rearrangement in each of the four families. Yet nearly all of the affected family members had tumors in the same area (the base of the skull).

Counting Copies

Most human DNA is present in two copies per cell (one from each parent), yet in each cell, certain regions are deleted or present in multiple copies—what are known as copy number variations, or CNVs. These changes are usually harmless, but certain types of rearrangements can lead to cancer and other diseases.

In the largest survey to date of frequent CNVs in the human genome, reported this month in Nature, researchers said that any two human genomes differ by more than 1,000 CNVs (about 0.8 percent of a person’s DNA sequence). The study authors predicted that genomic rearrangements are likely to play a role in rare as well as common diseases.

The chordoma study certainly supports this idea. It also underscores just how important advances in technology and persistence are in the search for susceptibility genes.

“We almost gave up hope of finding the gene on several occasions,” said Dr. Dilys Parry of DCEG, who launched the project in 1996 after identifying a chordoma family that now has 10 affected members spanning several generations. “But in the last 13 years, the technology has changed enormously, and we’ve been able to take advantage of the advances at every step along the way.”

This was perhaps most evident 2 years ago, when the team used new markers and tools to locate the region of chromosome 6 with the T gene. After negative results from DNA sequencing, the researchers used the array-CGH technology to screen 13 members of the 7 families (including 11 with chordoma) for genomic rearrangements.

New Beginning

The result made sense immediately to the researchers because the T gene is active in some chordoma tumor cells and it regulates the development of the notochord. However, they do not yet understand how the gene might cause chordoma, according to co-author Dr. Michael Kelley of Duke University Medical Center and a former NCI investigator.

Another question is what caused the disease in the three families without the T gene duplication. The researchers predict that mutations in other genes or an as-yet-unknown mechanism involving the T gene will eventually provide the answer. They are actively enrolling chordoma families to participate in an ongoing study to identify the other genes.

In some rare inherited cancers, there are not enough families—or the families are too small—to use traditional linkage studies to locate chromosome regions of interest. But in some of these cases, noted Dr. Yang, testing for genomic rearrangements may be informative.

“This study really highlights what we can do with new genomic technologies,” said Dr. Joan Bailey-Wilson, who studies the genetics of inherited diseases at NHGRI and was not involved in the research. “CNVs are another item in our tool box for locating genetic susceptibility variants, and most of us are excited about any new tool we can get.”

The discovery of a susceptibility gene always leads to important questions about biological processes that can take many years to answer, Dr. Bailey-Wilson added. “Once we find a gene that we believe is responsible for a linkage signal, we have to realize that the true work is only starting,” she said.

—Edward R. Winstead

A Closer Look

Does Mammography Sometimes Detect Too Much Breast Cancer?

Reader Suggested

The argument for screening women for breast cancer with mammography sounds simple: Mammography can detect cancers before they begin to cause symptoms. Clinical trials have shown that fewer women die of breast cancer when they are screened with mammography than when they are not.

But what if some of the very early stage breast cancers found by mammography are not destined to grow and become potentially lethal? Although the idea of a harmless cancer may seem counterintuitive, such cancers do exist.

Some cancers never grow, or they grow so slowly that they never become clinically detectable. Autopsy studies have found breast tumors in women between age 40 and 70 who died of unrelated causes. And a 2008 study made the provocative suggestion that some very early stage invasive breast tumors may regress spontaneously.

Overdiagnosis

A woman receiving a mammogram. A mammogram uses ionizing radiation to image breast tissue and is used to screen for cancer. A mammogram uses ionizing radiation to image breast tissue and is used to screen for cancer.

The identification of tumors that would never have become a clinical problem in the patient’s lifetime is known as overdiagnosis.

“With overdiagnosis, we often end up ‘curing’ cancers that didn’t need to be cured in the first place,” said Dr. Barry Kramer, director of the NIH Office of Disease Prevention and an expert on cancer screening. 

Because doctors can’t distinguish breast cancers that will progress from those that will not, these “overdiagnosed” tumors will in most cases lead to surgery, possibly with radiation, chemotherapy, or hormone therapy. Some people, therefore, are receiving unnecessary treatment that is of no benefit to them, can be toxic, and often comes with significant side effects.

