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April 7, 2009 • Volume 6 / Number 7

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NEWS

A physician from NCI's Urologic Oncology Branch speaks with a patient

Cancer Survivors and Their Doctors Have Different Expectations about Care

A new survey of oncologists, primary care physicians, and their patients finds that it is not always clear who is responsible for meeting the medical needs of cancer survivors.

As highlighted by a recent report from the Institute of Medicine, cancer survivors have a complex set of medical needs that must be met in addition to regular care and screening. And, therefore, the discordant expectations about long-term health management likely complicate the care received by the approximately 12 million U.S. cancer survivors. Read more > >

COMMENTARY

Director's Update: New Resources for a Bright Future

The Obama administration's economic stimulus package, the American Recovery and Reinvestment Act, is a prime topic of discussion in official Washington and, one would certainly expect, at dinner tables across America, as well. Commonly referred to as ARRA, the $787 billion stimulus plan aims to create and protect jobs and help stabilize our nation's economy. Read more > >

A Conversation With...Dr. Rashmi Sinha

The NCI investigator and lead author of a prospective study on meat intake and mortality discusses the study's findings. Read more > >

IN DEPTH

UPDATES

  • FDA Update

    • New Treatment for Advanced Kidney Cancer Approved
    • ODAC Recommends Approval of Bevacizumab for GBM
  • CMS Update

    • Medicare Expands Coverage of PET Scans for Most Solid Cancers
  • Cancer.gov Update

    • Cancer.gov Introduces "NCI Features"
  • Notes

    • Clinical Trials Promotional Tools Available from NCI
    • NCI-Frederick Prepares for Annual Spring Research Festival
    • CTCAE 4.0 Posted for Public Review
    • Meet NCI Experts at AACR

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

Cancer Survivors and Their Doctors Have Different Expectations about Care

A physician from NCI's Urologic Oncology Branch speaks with a patient. A physician from NCI's Urologic Oncology Branch speaks with a patient

As highlighted by a recent report from the Institute of Medicine, the approximately 12 million cancer survivors living in the United States have a complex set of medical needs that must be met in addition to regular care and screening. Now, a new survey of oncologists, primary care physicians, and their patients finds that it is not always clear who is responsible for meeting the medical needs of cancer survivors. And, according to the study authors, these discordant expectations about long-term health management likely complicate the care received by cancer survivors.

The study was published online March 30 in the Journal of Clinical Oncology.

Patients in the study, led by Dr. Craig Earle from the Institute for Clinical Evaluative Sciences in Toronto, Canada, had higher expectations than their oncologists that the oncologists would regularly participate in noncancer-related survivorship care, including routine screening for other cancers. In contrast, primary care practitioners had higher expectations than their patients for their involvement in survivorship care, including follow-up monitoring and treatment for the patients' primary cancers.

Online resources to help assemble a survivorship care plan

ASCO Cancer Treatment Summaries and Survivorship Care Plans
These downloadable forms help breast and colon cancer survivors assemble a care plan; forms for additional types of cancer are coming soon. ASCO also provides summary forms for doctors to record treatments, which can be shared with others involved in follow-up care.

Lance Armstrong Foundation Survivorship Worksheets
Several tools can help cancer patients organize information about their care, including a Cancer Survivor's Medical Treatment Summary (PDF - 842KB), which contains sections for suggested follow-up care.

OncoLife Survivorship Care Plan
This online tool helps patients and their healthcare teams keep track of cancer treatments received. The tool then generates a list of potential late side effects of treatment that patients and their doctors should monitor.

National Coalition for Cancer Survivorship
Elements of a successful survivorship care plan are listed here. The coalition's Web site also includes the Cancer Survival Toolbox® module, an audio teaching program that includes survivorship issues.

Institute of Medicine Survivorship Care Fact Sheet (PDF - 88KB)
This document outlines the elements that should be included in a survivorship care plan, as well as questions that patients should ask their health care providers.

"My interest in survivorship grew out of the observation in the clinic that patients would ask me things like, 'Is my thyroid dose right?' or 'How's my cholesterol?' and expected that I would do this type of routine care, when in fact I was just following them for their colon cancer," explained Dr. Earle, an oncologist. "That got me wondering: If they think I'm doing these things and I don't think I'm doing them, is necessary care falling through the cracks?"

Dr. Earle and his colleagues recruited 431 survivors who had received at least part of their cancer treatment at the Dana-Farber/Brigham and Women's Cancer Center in Boston, MA, along with 255 primary care physicians and 123 oncologists who had participated in those patients' care.

Patients answered questions about the degree of responsibility that they believed their oncologist and primary care physician should take in four main areas of survivorship care: surveillance of their cancer, screening for other cancers, general preventive health, and ongoing management of other health problems. Both oncologists and primary care physicians answered questions about their perceived roles in the same four areas.

The agreement in expectations between patients and physicians ranged widely, from 29 percent to 91 percent between patients and oncologists and from 35 percent to 92 percent between patients and primary care physicians. Expectations between oncologists and primary care physicians were discordant, with only 3 percent agreeing on who should be responsible for primary cancer surveillance and 44 percent agreeing on who should be responsible for routine cancer screening.

"We found that there are uncertainties surrounding the perceived responsibilities of physicians and the delivery of care to cancer survivors, especially with respect to primary cancer follow-up and screening for other cancers," the researchers concluded. "With a lack of clarity about which provider is responsible for care, patients may not receive necessary services of demonstrated benefit."

