HPV Infection Drives Disparity in Head and Neck Cancer Survival
These CT scans show an HPV-positive tonsil cancer in a patient with no history of tobacco or alcohol use. The arrow in the left panel points to the swollen tonsil with the primary tumor. Arrows in the right panel point to cancerous lymph nodes on both sides of the neck. The patient went into complete remission following concomitant chemotherapy and radiation. Click to enlarge 20
A new study provides what researchers are calling a “missing link” that helps to explain why black patients with head and neck cancer live significantly shorter after treatment than white patients. Unlike several other cancers, where racial disparities in outcomes have been attributed in large part to socioeconomic factors, this new study points directly at a biological difference: infection rates of human papillomavirus 21 type 16 (HPV 16).
The study 22, published July 29 in Cancer Prevention Research, is the latest to show that head and neck cancer patients, particularly those with cancer of the oropharynx 23, who are HPV 16-positive have superior outcomes 24 with standard treatment (concurrent chemotherapy and radiation) compared with those who are HPV 16-negative. But this study is the first to show that black patients with head and neck cancer have dramatically lower rates of HPV infection than white patients and that HPV status directly correlates with the significant survival disparities between the two patient groups.
The finding that so few black patients are HPV positive “in a completely statistical sense explains why historically we have seen that black patients [with head and neck cancer] do poorly,” said Dr. Kevin J. Cullen, the study’s senior author and director of the University of Maryland (UMD) Marlene and Stewart Greenebaum Cancer Center.
Digging Deeper
The researchers performed a retrospective analysis of data from 95 black and 106 white patients with similar stages of head and neck cancer who received similar treatments at the Greenebaum Cancer Center, and a prospective analysis of 224 patients for whom HPV status could be determined in the recent randomized clinical trial TAX 324 25. In the prospective study, the majority of the patients (196) were white.
Both analyses showed that black patients with head and neck cancer fared far worse than white patients, but this difference was driven primarily by the outcomes for patients with oropharyngeal cancer. For example, explained Dr. Cullen during a press briefing, while there was a nearly twofold difference in overall survival between black and white patients in the cohort treated at UMD, it was entirely due to the threefold difference in survival between black and white patients with oropharyngeal cancer, 70 months versus 25 months. Patients with cancers at other sites in the head and neck, such as the larynx 26 and hypopharynx 27, had identical survival regardless of race.
“Frankly, we were shocked to see that within our own institution, where half of the patients we treat are African Americans, that that difference existed,” Dr. Cullen said.
Explaining the Discrepancy in HPV Rates
In an accompanying editorial 28 in Cancer Prevention Research, Dr. Otis Brawley, chief medical officer of the American Cancer Society, suggested that differences in sexual practices between young blacks and whites may explain, at least in part, the different rates of oral HPV infections. Dr. Brawley cited a study 29 published earlier this year linking oral HPV infections with oral sex and survey data showing that white males and females were more likely to have engaged in oral sex than their black counterparts.
Dr. Brawley said during the press briefing that “the changing sexual practices over the last 20 years, especially as it relates to oral sex, are increasing rates of head and neck cancer, and may be increasing rates of other cancers, as well.”
Dr. Kreimer agreed that changing sexual practices clearly play an integral role in HPV infection rates and cancer incidence in the oropharynx and possibly other anatomical sites. But it’s important, she stressed, not to lose sight that tobacco and alcohol use remain the primary risk factors for other head and neck tumors.
The analysis of the TAX 324 trial revealed a similar survival disparity. But the research team then took the investigation a step further and showed that the disparity was explained entirely by HPV status. In the overall analysis, 34 percent of the 196 white patients were HPV positive, including approximately half of patients with oropharyngeal cancer. In contrast, just 1 of the 28 black patients was HPV positive. Patients who were HPV positive had a fivefold improvement in overall survival compared with HPV-negative patients.
HPV status was clearly the distinguishing factor. “When you subtracted out the HPV-positive white patients, the rest of the patients—the black and white patients—behaved identically,” Dr. Cullen stressed.
Dr. Aimee Kreimer, an investigator in NCI’s Division of Cancer Epidemiology and Genetics 30, said the study provides “very important data that might explain previously observed survival differences by race.” She cautioned, however, that replication of these initial findings would be important, since the study included only a modest number of black patients with HPV results. “Replication efforts should pay close attention to other known prognostic factors such as disease stage,” Dr. Kreimer noted.