Studies strongly suggest that overdiagnosis occurs with screening for several cancers, including prostate and lung cancer, as well as breast cancer, said Dr. Kramer.

The precise extent of breast cancer overdiagnosis is unclear. In a paper published in July in the British Medical Journal, Danish researchers estimated that one out of every three tumors detected by screening mammography was overdiagnosed. Their estimate was based on an analysis of breast cancer rates before and after the implementation of government-run mammography screening programs in Australia, Canada, Norway, Sweden, and the United Kingdom.

Learn more about the benefits and limitations of breast cancer screening with mammography:

Breast Cancer Screening (PDQ®):
Patient version
Health professional version

U.S. Preventive Services Task Force Recommendations on screening for breast cancer

A 2006 study that was based on 25 years of follow-up with women who were screened with mammography in Sweden concluded that one in six breast cancers was overdiagnosed. Other estimates of overdiagnosis have ranged from 5 percent to 32 percent.

“Pulling Cases Out of the Future”

Several factors can lead to varying estimates of breast cancer overdiagnosis. One is whether researchers count both early stage invasive tumors and ductal carcinoma in situ (DCIS) detected by mammography, or only invasive tumors. “If you count only invasive cancers, estimates will be lower. If you also count DCIS, they will generally be higher,” said Dr. Kramer.

Another factor is what assumptions researchers make about time trends in cancer rates. “In the absence of overdiagnosis, [mammography] should be pulling cases out of the future into the present,” said Dr. Kramer. In other words, every breast cancer detected early by mammography should equal one less cancer detected later on.

This is what the Danish researchers assumed would happen, explained Dr. Kathleen Cronin of NCI’s Statistical Research and Applications Branch. “They assumed that the number of new breast cancer cases diagnosed each year after mammography screening began would have followed the same trend seen before mammography was introduced,” she said.

But in fact, from the 1980s through 2001, a span of time roughly corresponding to the period during which mammography screening programs became established, the number of newly diagnosed breast cancer cases increased year by year. And, as noted in this week’s Journal of the American Medical Association, the incidence of aggressive or later-stage disease has not decreased at a rate that would be explained by an increase in earlier diagnoses.

Changes in breast cancer risk factors––more women delaying childbirth or using postmenopausal hormone therapy, for example––may have contributed to the increase in breast cancer cases, said Dr. Kramer. Overdiagnosis may have, too.

Molecular Features

The bottom line? Many other researchers think the Danish investigators may have overestimated the level of breast cancer overdiagnosis. Most agree, however, that mammography does diagnose some breast cancers that would never have needed to be treated.

Recognizing that current estimates of the extent of the problem are unsatisfactory, researchers are striving to develop more accurate ways of estimating just how much overdiagnosis of breast cancer results from mammography in the hopes of sparing some women from unnecessary and often toxic treatments. Dr. Cronin is scientific coordinator for an NCI-supported consortium of researchers who are working to better understand how mammography, among other factors, influences breast cancer rates.

Overdiagnosis can be identified at a population level by comparing cancer rates in groups of people over time. Relevant data are provided by the Breast Cancer Surveillance Consortium (BCSC) and NCI’s Medicare SEER database. Longitudinal data are a critical aspect of these efforts. Over its 15-year existence, the BCSC has collected information on 2,017,869 women, including 86,700 with cancer.

Researchers agree that one solution to the problem of breast cancer overdiagnosis may ultimately emerge from advances in molecular medicine that will enable doctors to distinguish mammography-detected tumors likely to progress from those unlikely to do so.

“If we can identify tumors that are not destined to become a problem, we can avoid treating patients unnecessarily,” said Dr. Sudhir Srivastava, chief of NCI’s Cancer Biomarkers Research Group. “And differentiating progressive and nonprogressive tumors on the basis of molecular features is currently an active area of research within the NCI-supported Early Detection Research Network,” he explained.