This study highlights the urgent need "for some sort of survivorship care planning," said Dr. Earle. "It all comes down to communication and making sure that whoever is involved knows who is going to be taking responsibility for what actions going forward. We need to provide primary care physicians with actionable information about the specific patients they have in their practice, and we as specialists are able to provide that sort of expertise and those recommendations."

"As the Institute of Medicine pointed out, it's important to develop a care plan," agreed Dr. Noreen Aziz, senior program director of NCI's Office of Cancer Survivorship in the Division of Cancer Control and Population Sciences. "One of the aspects of that plan should be to outline who is responsible for what aspect of care, so that everyone is on the same page. Developing such a care plan would be a terrific idea, and I think that the [oncology] field is moving towards that."

—Sharon Reynolds

Cancer Research Highlights

Ovarian Cancer Screening Resulted in Many Unnecessary Surgeries

Screening women for ovarian cancer often led to unnecessary surgeries and failed to detect the disease in its early stages, according to new results from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. The analysis focused on the 34,000 women in the NCI-sponsored trial who were screened annually for signs of ovarian cancer using transvaginal ultrasound and/or the CA-125 blood test.

Many of the positive screening results turned out not to be cancer. The researchers estimate that out of every 100 women who test positive for signs of ovarian cancer with these tests, only 1.6 actually have cancer. In another measure of the screening program, the ratio of surgeries to detected cancers over all four rounds of screening was 19.5 to 1.

Screening effectively doubled the rate of oophorectomy (removal of the ovaries) among this group, which included women aged 55 to 74 years old. Screening with transvaginal ultrasound accounted for most of the unnecessary surgeries, but this method also detected the most early stage cancers. Overall, however, 70 percent of the ovarian cancers found in the study were in their late stages (stage III or later), when treatment options are limited.

The results are consistent with the current guidelines of the U.S. Preventive Services Task Force that do not recommend ovarian cancer screening with CA-125 and transvaginal ultrasonography, the researchers concluded in the April Obstetrics & Gynecology. The question of whether the screening program saves lives will be addressed in future studies that include results from women who did not undergo screening.

"We need a test that is more sensitive and more specific so we find the cancer earlier and we catch the biological markers that give us stronger clues," lead investigator Dr. Edward Partridge, who directs the University of Alabama at Birmingham Comprehensive Cancer Center, said in a statement. He discussed the findings in a short video here.

 

Racial Disparity in Colon Cancer Linked to p53 Gene

African Americans have the highest incidence and mortality from colon cancer of any ethnic or racial group in the United States. Researchers have investigated differences in diet, alcohol consumption, socioeconomic factors, and physical activities as possible explanations for these disparities. Because genetic and biological differences may also play a role, some researchers are looking for markers that predict the aggressiveness of tumors and clinical outcomes.

A new study suggests that the p53 gene, which normally helps to suppress tumors and is frequently mutated in cancer, could be such a marker. A form of the gene called Pro72 was more common in African Americans than Caucasians in the study, and the variant was associated with an increased number of p53 mutations, more advanced tumors, and shorter survival time compared with other forms of the gene.

If the results are confirmed, Pro72 could be a prognostic marker and eventually lead to more personalized treatments for people who carry this form of the p53 gene, said Dr. Upender Manne of the University of Alabama at Birmingham and his colleagues in the April 1 Clinical Cancer Research.

The study included 137 African Americans and 236 Caucasians. Both groups had similar rates of p53 mutations, but 17 percent of the African Americans carried two copies of the Pro72 variant compared with 7 percent of Caucasians. The presence of this variant in African Americans was associated with a more than twofold increase in mortality due to colorectal cancer. The variant had no effect on mortality from colorectal cancer among Caucasians.

In the subset of patients with colorectal cancer who inherit the Pro72 variant, the susceptibility to disruptive changes in the p53 protein may be a possible molecular explanation for the racial disparity, the researchers concluded.

 

Multifocal Lung Tumors May Arise from a Single Cell

In a small percentage of patients with lung cancer, multiple tumors that look similar under the microscope can arise in several parts of the lung, either synchronously (at the same time) or metachronously (in succession). Whether these multifocal tumors arise from a single malignant cell or form separately due to widespread carcinogenic effects on the lung tissue—from exposure to tobacco smoke, for example—has not been clear.

A new study led by researchers from Indiana University and published online April 7 in the Journal of the National Cancer Institute provides genetic evidence indicating that the majority of these cancers may arise from a single cell and should therefore be classified as advanced-stage cancers.

The researchers collected formalin-fixed, paraffin-embedded tissue samples from 30 patients (23 women and 7 men) with multifocal lung cancer, for a total of 70 separate tumor samples. Three different types of genetic changes were analyzed in the tumor samples: loss of genetic material on several chromosomes; mutations in a gene called TP53; and epigenetic changes on the X chromosomes in samples taken from women.

Complete concordance, or an identical loss of genetic material among multifocal tumors, was seen in 26 out of 30 patients. Out of 18 patients whose samples could be screened for TP53 mutations, 10 had identifiable mutations, and in 8 patients these mutations were identical among multifocal tumors. Out of 19 women whose tumor samples could be used for epigenetic analysis, 15 had a concordant pattern of changes between multifocal tumors.

When results of the three analyses were combined, "23 (77 percent) of 30 patients had identical genetic changes, consistent with a monoclonal origin of these separate tumors rather than separate independent primary lung tumors. Our findings support the current classification of multifocal lung cancers as advanced-stage cancers…rather than separate primary cancers and the use of therapeutic strategies tailored for patients with advanced-stage cancers," concluded the authors.