The study does confirm that HPV-positive and HPV-negative oropharyngeal cancers have a distinct biology and natural history, and, as a result, require different treatments, said Dr. Scott Lippman, chair of the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas M. D. Anderson Cancer Center, during the press briefing.
Identifying these differences is particularly important, Dr. Lippman continued, because of oropharyngeal cancer’s rapidly increasing incidence 31 (while rates of cancer at other sites in the head and neck are generally declining). Among head and neck cancer experts, he noted, there is “a real sense that the data are starting to show that we’re on the cusp of an epidemic of this disease.”
There is broad agreement among researchers that HPV infection is the major driver behind this trend, with as many as 70 percent of cases now being HPV-related, Dr. Lippman said. (See sidebar.) This is far different than it was just 20 years ago, when such cancers were less common and typically were more often related to heavy tobacco and alcohol use.
What’s Next?
Exactly why HPV-positive cancers are so much more amenable to chemotherapy and radiation is unclear, Dr. Cullen said. His group at UMD, however, will publish a paper soon in which they show that HPV-positive cancers have a lower expression of genes linked to chemotherapy and radiation therapy resistance.
Clinical trials have been designed that stratify patients by their HPV status or will enroll patients based on their HPV status, Dr. Lippman said. For HPV-positive patients, they will assess whether patients can do just as well with lower chemotherapy and radiation doses. For HPV-negative patients, they will look at whether more aggressive treatments can improve outcomes.
The findings with regard to the role of HPV in head and neck cancer, Dr. Cullen said, should also cause those in the field to rethink some of the improvements in outcomes 32 that have been seen over the past decade with chemotherapy and radiation. Those improvements may have had a lot to do with “a patient population that was shifting” toward HPV-positive patients, who are more likely to respond to those treatments.
HPV’s role in head and neck cancer, Dr. Cullen stressed, is rapidly changing the field. “Just in the month or so since we completed this study,” he said, “it’s changing the way I see patients in my clinic.”
—Carmen Phillips
Blood Type Influences Pancreatic Cancer Risk
A variation in the gene that determines ABO blood type influences the risk of pancreatic cancer, according to the results of the first genome-wide association study (GWAS) for this highly lethal disease. The genetic variation, a single nucleotide polymorphism 33 (SNP), was discovered in a region of chromosome 9 that harbors the gene that determines blood type, the researchers reported 34 August 2 online in Nature Genetics. The ABO gene produces proteins that direct certain carbohydrates onto the surface of red blood cells, the result of which determines the blood type. Compared with people who have type O blood, a SNP that produces the blood types A, B, or AB was associated with higher pancreatic cancer risk.
“Although it will take much more work, this finding may lead to improved diagnostic and therapeutic interventions that are so desperately needed,” stated study co-author Dr. Patricia Hartge from NCI’s Division of Cancer Epidemiology and Genetics 30 (DCEG).
The study had two stages. In the first, the researchers analyzed genomes of 1,896 patients with pancreatic cancer and 1,939 control subjects who were part of 12 prospective cohort studies, including the Nurses’ Health Study 35 and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening 36 trial, and one hospital-based case-control study, to identify SNPs associated with increased pancreatic cancer risk. In the second stage, they attempted to validate any risk-associated SNPs via a “fast-track replication” study of more than 5,000 pancreatic cancer cases and control subjects drawn from 8 pancreatic cancer case-control studies. The SNP in the ABO gene emerged from this process.
Another SNP associated with pancreatic cancer risk was identified in the first stage—one in the SHH gene which other research has suggested is related to pancreatic cancer development—but the finding was not duplicated in the validation stage. Further research into SHH’s potential role in pancreatic cancer is needed, the research team concluded.
Another GWAS study to find SNPs associated with pancreatic cancer risk is already under way, involving pancreatic cancer cases and controls from the eight studies included in the replication phase of this current Nature Genetics study.
“Pancreatic cancer is the newest beneficiary of high-throughput genotyping that, over the past 2 years, has yielded scores of genetic hot-spots linked to risk for cancer and other diseases,” said co-author Dr. Stephen Chanock, chief of DCEG’s
Laboratory of Translational Genomics 37. “As more variants are discovered and follow-up studies are conducted to examine the biological effects of these variants, a better understanding will emerge of the inherited risk factors and mechanisms that lead to the development of pancreatic cancer.”