In the meantime, for women aged 40 and over who may be wondering if they should continue having regular mammograms, Dr. Stephen Taplin, a breast cancer screening specialist with NCI’s Applied Research Program, offered this advice:

“Today, regardless of age, women are less likely to die of breast cancer than they were 20 years ago because of improvements in treatment and wider use of screening. There is no simple way for a woman to measure the benefit of mammography to her as an individual, but research is under way to improve our ability to estimate a woman’s risk. What we do know is that, on average, for women aged 50 to 75, mammography reduces the likelihood of dying from breast cancer by about 20 percent. For women aged 40 to 49, the reduction in mortality is smaller, although still real, and the balance of benefits versus harms may be more uncertain.

“The balance of benefits and harms is something that is best done by each woman with her health care provider,” Dr. Taplin continued. “Think about what is important to you. Think about how you would feel if you had an abnormal mammogram. Then make the decision that is right for you.”

Eleanor Mayfield

Featured Clinical Trial

Testing Satraplatin in Advanced Prostate Cancer

Name of the Trial
Phase II Study of Satraplatin and Prednisone in Patients with Progressive, Metastatic Androgen-Independent Prostate Cancer (NCI-08-C-0074). See the protocol summary.

Dr. William L. Dahut Dr. William L. Dahut

Principal Investigator
Dr. William Dahut, NCI Center for Cancer Research

Why This Trial Is Important
Men with metastatic prostate cancer that does not respond to hormone therapy (androgen-independent prostate cancer) have very few treatment options available. Chemotherapy with docetaxel or other drugs is often used to alleviate symptoms and delay disease progression, but most men continue to get worse despite this treatment.

Satraplatin is a third-generation, orally administered platinum drug that may delay disease progression in men with androgen-independent prostate cancer. Previous preclinical and clinical research has shown that satraplatin is active against androgen-independent prostate cancer and that it may overcome the resistance to platinum drugs commonly seen in advanced disease.

In this trial, men with androgen-independent metastatic prostate cancer that has progressed after first-line chemotherapy will be treated with satraplatin and prednisone. The researchers want to see if this regimen can delay disease progression and if alterations in the ERCC1 gene are associated with improved progression-free survival. ERCC1 is an important DNA repair gene that may contribute to resistance to platinum drugs. The researchers believe that DNA variations in ERCC1 may be related to satraplatin’s observed ability to overcome this resistance.

“A phase III study of satraplatin and prednisone in patients with metastatic androgen-independent prostate cancer has demonstrated that satraplatin can significantly improve progression-free survival and help alleviate cancer-related pain, although patients receiving satraplatin in this study did not live longer overall than those receiving a placebo,” said Dr. Dahut.

“Our trial is unique because it aims to determine whether the presence of ERCC1 gene polymorphisms may be associated with an impact on the progression-free survival of patients with metastatic prostate cancer,” he said. “This trial will provide critical information about patient selection for satraplatin therapy.”

For More Information
See the lists of entry criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

An archive of "Featured Clinical Trial" columns is available at /clinicaltrials/ft-all-featured-trials.

Cancer Center Profile

University of Chicago Cancer Research Center

Director: Dr. Michelle M. Le Beau • 5841 South Maryland Avenue, MC1140, Chicago, IL 60637
Phone: 773-702-6180 • Web site: http://uccrc.uchicago.edu

Background

Founded in 1973, the University of Chicago Cancer Research Center (UCCRC) is one of two NCI-designated comprehensive cancer centers in Illinois. The University of Chicago has been a leader in cancer research for many decades. Its scientists have made groundbreaking discoveries that have led to advances in chemotherapy, hormonal therapy, gene therapy, and bone marrow transplantation.

The Gwen and Jules Knapp Center for Biomedical Discovery The Gwen and Jules Knapp Center for Biomedical Discovery, which houses the UCCRC, opened in the summer of 2009.

In 1943, the University of Chicago’s Dr. Leon Jacobson performed the first successful cancer treatment using chemotherapy and demonstrated the potential of bone marrow transplantation. In FY 2009, UCCRC’s pediatric and adult bone marrow transplant programs performed 180 bone marrow transplants.

Nobel Prize recipient Dr. Charles Huggins discovered in 1966 that cells were not autonomous and self perpetuating, as previously believed, but were dependent on chemical signals, such as hormones, to grow and survive. His discoveries offered researchers new perspectives on the behavior of hormone-responsive cancers and redefined treatment of metastatic cancers.