 

Alcohol-induced Flush Warns of Esophageal Cancer Risk

"Asian flush," a response to alcoholic beverages caused by a buildup of acetaldehyde, is most often seen in Japanese, Chinese, and Koreans who are unable to metabolize alcohol effectively. It is also strongly associated with risk for esophageal cancer: People who turn red after drinking have a dramatically higher risk of developing the disease than those who don't flush.

In the March issue of PLoS Medicine, study authors Dr. Philip Brooks of the National Institute on Alcohol Abuse and Alcoholism, and his collaborators at Duke University and the National Hospital Organization Kurihama Alcoholism Center in Japan wrote that because flushing is easily apparent and also strongly linked with cancer risk, it should be a routine cancer screening factor in primary care settings.

They noted that 36 percent of East Asians, or approximately 540 million people worldwide, carry a defective copy of the gene for aldehyde dehydrogenase 2 (ALDH2), the enzyme that helps break down acetaldehyde, a product of ethanol metabolism, into acetate. Acetaldehyde is strongly carcinogenic, the authors explained.

People who carry two defective copies of the ALDH2 gene are usually unable to drink significant amounts of alcohol due to the severity of their reaction. However, those who have only one defective copy of the gene can develop tolerance, and prospective studies have shown that the risk for developing cancers in the upper aerodigestive tract is approximately 12 times higher in these individuals. Furthermore, because acetaldehyde lingers in saliva, particularly in those who smoke, they are at an even greater risk for cancer.

Pointing out other social trends that pose increased risk among this population, the authors wrote, "Clinicians need to be aware of the risk of esophageal cancer from alcohol consumption in their ALDH2-deficient patients…[and should] determine whether an individual of East Asian descent is ALDH2 deficient simply by asking whether they have experienced the alcohol flushing response."

Director's Update

New Resources for a Bright Future

Dr. John E. Niederhuber Dr. John E. Niederhuber

The Obama administration's economic stimulus package, the American Recovery and Reinvestment Act, is a prime topic of discussion in official Washington and, one would certainly expect, at dinner tables across America, as well. Commonly referred to as ARRA, the $787 billion stimulus plan aims to create and protect jobs and help stabilize our nation's economy. It is also a commitment to American ingenuity. When he signed ARRA into law February 17, President Obama said, "I hope this investment will ignite our imagination once more, spurring new discoveries and breakthroughs in science, in medicine, in energy, to make our economy stronger and our nation more secure and our planet safer for our children."

I and the other leaders of NCI take most seriously all that the President has asked us to accomplish with ARRA funds, including his admonition that we act with a heightened sense of public accountability and transparency. We will not allow this infusion of nearly $1.3 billion to simply fund business as usual at NCI. We will expand and protect America's scientific workforce; we will invest in the next generation of science and scientists; and we will launch a coordinated platform to both support and nurture the virtual explosion of scientific discovery in the still-young 21st century. ARRA is a once-in-a-lifetime opportunity, which requires our very best efforts and our strongest vision.

Visit www.cancer.gov/recovery for the latest information available about the implementation of ARRA and NCI-specific funding opportunities.

One of the most tangible signs of NCI's commitment to outstanding science—and to the goals of ARRA—will be our vigorous support of individual laboratory and translational investigators who receive Research Project Grants, better known as R01 grants. In the 2008 fiscal year, NCI funded 3,732 R01 grants, principally at research universities across the United States. Using the increased appropriation that, for the current fiscal year, gives NCI an increase of about 3 percent, we will raise the R01 payline (the line of demarcation between grants that will and will not be funded, based on the results of peer review) for 5-year grants. Although our planning for the allocation of ARRA funds is not yet complete, we hope to allocate a substantial amount to further increase the payline, through a combination of 2-year and longer-term grants. Likewise, we will significantly increase the payline for the Star R01 grants that are designated for young, first-time grantees.

NCI also plans to vigorously support an initiative to assist research universities in helping new faculty members establish their university careers and launch their laboratories.

Importantly, we realize that across the cancer research enterprise, new knowledge of the genetic basis of cancer, coupled with dramatic improvements in the technologies that drive these discoveries, will necessitate a rebalancing of our scientific workforce, in some cases toward more directed research. Huge volumes of data coming from genome-wide studies are elucidating a range of questions from the genetic alterations of cancer initiation to the origins of metastasis to the influence of genes on behavior. From this knowledge we must come to better understand cancer's causal pathways and functional biology and then convert what may today be considered "undruggable" into tomorrow's "druggable" target.

Moving forward—in an effort enhanced by ARRA funds—NCI will expand a drug development platform which will help give structure and greater scientific support to the path from discovery to patient delivery. This unified, unparalleled translational science program will require data integration and a renewed push for development of electronic medical records through NCI's caBIG and BIG Health initiatives; state-of-the-art biospecimen collection, tissue characterization, cataloguing, and analysis through the new caHUB program; and the commitment and contributions of biologists, chemists, informaticians, and clinical scientists. One key component of this drug development platform will be the introduction of electronic health records at the community level, a move that will enable the creation of a national cohort of highly characterized patients, to facilitate translational research of the future. In short, NCI's drug development initiative will help lead to the much-talked-about era of personalized medicine, when we will use our knowledge of the genetics of cancer and of patients to create individualized methods of prevention, diagnosis, and treatment.