Second Cancer Patient has Genome Sequenced
Researchers from the Washington University School of Medicine in St. Louis have sequenced the genomes of cancer cells and normal skin cells taken from a 38-year-old man with acute myeloid leukemia 38 (AML). By comparing the results with other patients with AML, the researchers identified recurring mutations that may play a role in the disease, according to findings 39 in the August 5 New England Journal of Medicine. Last year, these researchers sequenced 40 the genome of a woman who died from the disease.
In the current study, the researchers found 10 non-inherited (somatic) mutations 41 and 2 DNA insertions or deletions in parts of the genome that code for proteins or small functional RNAs. In addition, they found 52 somatic mutations in parts without a known gene but with potential regulatory functions. The investigators then probed samples from 187 other patients with AML to search for these 64 mutations; 4 of them appeared in at least one other patient. These included a mutation in the gene IDH1, which has been shown 42 to be mutated in some malignant gliomas, and two mutations (in the genes NPM1 and NRAS), which were previously linked to AML. The fourth was found in a regulatory segment.
The fact that these four mutations were found in the genome of more than one AML patient suggests “that these mutations are not random and are probably important for the pathogenesis of this tumor,” explained the authors. However, they cautioned that to understand the full range of mutations that can drive cancer, thousands of additional cancer genomes will likely need to be sequenced.
The researchers noted that rapid advances in sequencing technology since they published the first AML genome 10 months ago allowed them to sequence more of the genome while simultaneously reducing the technical work and time it required.
“This study opens a clear window into the rapid advancements that are being made in cancer-genome sequencing,” said Dr. James Downing from St. Jude Children’s Research Hospital in an accompanying editorial. As the technology in the field continues to improve, “the cost of obtaining the complete DNA sequence of a cancer cell will rapidly decrease, thus making it possible to acquire data from a larger number of cancers.”
Many Prostatectomy Patients Face Low Risk of Prostate Cancer Death
The first large-scale, multi-institution study of prostate cancer mortality since prostate-specific-antigen (PSA 43) screening has become widely used found that men who undergo prostatectomy 44 have a very high chance of surviving at least 15 years. Among nearly 13,000 patients with a median age of 61, prostate cancer mortality was 12 percent, compared with 38 percent from all causes, according to a July 27 report 45 in the Journal of Clinical Oncology.
Researchers developed a risk assessment tool to determine each patient’s risk of death from prostate cancer according to various clinical factors (such as PSA score) and analysis of the tumor characteristics at biopsy (Gleason score 46). When patients were stratified into 4 groups according to their calculated risk, 73 percent were in the lowest quartile with only a 5 percent risk of death, and only 2 percent were in the highest quartile with a 38 percent risk.
So many men faced such a low risk, wrote lead author Dr. Andrew J. Stephenson of the Cleveland Clinic, that “potentially many of these patients may have had a similarly low risk of prostate cancer-specific mortality had they received no treatment.” The authors observed that “in the United States, only 2 percent of patients younger than 65 years choose active surveillance,” with most opting for radiation and/or surgery. The study did not compare radical prostatectomy with other forms of treatment.
Cases diagnosed more recently had a better outcome, perhaps reflecting more effective prostate screening and treatment methods in recent years, the authors noted. Other factors, such as PSA velocity and body-mass index, had no statistically significant relationship with risk.
As for the most aggressive cancers, the authors acknowledged “the difficulty in identifying patients at substantially increased risk based on clinical factors alone,” and called for the development of “novel markers specifically associated with the biology of lethal prostate cancer.”
Low Glucose around Tumors Can Cause Cancer-fueling Mutations
Low levels of glucose around tumors may fuel the development of genetic mutations that help colorectal cancer cells thrive, researchers from Johns Hopkins University reported 47 online August 6 in Science Express. Colorectal tumors with cells harboring these same genetic mutations, however, may be susceptible to treatments that target cancer cells’ ability to turn glucose into energy.
The researchers showed 48 that in colorectal cancer cell lines with mutations in the KRAS or BRAF genes, expression levels of the GLUT1 gene, which produces proteins that help cells absorb glucose, were consistently elevated compared with cells that had the normal, or “wild-type,” forms of the genes. Cancer cells with these genetic mutations showed enhanced glucose uptake and glycolysis, a preferential mechanism by which cancer cells metabolize glucose.