Dr. Janet Rowley’s discoveries of recurring chromosomal abnormalities in leukemias and lymphomas revolutionized the understanding and treatment of cancer. President Barack Obama honored Dr. Rowley with the Medal of Freedom, the nation’s highest civilian award, earlier this year.

Research

Building on this tradition of excellence, the UCCRC laboratory research programs have made fundamental discoveries in the molecular genetics of cancers, cancer immunology, hormonal therapy, bone marrow transplantation, cell signaling, and advanced imaging techniques. Clinical researchers have made critical breakthroughs in the investigation of breast, head and neck, lung, kidney, and prostate cancers, leukemia, mesothelioma, and cancer genetics.

Prevention and control research at the UCCRC emphasizes identifying genetic risk factors for cancer, investigating potential chemoprevention agents, and studying early detection, health disparities, and quality-of-life issues. UCCRC members are world-renowned experts in advanced imaging, radiation treatment, the development of novel anticancer drugs, and pharmacogenomics.

Active UCCRC research programs include a Specialized Program of Research Excellence (SPORE) in breast cancer, participation in a SPORE in prostate cancer (with Lurie Comprehensive Cancer Center of Northwestern University), the Pharmacogenetics of Anticancer Agents Research Consortium (U01), a Specialized Center of Research (SCOR) in hematological malignancies, the Ludwig Center for Metastasis Research, a National Center for Complementary and Alternative Medicine Center of Excellence in Research, and the Chicago Center for Systems Biology.

Patient Care

UCCRC offers the full range of specialty and primary care services for adults and children. The center had 25,300 admissions in FY 2009 and 150,000 patient days annually. Cancer patients make up a large portion of the patient base, with almost 5,000 new cancer patients annually. Cancer patients account for over 61,500 outpatient visits.

Advanced cancer care will be a priority of the 1.2 million-square-foot New Hospital Pavilion (NHP) that is currently under construction.

Translational Research

The NHP will be adjacent to two new research facilities. The 400,000-square-foot Ellen and Melvin Gordon Center for Integrative Science (GCIS), the university’s largest science building, opened in 2005. The GCIS is the home of the Ben May Department for Cancer Research. The Gordon Center brings scientists from the biological and physical sciences together under one roof, enabling new research collaborations.

The 330,000-square-foot Gwen and Jules Knapp Center for Biomedical Discovery (KCBD), which is the home of the UCCRC, opened in 2009. This facility houses 22,000 square feet of wet lab space for UCCRC investigators, as well as the D.K. Ludwig Center for Metastasis Research and the Institute for Genomics and Systems Biology. The proximity of the GCIS, KCBD, and NHP will encourage and facilitate interdisciplinary and translational research. The three facilities represent the continuum of research that transforms fundamental discoveries into advanced cancer care.

Legislative Update

Experts Testify on Pending Breast Cancer Legislation

On October 7, a panel of cancer survivors, advocates, and researchers testified before the U.S. House of Representatives Committee on Energy and Commerce, Subcommittee on Health, at a hearing on the Eliminating Disparities in Breast Cancer Treatment Act of 2009. Panel members included Dr. Stephen Taplin, chief of NCI’s Applied Cancer Screening Research Branch; Dr. Otis Brawley, chief medical officer of the American Cancer Society; Jenny Luray, president of the Susan G. Komen for the Cure Advocacy Alliance; Debra L. Ness, president of the National Partnership for Women and Families; Fran Visco, president of the National Breast Cancer Coalition; and Dr. Marisa C. Weiss, president and founder of Breastcancer.org.

The legislators and panelists called for greater emphasis on tailoring prevention and treatment to an individual’s risk, improved early detection methods, and increased access to health care that covers the entire screening and treatment process. Dr. Taplin stressed the need for additional research to improve the accuracy of breast cancer screening to avoid overtreatment, and he discussed the importance of addressing screening as a multi-step process.