Recently, I and other NIH leaders attended a House Appropriations subcommittee hearing on Capitol Hill with Dr. Raynard Kington, the acting director of NIH. One member of the panel asked what areas of exciting research would be the most appropriate for the President to cite as examples of progress, as proof that the national investment in biomedical research matters. I believe that NCI's actions most affirmatively answer his question: We are exploiting every opportunity to advance cancer science and offer solutions to every cancer patient.

Dr. John E. Niederhuber
Director, National Cancer Institute

A Conversation With

A Conversation with…Dr. Rashmi Sinha

Dr. Rashmi Sinha is a senior investigator in the Nutritional Epidemiology Branch of NCI's Division of Cancer Epidemiology and Genetics. She is the lead author of a prospective study on meat intake and mortality, which was published March 23 in the Archives of Internal Medicine.

Dr. Rashmi Sinha Dr. Rashmi Sinha

What was the meat intake study and why did you do it?

Our study population of nearly 550,000 individuals came from the prospective NIH-AARP Diet and Health Study, which NCI launched in 1995. Although previous studies have linked meat intake to increased mortality from chronic disease, including cancer and heart disease, the nature of this association is not well defined. Using a food frequency questionnaire we sent to AARP members, we investigated red, white, and processed meat intakes as risk factors for total mortality and cause-specific mortality in men and women.

What were your main findings?
After 10 years of follow up, we found that consumption of red and processed meat was associated with modest increases in total mortality, cancer mortality, and cardiovascular mortality in both men and women. In contrast, white meat intake was related to a lower risk for total mortality and cancer mortality among both men and women.

We calculated the percentage of deaths that could be prevented if individuals adopted the lowest intake of red and processed meat seen among study participants. The approximate annual death rate for those individuals who ate the greatest amount of red meat would drop by 11 percent for men and 16 percent for women if they began to eat red meat at the levels consumed by individuals with the lowest intake of red meat.

What challenges did you encounter in conducting the study?
There are inherent limitations to recalling food intake over time. We attempted to remove the influence of confounding by adjusting our models for reported energy intake. To address other confounding factors - such as body mass index, family history of cancer, alcohol intake, and smoking - we reported results from models with and without these factors.

Our study population was largely non-Hispanic whites. And, on average, AARP members are more highly educated, consume less fat and red meat and more fiber and fruits and vegetables, and are less likely to be current smokers than similarly aged adults in the U.S. population, so our study results may not be true for other populations.

What are the public health implications?
The American Institute for Cancer Research and the World Cancer Research Fund both recommend reducing red and processed meat intake to decrease cancer risk.

There are various mechanisms by which meat may be related to mortality. In relation to cancer, meat is a source of several carcinogens, including chemicals which are formed when meat is cooked at high temperatures. Iron in red meat may also increase oxidative damage and the formation of carcinogenic compounds. Furthermore, meat is a major source of saturated fat, which has been shown to increase the risk of breast and colorectal cancer. As a next step, researchers should investigate the relationship between subtypes of meat and specific causes of mortality.

Special Report

Cervical Cancer Screening with HPV Test Reduces Advanced Cancers, Deaths

An 8-year trial conducted in India has shown that screening for cervical cancer with a single round of human papillomavirus (HPV) DNA testing halved the rate of advanced cervical cancers and deaths from cervical cancer. HPV screening was much more effective than other screening methods, including Pap testing or visual inspection with acetic acid. In the study, published April 2 in the New England Journal of Medicine (NEJM), no women who had a negative HPV DNA test died from invasive cervical cancer after 8 years of follow up.

The findings have "immediate and global" implications, wrote Drs. Mark Schiffman and Sholom Wacholder of NCI's Division of Cancer Epidemiology and Genetics in an editorial accompanying the study. "International experts in cervical-cancer prevention should now adapt HPV testing for widespread implementation," they added, noting that additional research and efforts will be required in some communities, including the development of an infrastructure for the treatment of HPV-positive women.

HPV16 E6 shown in green, in the nucleus of a mammalian cell (Image courtesy of Dr. Zhi-Ming Zheng, NCI Center for Cancer Research) HPV16 E6 shown in green, in the nucleus of a mammalian cell (Image courtesy of Dr. Zhi-Ming Zheng, NCI Center for Cancer Research)

In developing countries like India, noted the study's lead author, Dr. Rengaswamy Sankaranarayanan and colleagues from the International Agency for Research on Cancer (IARC) in France, there has been "no clinically significant reduction in cervical cancer incidence in three decades." As a result, approximately 80 percent of the half million cases of cervical cancer diagnosed around the globe each year are in low-resource countries.

Cervical cancer screening programs in the United States and other developed countries are one of biggest success stories in cancer prevention and early detection, explained Dr. Debbie Saslow, director of Breast and Gynecologic Cancers at the American Cancer Society.

"In the developing world, where they don't have screening and have little to no access to the HPV vaccine, this is the kind of data we've been waiting for," she said.

The study included more than 130,000 women aged 30 to 59 from more than 50 villages in northern India. The villages were randomized to one of four screening "clusters": A single round of HPV testing, cytologic testing, visual inspection, or routine care. In India, routine care rarely includes screening. In fact, only 8 participants in the trial had undergone some type of cervical cancer screening prior to enrollment. In this study, however, women in the routine care arm were given information on where to obtain cervical cancer screening.

At 8 years follow up, compared with the control group, HPV testing was associated with a 53 percent reduction in advanced cervical cancer diagnoses and a 47 percent reduction in cervical cancer deaths. By comparison, Pap smear was associated with 25 percent and 11 percent reductions, respectively.