Colorectal cancer cell lines with KRAS or BRAF mutations (the former mutation being present in nearly half of colorectal tumors) and wild-type forms of the genes fared equally well in a lab dish with normal glucose levels. However, when they were placed together in a low-glucose environment, like the types of environments that can exist within and around tumors, the cell lines with mutated KRAS or BRAF grew, whereas cell lines with the wild-type genesdid not. Eliminating GLUT1 in cell lines with the mutations eliminated this advantage.
In addition, the cancer cells with wild-type KRAS or BRAF that did survive under low-glycemic conditions had permanent increased expression of GLUT1, and a small percentage of these cells developed KRAS mutations.
“We think increased GLUT1 is a survival adaptation that makes cancer cells very efficient at gathering what little sugar exists in these areas,” said study co-author Dr. Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at the Johns Hopkins Kimmel Cancer Center, in a news release.
The findings, added the study’s lead investigator, Dr. Nickolas Papadopoulos, suggest that low-glucose environments favor the development of KRAS mutations “and maybe mutations yet to be identified in the same pathway.”
Finally, the researchers showed that low doses of an experimental compound that inhibits glycolysis, called 3-bromopyruvate (3-BrPA), could significantly inhibit tumor growth in animal models of colorectal cancer that harbor KRAS or BRAF mutations. In addition, 3-BrPA was far more toxic to cell lines that bore these mutations than to those that did not. The compound is one of several such glycolytic inhibitors being investigated 49 as anti-cancer agents. The findings, the researchers wrote, “provide proof of principle that glycolytic inhibitors can retard tumor growth at doses that are nontoxic to normal tissues in vivo.”
Review Finds No Firm Evidence that Green Tea Prevents Cancer
Firm recommendations on the use of green tea in liquid or extract form to prevent cancer cannot be made based on the available evidence from published studies, according to the authors of a new review 50 published last month in the Cochrane Database of Systematic Reviews. The conflicting evidence from the available studies, lead author Dr. Katja Boehm and colleagues concluded, means “that drinking green tea remains unproven in cancer prevention, but appears to be safe at moderate, regular, and habitual use.”
Fifty-one studies involving approximately 1.6 million people were included in the review, and 45 of those studies were conducted in Japan and China. Approximately half of the studies focused on gastrointestinal (GI) cancers, mostly those in the upper GI tract (e.g., pancreas, esophagus, liver). While a single case-control study showed a benefit of green tea consumption for the reduction of liver cancer risk, the studies looking at other GI cancer sites had “highly contradictory” results, the authors explained.
Other cancers covered by the review included lung, breast, ovarian, bladder, prostate, and oral cancer.
The review itself has limitations, the authors acknowledged, including the fact that the studies included were of varying methodological quality and were largely confined to Asian populations. Only one randomized clinical trial, for prostate cancer prevention, was available for the review (the trial 51 found a decreased risk of prostate cancer among high-risk men who received a green tea extract compared with those who received placebo).
“In our view, the possibility of measuring the therapeutic effect of green tea based on isolated case-control or cohort studies is not very likely as other confounding variables come into place,” the authors wrote. If the potential preventive effects of green tea are to be established, they continued, large, well-designed randomized clinical trials will be needed.
Despite the findings, said Dr. John Milner, chief of the Nutritional Science Research Group in NCI’s Division of Cancer Prevention 52, green tea is a food item worth investigating further. It’s likely, he noted, that “exposures and interactions with a host of environmental and genetic factors influence individuals’ response to green tea.”
Cancer Incidence in U.S. Hispanics Varies by Country of Origin
In the first study to estimate cancer rates for U.S. Hispanics based on their country of origin, substantial variability was found in the rates and the predominant types of cancer for several different Hispanic subpopulations. Overall, cancer rates were 40 percent higher for first-generation Hispanics in the U.S. than populations in their countries of origin. These results 53 were published in the August Cancer Epidemiology, Biomarkers & Prevention.
Researchers led by Dr. Paulo Pinheiro from the University of Miami Miller School of Medicine collected data on 301,944 people diagnosed with cancer in Florida between 1999 and 2001, using the Florida Cancer Data System. These individuals were classified as non-Hispanic white, non-Hispanic black, Hispanic, or mixed race and other non-Hispanic. Hispanics were further classified as Mexican, Puerto Rican, Cuban, or New Latino (including immigrants from Central and South America).