Rep. Debbie Wasserman Schultz (D-FL) is working on a new version of the EARLY Act, which drew concerns from many in the medical and scientific community when it was first introduced in March 2009. The revised bill will designate the CDC to lead the development of the educational messages required by the legislation, and those messages will focus on evidence-based actions that affect breast health over a woman’s lifetime.

More information on the hearing, including witness statements, can be found on the Committee Web site.

For more information about this and other NCI congressional activity, visit the NCI Office of Government and Congressional Relations Web site.

Congressional Delegation Visits NIH

NIH Director Dr. Francis Collins welcomes members of Congress during their visit to campus on October 6. NIH Director Dr. Francis Collins welcomes members of Congress during their visit to campus on October 6.

Fifteen members of Congress and 16 congressional staffers gathered at the NIH Clinical Center on October 6 to learn about NIH ventures, successes, challenges, and future directions. Rep. Ron Klein (D-FL), who requested and organized the visit, opened with congratulatory remarks to Dr. Francis Collins on his appointment as NIH director. In subsequent presentations, Dr. Collins provided an overview of NIH, introducing issues ranging from NIH’s contemporary role in medicine to evolving public health challenges. NIH Deputy Director Dr. Raynard Kington spoke about the impact of stimulus funding.

NCI Director Dr. John E. Niederhuber opened the presentation on cancer research at NIH and introduced Drs. Lee Helman, acting clinical director of NCI’s Center for Cancer Research, and Steven Rosenberg, chief of NCI’s Surgery Branch, who discussed new avenues in cancer research, focusing particularly on personalized medicine, targeted therapy, and immunotherapy. The congressional delegation also heard a presentation on the H1N1 virus by NIAID Director Dr. Anthony Fauci.

This was the largest congressional delegation to visit the NIH campus to date, and it provided NCI the opportunity to demonstrate how appropriated funds are being used.

FDA Update

FDA Approves Two HPV Vaccines: Cervarix for Girls, Gardasil for Boys

The FDA has approved a second vaccine to prevent cervical cancer and cervical precancers, the vaccine’s manufacturer, GlaxoSmithKline (GSK), announced last week. The approval is based on data from a large clinical trial showing that the vaccine, Cervarix, prevented precancerous lesions in 93 percent of those who received the full vaccine sequence of three injections over 6 months.

Cervarix is a bivalent vaccine, meaning it is specifically designed to protect against two human papillomavirus (HPV) types, HPV 16 and 18, which together are responsible for three-quarters of cervical cancers in North America. Clinical trial data also indicate that Cervarix offers more modest protection against precancerous lesions associated with HPV 31, GSK explained in a statement, as well as other tumor-causing (or oncogenic) HPV types. The company expects the vaccine to be available in the United States by the end of the year.

The FDA last week also approved the HPV vaccine Gardasil for the prevention of genital warts in boys. Gardasil is already approved and is being actively used in girls and young women for the prevention of cervical cancer. Gardasil is a quadrivalent vaccine that is designed to specifically protect against infections with four HPV types: 16, 18, 6, and 11. HPV types 6 and 11, which are not considered to be oncogenic, cause genital warts.

The agency’s approval of Gardasil for boys aged 9 to 26 is based on data from a randomized clinical trial of more than 4,000 males aged 16 to 26, which demonstrated 90 percent protection against HPV 6- and 11-related genital warts. In a press statement announcing the approval, the FDA explained that for boys aged 9 to 15, studies have been conducted to measure their immune response to the vaccine, and “the results showed that the immune response was as good as that found in the 16- to 26- year-old age group, indicating that the vaccine should have similar effectiveness.”

A number of studies have now linked infection with HPV 16 to certain types of head and neck cancers, in particular oropharyngeal cancer (the tonsils and base of the tongue), the rates of which have been increasing over the last decade. So there is a chance, some researchers believe, that widespread HPV vaccination of both males and females could have a broader cancer prevention effect.

“There is every reason to be optimistic that vaccination may help us to reduce the current trends of HPV-related tonsillar cancer,” said Dr. Maura Gillison, a researcher at Ohio State University who was among the first to identify the link between HPV and head and neck cancer. Dr. Gillison said she is hopeful that a clinical trial can be launched in the near future to assess whether vaccination can prevent oral HPV 16 infections.