"We found that HPV testing was the most objective and reproducible of all cervical screening tests and was less demanding in terms of training and quality assurance," the study authors wrote. Although the cost of the HPV test used in the study could be prohibitive in low-resource settings, a much cheaper HPV DNA test, designed for public health use and recently shown to be equally effective, is moving closer to availability in low-resource regions. As a result, the authors noted, HPV DNA testing could be a viable and appropriate "primary screening approach in low-resource settings for women who are at least 30 years of age."

Studies have shown that screening with the HPV DNA test should not begin earlier because HPV infections in younger women who are sexually active are extremely common but typically resolve on their own. By age 30, however, positive HPV tests are more likely to be picking up persistent infections with the types of HPV shown to induce the changes that lead to cervical cancer, including types 16 and 18, which are responsible for 70 percent of all cervical cancers.

Dr. Schiffman and Dr. Wacholder highlighted some points of caution. In this particular study, for instance, the screening program based on HPV DNA testing worked because only 10 percent of women tested HPV-positive. For unknown reasons, HPV prevalence is more than 20 percent in some low-resource regions, something NCI, IARC, and others are investigating. "At this prevalence level, too many women must undergo triage or treatment for a screening program to be practical without a more specific assay," they wrote.

Even so, said Dr. Saslow, from a scientific standpoint, "these barriers are surmountable." What is less predictable and perhaps more problematic, she stressed, are the political, economic, and cultural factors.

"These are often countries where safe drinking water is scarce, where even something like a dollar per [HPV] test might not be doable," she said. "It may often come down to what the priorities are. Because this is a women's health issue, it gets less priority in some countries than it would if it were a men's health issue."

In 2007, Digene, the company that developed the HPV test used in this trial, Hybrid Capture 2, as well as the newer, inexpensive test called careHPV, was acquired by Qiagen, a provider of sample and assay technology. The careHPV test was developed in part with support from the global health organization Program for Appropriate Technology in Health, with funding from the Bill and Melinda Gates Foundation, specifically for use in low-resource countries. The test has its own water supply, can be conducted on portable equipment, will run on batteries, and can produce results in less than 3 hours.

Qiagen announced on April 1 that over the next 5 years it will donate one million HPV tests for use in screening programs in low-resource countries.

—Carmen Phillips

Spotlight

Mapping the Risk of Breast Cancer in Thousands of Women

Some women inherit relatively rare mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 that raise their risk of developing the disease significantly. But for most women, the predisposition to breast cancer appears to be determined by a large collection of common and uncommon genetic variations, each with a small individual effect on cancer risk.

The human genome is extremely complicated, and there are many sources of variation that need to be considered as underlying causes of cancer risk. - Dr. John Witte

This view has emerged from large-scale genomic studies, including genome-wide association studies, that have begun to pinpoint chromosome regions associated with breast cancer risk. In recent years, a first generation of studies, which included thousands of women, conclusively linked six chromosome regions to breast cancer risk, and now four more regions have been identified.

"These studies have shown us that there are dozens, if not hundreds, of regions that each contribute a small amount to a woman's overall breast cancer risk," said Dr. David Hunter of the Harvard School of Public Health and a leader of NCI's Cancer Genetic Markers of Susceptibility (CGEMS) project, which has conducted genome-wide association studies for breast cancer and prostate cancer. "This idea was hypothesized 3 or 4 years ago, and now we have the beginnings of the proof."

In a planned follow-up to earlier breast cancer genome-wide association studies, the CGEMS team identified and validated regions of interest on chromosomes 1 and 14. A second study, led by Dr. Douglas Easton of Cancer Research UK, similarly identified regions on chromosomes 3 and 17 in close collaboration with the CGEMS initiative. Findings from both studies appeared online in Nature Genetics on March 29.

"These two studies represent the second wave of genome-wide association studies for breast cancer involving very large numbers of women," said Dr. Stephen Chanock of NCI's Division of Cancer Epidemiology and Genetics and a leader of CGEMS. "We now know that we are going to continue to reap novel insights from this strategy, and also that we will need to do further follow-up work to understand the basic mechanisms underlying risk."

The CGEMS team also confirmed previous reports that risk factors for breast cancer may reside on six other regions, on chromosomes 2, 5, 8, 10, and 16.

Identifying the Landmarks

The first step in all of these studies was to compare DNA from women with breast cancer and healthy women using single nucleotide polymorphisms (SNPs) as markers. These are places in the genome where a single unit of DNA varies from person to person with high enough frequency to be tested effectively. Tracking the distribution of SNPs in women with and without cancer can reveal inherited variants that are significantly more common in those with an increased or decreased risk of disease.

Because of their unbiased approach, genome-wide association studies have frequently pointed to parts of the genome where no one had thought to look previously for cancer risk factors. While this has generated new leads, it has also underscored a challenge facing the entire field: How do researchers make sense of risk signals in poorly characterized regions of the genome?

"Even when the genomic architecture of a region has been explored, mapping and then understanding the source of the risk can be difficult," noted Dr. Chanock, who last month hosted a scientific meeting on this subject for experts in genome-wide association studies.

"We know that each of these regions is complex," he continued. "A risk signal may be a marker for a particular set of variations or structural changes in the genome. The challenge is to dissect each region and understand how changes in that region contribute to breast cancer risk."

These types of studies are not designed to measure all of the variation in the human genome, so when a signal is found, much more work is needed to discover its source, added Dr. John Witte of the University of California, San Francisco, who uses the approach to investigate prostate cancer genetics.