Overall cancer incidence rates were lower in Hispanics than non-Hispanic whites and blacks. However, Hispanics had higher incidence rates of some individual cancer types, including stomach and liver cancers. Rates of prostate, colorectal, and endometrial cancers were similar between Hispanics and whites, which contrasts with the results of many previous studies.
Cancer rates for U.S. Hispanics in Florida varied substantially by country of origin. Puerto Ricans had much higher cancer rates than Mexicans (53 percent higher for men and 30 percent higher for women). Cubans had lower overall cancer rates than Puerto Ricans but higher than Mexicans. The incidence rates for individual cancer types also differed between the Hispanic subpopulations.
“Targeted interventions for cancer prevention and control should take into account the specificity of each Hispanic subgroup,” said Dr. Pinheiro in an accompanying press release.
ALSO IN THE NEWS
SATURN Trial Shows Small Improvement in Lung Cancer Survival
Maintenance therapy 54 with erlotinib 55 (Tarceva) results in a small but statistically significant improvement in overall survival 56 in patients with advanced non-small cell lung cancer, researchers reported last week. The updated survival results from the international SATURN 57 trial were presented at the World Conference on Lung Cancer 58 in San Francisco. Patients who were randomly assigned to receive erlotinib following standard first-line chemotherapy had a median overall survival of 12 months, compared with 11 months for patients in the placebo arm. The SATURN trial is one of several recent trials testing the maintenance therapy approach 59in this patient population.
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ACTNOW Opens the Gate for Timely, Novel Research
Dr. John E. Niederhuber
The 2009 American Recovery and Reinvestment Act 60 (ARRA) provides a tremendous opportunity to significantly increase our support of cancer research by raising the payline, launching new multidisciplinary and collaborative programs, and accelerating clinical trials that will get treatments to patients more rapidly. The success of NCI’s ARRA investments will, in my opinion, be measured not only in terms of economic recovery, but also in our ability to report scientific advancements and what we have done to help patients.
To the latter goal, I am very pleased to announce a new program that distributes a portion of our ARRA funds to ACTNOW (Accelerating Clinical Trials of Novel Oncologic Pathways), a program that is uniquely poised to advance targeted, personalized cancer treatment in an accelerated timeframe, so that the results benefit patients and the research community as quickly as possible.
The ACTNOW program funds 37 early phase clinical trials of new treatment regimens that we hope will soon expand our ability to provide targeted, personalized medicine. The program has dedicated $31 million for phase I and II trials, plus $5 million for support contracts, including those to assist the investigators with data monitoring and statistical analysis. This is money that will pay compound dividends in health care and jobs for physician scientists, oncology nurses, clinical research coordinators, statisticians, medical assistants, and other staff members who will help administer ACTNOW trials at institutions all over the country.
Members of NCI’s funded clinical trial networks nominated the studies, which were chosen by a peer-review panel composed of NCI and non-NCI clinicians. The review criteria stressed the scientific evidence for the clinical research and selected strong early phase trials that were stalled by lack of available funding. In other words, these trials would not have been started without ARRA.
One of these clinical trials will test a compound called ABT-888 61, which inhibits the function of certain nuclear proteins that sense and repair DNA damage. The idea is that combining the compound with DNA-damaging treatments, such as chemotherapies and radiation, will make them more effective at killing cancer cells by blocking the cells’ ability to repair damaged DNA. Without the ability to repair, the therapy-induced, DNA-damaged cell cannot survive.
Previous studies with ABT-888, including results from a phase 0 trial published 62 just a few months ago, have shown promising results. Now a phase I trial funded through ACTNOW will test the safety of ABT-888 as a potentiator of carboplatin and paclitaxel for patients with BRCA gene mutations who have inoperable breast cancer, as well as other solid tumors. Although BRCA-deficient tumors are more likely to be sensitive to ABT-888, patients with BRCA-deficiency, who lack normal DNA repair machinery, could be at higher risk for toxicity when exposed to the combination regimen of carboplatin, paclitaxel, and ABT-888; therefore, the safety of this drug combination needs to be tested first. If it proves safe and increases tumor shrinkage, then definitive trials to determine its ultimate role in improving survival will be undertaken.
Another trial will explore the use of two experimental agents, an oral gamma-secretase inhibitor (which alters the function of certain protein machinery in cells) and GDC-0499 (an inhibitor of the hedgehog signaling pathway that has been implicated in numerous cancers), to treat women with invasive breast cancer.