The CDC’s Advisory Committee on Immunization Practices, which makes recommendations on the administration of FDA-approved vaccines to the medical community, will decide later this week whether to recommend that males be vaccinated against HPV to prevent genital warts.

FDA Approves New Targeted Therapy for Kidney Cancer

There are now six agents available for the treatment of advanced kidney cancer, with the FDA’s approval yesterday of pazopanib (Votrient). The approval is based on the results of an international phase III clinical trial that showed an improvement in progression-free survival (PFS)—survival in the absence of tumor growth—compared with patients who received a placebo. The trial found no improvement in overall survival with the drug.

Earlier this month, the agency’s Oncologic Drugs Advisory Committee voted 10-0 in favor of approving pazopanib. This came despite concerns raised by the agency’s own review staff about some of the side effects associated with pazopanib in the trial, including three deaths caused by severe liver injury. The side effects call into question “the benefit-to-risk ratio of pazopanib in the intended population of patients,” particularly considering the availability of other effective therapies, FDA reviewers wrote in a briefing document.

In the trial, the results of which were presented earlier this year at the American Society of Clinical Oncology annual meeting, PFS more than doubled in patients given pazopanib compared with those who received placebo, 9.2 months versus 4.2 months. The PFS improvement was the strongest in patients who had not been previously treated, 11.1 months versus 2.8 months. The most common side effects associated with pazopanib in the trial were diarrhea and hypertension, as well as an elevation in the ALT liver enzyme, a common indicator of liver injury.

An industry-sponsored phase III trial comparing pazopanib against sunitinib (Sutent) is currently enrolling patients.

Notes

NIH Mourns Passing of Former Director Dr. Ruth Kirschstein

Dr. Ruth Kirschstein Dr. Ruth Kirschstein

NIH employees and members of the scientific community mourned the loss of former NIH Deputy Director Dr. Ruth Kirschstein, who passed away on October 6 at the NIH Clinical Center in Bethesda, MD, after a long illness.

Dr. Kirschstein and her husband, NCI Deputy Director Dr. Alan Rabson, came to NIH in the 1950s to work as pathology researchers. While at NIH’s biologics division, later part of the FDA, Dr. Kirschstein investigated a disease-causing batch of polio vaccine and helped choose the Sabin vaccine for world-wide use. In 1974, she became the first woman to direct an NIH institute, the National Institute of General Medical Sciences. During her 19 years there she promoted cell and molecular biology and pushed to support young investigators and diversity in science.

Dr. Kirschstein later served as NIH deputy director for 6 years when NIH Director Dr. Harold Varmus became director in 1993. She also served twice as acting NIH director, including 29 months before Dr. Elias Zerhouni became director in 2002 and made her a senior adviser. In 2002, Congress renamed NIH’s graduate student fellowship program after Dr. Kirschstein.

“Ruth embodied the spirit of the NIH. She was an icon,” wrote current NIH Director Dr. Francis Collins in a memo to staff. “She was loved and admired by so many at the NIH, across the medical research community, among hundreds of members of Congress, and around the world.”

NCI Cancer Bulletin Recognized with NIH Merit Award

The NCI Cancer Bulletin was honored today with a 2009 NIH Merit Award for “outstanding contribution to cancer research communications” at the NCI Director’s Awards Ceremony. Now in its 6th year of publication, the newsletter currently maintains a circulation to over 48,000 researchers, physicians, nurses, survivors and their family members, and others. Many of the Bulletin’s editorial and technical staff were on hand to receive the award.

International Palliative Care Resources Available Online

IPCRC Web site

The Institute for Palliative Medicine at San Diego Hospice launched the International Palliative Care Resource Center, IPCRC.net, on October 1. The Web site provides online access to global information and education resources on palliative care, including comfort, supportive, hospice, end-of-life, and bereavement care. IPCRC.net is designed to be constantly updated with contributions from physicians, nurses, patients, families, caregivers, and other site users. Offering easy access over high- and low-speed communication links, IPCRC.net can be accessed in developed and resource-limited nations, promoting worldwide information exchange and collaboration. NCI’s Office of International Affairs helped fund the site’s development.