In just the last few years, new technologies have revealed a surprising amount of both normal and abnormal variations across the genome, including gains and losses of DNA and variation in the number of gene copies. "The human genome is extremely complicated, and there are many sources of variation that need to be considered as underlying causes of cancer risk," Dr. Witte said.

These association studies have provided important new clues to genetic mechanisms underlying cancer risk. In the case of prostate cancer, researchers have suspected that genetic factors contribute to risk because of familial patterns, but until genome-wide association studies there had been essentially no biomarkers of inherited risk.

Scanning the Horizon

Even with the recent progress, these are early days. In breast cancer, for example, the chromosome regions identified to date account for only a small percentage of the overall inherited risk for the disease. But as the new results suggest, collaborations involving tens of thousands of DNA samples and the careful validation of results should reveal additional sources of risk.

"The lesson we've learned from genome-wide association studies is that because the strength of the signal at each marker is relatively weak, no single study has the power to pick up more than a small number of all the regions that are out there, so larger sample sizes and pooling of data are needed," said Dr. Hunter.

"But by bringing together resources from within NCI and its external collaborators," he continued, "we were able to do in several years what it would take an individual group many more years to achieve."

—Edward R. Winstead

Cancer Center Profile

The Wistar Institute Cancer Center

Director: Dr. Russel E. Kaufman • 3601 Spruce Street, Philadelphia, PA  19104
Phone: 215-898-3700 • Web site: http://www.wistar.org/cancercenter

Background

Since 1972, The Wistar Institute has been a National Cancer Institute-designated Cancer Center focused on basic biomedical research, more specifically on understanding the causes, treatment, and prevention of cancer. The Wistar Institute Cancer Center holds the distinction of being one of seven NCI-designated cancer centers focused on basic science, and has a history of significant advances in cancer genetics, cancer biology, and tumor immunology and virology. These accomplishments include:

The Wistar Institute Cancer Center The Wistar Institute Cancer Center
  • Identification of genes associated with breast, lung, and prostate cancer
  • Development of monoclonal antibodies used to study the pathways and proteins involved in tumor development
  • Contributions to improved cancer treatments and diagnostic tests

Wistar Cancer Center scientists pursue research in gene expression and regulation, molecular and cellular oncogenesis, and immunology. Scientists benefit from numerous shared core facilities that provide essential technical support and instrumentation in areas such as small molecule screening and bioinformatics. One of the great strengths of the Center is its emphasis on collaboration, both internally across research programs and externally across the nation and around the world.

Research

Scientific collaboration is a core value at The Wistar Cancer Center, and team science is the common approach. The Cancer Center promotes interdisciplinary coordination, cooperation, and collaboration among its members through a variety of seminars, meetings, and other venues. Wistar's size and physical organization encourage formal and informal interactions among faculty, staff, and research trainees and students.

The Cancer Center's success in interdisciplinary collaboration is evidenced in the academic literature by its prolific record of publications listing co-authors from other research programs and teams. Wistar researchers also hold a number of joint federal grants for research in areas including melanoma, aging, and esophageal cancer.

Locally, the Institute and the Cancer Center benefit from Philadelphia's rich intellectual environment and the many opportunities for collaboration with neighboring academic institutions. Located in West Philadelphia, Wistar enjoys particularly extensive collaboration with the University of Pennsylvania School of Medicine.

Notable Research Programs

Cancer
A recent discovery by a Wistar researcher may lead to the development of a new class of highly targeted cancer drugs. The scientist decoded a key structure of the enzyme telomerase, which plays a significant role in cancer. The enzyme is active in up to 90 percent of human tumors, making it a top target for the creation of new cancer treatments.

Melanoma
Wistar's melanoma research program is a leading example of the success of the Center's partnership efforts. Conducted in collaboration with the University of Pennsylvania, the program has brought biologists, immunologists, and geneticists together with clinical experts in pathology, oncology, and surgery. In 2001, the program was recognized as a skin cancer SPORE (Specialized Programs of Research Excellence) by NCI. With the support of this prestigious grant, Wistar investigators have pioneered novel approaches to the diagnosis and treatment of melanoma.

Lung cancer
By the time most lung cancers are diagnosed, the disease usually has advanced to the point that treatment options are limited. Wistar scientists are developing a blood biomarker test that would detect the disease early, potentially saving lives. In the lab, their prototype test has shown promise for diagnosing early stage lung cancer.

Featured Clinical Trial

Targeting Resistance to Endocrine Therapy in Advanced Breast Cancer

Name of the Trial
Phase III Randomized Study of Tamoxifen Citrate or Letrozole with Versus without Bevacizumab in Women with Hormone Receptor-Positive Stage IIIB-IV Breast Cancer (CALGB-40503). See the protocol abstract.

Dr. Maura Dickler Dr. Maura Dickler

Principal Investigator
Dr. Maura Dickler, Cancer and Leukemia Group B

Why This Trial Is Important
The female hormone estrogen, which is an endocrine hormone, can stimulate the growth of many breast cancers. In addition, estrogen can promote the growth of new blood vessels (angiogenesis) to tumors, which helps the tumors get the oxygen and nutrients they need for continued growth. Hormonal therapies, such as letrozole and tamoxifen, can help delay the progression of breast cancers that grow in response to estrogen. Letrozole, an aromatase inhibitor, interferes with the body's ability to produce estrogen, and tamoxifen, an antiestrogen, competes with estrogen for binding to estrogen receptors. However, most patients with advanced breast cancer eventually develop resistance to hormonal therapy and experience relapse.

Some preclinical research has suggested that a possible cause for this resistance is the hormone-independent growth of blood vessels to tumors. Doctors want to know if inhibiting this angiogenesis with an antibody known as bevacizumab can help delay the development of resistance to hormonal therapy. Bevacizumab blocks the activity of vascular endothelial growth factor (VEGF), a protein that is important for angiogenesis.

In this trial, women with advanced, hormone receptor-positive breast cancer will be randomly assigned to receive hormonal therapy (with letrozole or tamoxifen) and either bevacizumab or a placebo. The decision of whether to take letrozole or tamoxifen will be made by patients and their doctors. Researchers want to determine whether the addition of bevacizumab will slow disease progression in women receiving hormonal therapy.

"This trial is intended to provide definitive proof of whether anti-VEGF therapy adds to the benefit of endocrine therapy in advanced breast cancer," said Dr. Dickler.

"One important aspect of this trial is that women do not have to have a measurable tumor to be included," she added. "Many women experience recurrence in the form of non-measurable disease, such as bone metastases, pleural effusions, or lymph node metastases, and these women may be eligible for this study."

The investigators plan to answer additional questions with the trial. For example, women will be monitored to see if the addition of bevacizumab causes more, or different, side effects than does letrozole or tamoxifen alone.

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 /clinicaltrials/ft-all-featured-trials.

FDA Update

New Treatment for Advanced Kidney Cancer Approved

The FDA has approved everolimus (Afinitor) for advanced renal cell carcinoma in patients whose disease has progressed after treatment with one of two other targeted therapies, sunitinib (Sutent) and sorafenib (Nexavar).

Everolimus (Afinitor) logo

The approval is based on the most recent results of a 416-patient, phase III trial dubbed RECORD-1—presented last fall at the European Society for Medical Oncology annual meeting—which showed that everolimus treatment improved progression-free survival by 67 percent compared with patients given placebo, 4.9 months versus 1.9 months.

Everolimus targets a protein known as mTOR, which affects tumor cell division, angiogenesis, and cell metabolism. According to the drug's manufacturer, Novartis, everolimus is being investigated as a treatment for other cancers in which mTOR is thought to play a prominent role, including breast, gastric, and liver cancer, and non-Hodgkin lymphoma. NCI's Cancer Therapy Evaluation Program is sponsoring the development of studies that will include the use of everolimus to treat neuroendocrine tumors.

ODAC Recommends Approval of Bevacizumab for GBM

Last week, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted unanimously in favor of accelerated approval of bevacizumab (Avastin) for previously treated glioblastoma multiforme (GBM). Accelerated approval is granted to treatments for life-threatening diseases on the basis of preliminary evidence, with the requirement that additional studies be conducted to confirm a true clinical benefit.

Bevacizumab (Avastin) logo

The drug's manufacturer, Genentech, requested accelerated approval based on results from two early phase clinical trials, neither of which had a control arm. The first trial included 85 patients from several study sites, and approximately one quarter had partial responses, or tumor shrinkage of greater than 50 percent. There were no complete responses, meaning none of the tumors completely disappeared. One-year survival was nearly 38 percent, Genentech noted in its presentation to the committee, compared with the 25 percent historically seen in patients treated with salvage chemotherapy. In the second trial, a single-center, 56-patient study led by Dr. Howard Fine of NCI's Center for Cancer Research (CCR) at the NIH Clinical Center, the objective response rate was approximately 20 percent, with no complete responses.

FDA staff argued in a briefing document that using MRI to assess the effect of bevacizumab on GBM tumors is complicated because the drug affects the shape and function of blood vessels, making it difficult to determine whether it shrank the tumor or simply reduced swelling around the tumor. However, even a reduction in swelling, known as edema, can have important quality of life implications for patients, committee members noted, in addition to any tumor-related effects.

"What influenced the committee, in looking at the totality of data, is the overall sense from the two trials that there really was a benefit to patients associated with bevacizumab," said ODAC member and CCR Senior Investigator Dr. Wyndham Wilson.

The FDA is expected to make a decision about approval by May, according to Genentech, and a global, randomized phase III trial of bevacizumab in patients with newly diagnosed GBM will start some time in 2009.

CMS Update

Medicare Expands Coverage of PET Scans for Most Solid Cancers

Medicare will now cover PET scans as an initial diagnostic test for cancer patients, the Centers for Medicare and Medicaid Services (CMS) announced on April 3. Under the national coverage determination (NCD), treating physicians will no longer have to submit PET scan data to the National Oncologic PET Registry (NOPR) for diagnosing and staging most solid tumors.

The requirement to submit data to the NOPR, instituted in 2005, was the first such effort under CMS' Coverage with Evidence Development (CED) program. An analysis of NOPR data published last spring found that PET scan results altered how physicians intended to manage patients more than one-third of the time, including the type of treatment they would prescribe. "CED allowed us to cover an emerging technology, learn more about its usage in clinical practice, and adjust our coverage policies accordingly," said CMS Acting Administrator Charlene Frizzera.

The NCD also covers PET scans for subsequent follow-up testing in Medicare beneficiaries being treated for cervical cancer, ovarian cancer, and myeloma. CMS will still require treating physicians to submit PET scan data to the NOPR from scans conducted to monitor the progress of treatment and remission of some cancers.

Cancer.gov Update

Cancer.gov Introduces "NCI Features"

Cancer.gov

On April 6, Cancer.gov's home page debuted a banner that highlights National Cancer Control Month. The banner links to a new Cancer.gov Web page called "NCI Features," which contains additional information about the Institute's cancer control efforts and links to further resources.

Each month or so the home page banner will be refreshed with a new theme or set of messages of strategic importance to the Institute. The "NCI Features" page will also change accordingly to highlight related NCI resources and initiatives.

Notes

Clinical Trials Promotional Tools Available from NCI

Ask Me button design

NCI recently made available two patient education posters and a pin to increase awareness about clinical trials by sparking discussions with cancer patients who may be interested in enrolling in a trial. The posters and pins introduce patients to the concept of clinical trials, complement education and recruitment efforts, and serve as conversation starters to discuss trials in a general context before exploring specific trials with patients. The pins can also be worn by patients participating in clinical trials or their family members and friends—individuals who can help increase awareness.

For more information about the posters and pins, call NCI's Cancer Information Service toll free at 1-800-4-CANCER or order them online by clicking: https://pubs.cancer.gov/ncipl.

NCI-Frederick Prepares for Annual Spring Research Festival

NCI-Frederick 13th Annual Spring Research Festival logo

The National Cancer Institute at Frederick, in partnership with the National Interagency Confederation for Biological Research at Fort Detrick, will hold the 13th Annual Spring Research Festival on April 29 and 30 in Frederick, MD. Scientific staff, including students, technical support staff, postdoctoral fellows, and principal investigators, will present posters describing their research to the joint scientific communities. This year's festival will also include a health and safety exposition, educational information, safety and scientific displays, and commercial exhibits on the latest scientific equipment and technologies. More information is available online.

CTCAE 4.0 Posted for Public Review

NCI's Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 is widely accepted throughout the oncology research community as the standard grading scale for defining protocol parameters such as maximum tolerated dose, dose modification, and comparison of safety profiles between interventions.

NCI's Cancer Therapy Evaluation Program and Center for Bioinformatics have revised CTCAE version 3.0 to address agreement with the Medical Dictionary for Regulatory Activities (MedDRA) terminology, integration with caBIG data systems, and long-term governance of CTCAE. A draft of CTCAE version 4.0 is available for public review at http://ctep.cancer.gov/ under “CTEP Highlights" through April 10. The site includes further information about the revision and instructions for submitting comments. Questions should be addressed to ctcae4@bah.com.

Meet NCI Experts at AACR

Logo for the American Association for Cancer Research 100th Annual Meeting 2009    NCI exhibit booth

Join Dr. John E. Niederhuber on Monday, April 20, at 11:45 a.m. for the NCI Director Session during the American Association for Cancer Research Annual Meeting. Learn about NCI's programs and Web sites by visiting booth #306 in the exhibit hall. NCI experts will be available to talk about a wide range of topics. See the schedule below.

Sunday, April 19
1:00 p.m.NCI Intramural Fellowships 
 Jonathan Wiest, Center for Cancer Training
2:00 p.m.NCI-Funded Research Portfolio 
 Lisa Krueger, Division of Extramural Activities  
3:00 p.m.The Cancer Biomedical Informatics Grid: Resources to Support Translations Research 
 Donna Messersmith, Center for Biomedical Informatics and Information Technology
4:00 p.m.Collaborating with NCI in Pediatric Oncology Drug Development—From Target Discovery to Early Phase Clinical Trials
 Malcolm Smith, Cancer Therapy Evaluation Program
  
 
Monday, April 20
9:00 a.m.NCI Career Development Awards
 Lester Gorelic, Center for Cancer Training
10:00 a.m.Cancer Nanotechnology—Opportunities and Challenges
 Piotr Grodzinski, Center for Strategic Scientific Initiatives
11:00 a.m.Epigenetics and Cancer Epidemiology
 Mukesh Verma, Division of Cancer Control and Population Sciences
12:00 p.m.NCI-Funded Research Portfolio
 Michelle Vos, Division of Extramural Activities
1:00 p.m.NCI Cancer Complementary and Alternative Medicine Program
 Libin Jia, Office of Cancer Complementary and Alternative Medicine
2:00 p.m.Prostate Cancer Epidemiology—What's New?
 Ann Hsing, Division of Cancer Epidemiology and Genetics
3:00 p.m.NCI-Funded Research Portfolio
 Lisa Krueger, Division of Extramural Activities
  
 
Tuesday, April 21
9:00 a.m.NIH K99/R00 Pathway to Independence Award 
 Nancy Lohrey, Center for Cancer Training
10:00 a.m.NCI-Funded Research Portfolio 
 Lisa Krueger, Division of Extramural Activities
11:00 a.m.Advancing Protein Science for Personalized Cancer Care
 Henry Rodriquez, Clinical Proteomic Technologies for Cancer, Center for Strategic Scientific Initiatives 
12:00 p.m.Streamlining Clinical Trials Contract Negotiations
 Sheila Prindiville, Coordinating Center for Clinical Trials 
1:00 p.m.How to Tap into NCI SBIR Dollars to Support Innovative Cancer Research
 Michael Weingarten, Small Business Innovation Research Program
2:00 p.m.Quality Biospecimens are the Key to Personalized Medicine 
 Carolyn Compton, Office of Biorepositories and Biospecimen Research, Center for Strategic Scientific Initiatives
3:00 p.m.NCI-Funded Research Portfolio 
 Lisa Krueger, Division of Extramural Activities
  
 
Wednesday, April 22
9:00 a.m.Cancer Genetics Network
 Scott Rogers, Division of Cancer Control and Population Sciences
11:00 a.m.Clinical Grants & Contracts
 William Merritt, Cancer Therapy Evaluation Program