Still another trial will test the use of temsirolimus 63, the drug recently approved for renal cell carcinoma, along with an antibody that targets the IGF-1 receptor for people who have metastatic soft tissue and bone cancers.
These trials are ideal uses of ARRA dollars and will now be moving forward at universities, cancer centers, and private research organizations across the country.
Importantly, all of the ACTNOW studies are designed to integrate the latest imaging technologies and correlative laboratory research studies to help us understand the underlying biological mechanisms of action. Examples include comparing a positron emission tomography (PET) probe that tracks DNA replication and cell proliferation with standard computed tomography (CT) in assessing treatment response in early stage, resectable, non-small cell lung cancer. Another trial involving patients with late-stage Hodgkin lymphoma will use response-adapted therapy using early interim PET with a probe that measures glucose metabolism. To ensure reproducibility and reliability of the data, the assays will be CLIA (Clinical Laboratory Improvement Amendments) certified.
ACTNOW awards are also contingent on a very strict, accelerated timeline. Study investigators will be required to finalize institutional review board approval and begin enrolling patients within 90 days, and enrollment must be completed within 2 years. Investigators will submit metrics related to the economic impact of their project quarterly throughout the funding period.
Most of the ACTNOW studies are being funded as grants, but NCI was able to use contracting agreements to fund a portion of these clinical trials. Contracts are particularly useful for implementing ARRA-funded programs and projects because they have targeted deliverables and built-in reporting requirements that align with the accountability that is integral to ARRA spending.
As we approach the end of this fiscal year, ACTNOW is an excellent example of how NCI and researchers in the extramural community are working together expeditiously toward the goals that the leaders of our country laid out with ARRA last February: to stimulate the economy through scientific research; to initiate new programs that would require new jobs; to make health care more cost-effective by developing personalized, targeted treatments; and to do these things with the highest standards for transparency and accountability to benefit the people of our country.
We look forward to watching the effects of these awards begin to unfold this autumn and throughout the course of the coming 2 years. Look for periodic updates on their outcomes at http://www.cancer.gov/recovery.
Dr. John E. Niederhuber
Director, National Cancer Institute
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A Conversation with…Dr. James Doroshow
The NCI Chemical Biology Consortium was launched on August 10 at an inaugural meeting on the NIH campus. Dr. James H. Doroshow, director of the NCI Division of Cancer Treatment and Diagnosis 64 (DCTD), discusses the background and goals of the CBC.
What is the Chemical Biology Consortium?
The Chemical Biology Consortium 65 (CBC) consists of 12 centers chosen for their world-class screening and chemistry qualifications to mobilize the NCI cancer drug discovery process with greater breadth and depth. With a research and development pipeline linked to the academic community, the CBC will position the institute as a world leader in innovative cancer therapeutics discovery.
For the first time, the government is building a unified drug discovery and development process. NCI will establish milestones that support either the transition of a molecule to its next step in the drug development process or the decision to eliminate the molecule from the institute’s pipeline. This will ensure that projects are on time and on budget.
The CBC drug discovery and development process is divided into five stages, from screening through clinical evaluation of candidate drugs. The consortium will provide cutting-edge chemical tools for examining complex biochemical signaling pathways related to cancer and may be instrumental in generating new targeted therapies. The research will focus on therapeutic needs in oncology that are not currently addressed by the private sector, including an emphasis on pediatric and rare cancers.
The CBC is a component of NCI’s Experimental Therapeutics (NExT) program 66, a partnership between DCTD and NCI’s Center for Cancer Research 67.
Who will benefit from the services being offered by the CBC?
Investigators from academia and the CBC awardees themselves will be the first beneficiaries of CBC services. They, and a broad range of subsequent participants, will present proposals for compounds that are at any stage of drug development. After review and acceptance by a panel of extramural scientific experts, a project will be assigned to one of the CBC centers, which will conduct the needed laboratory work to move the compound through various stages of the drug development pipeline. A unique aspect of the CBC program is that scientists whose proposals are accepted will maintain any intellectual property rights associated with the compound. This also benefits small drug companies and biotechnology firms, which are eligible to submit proposals to the CBC program.
How does the CBC fit into NExT?
The CBC is part of the new, rapidly evolving NExT program, which is opening the oncology drug discovery and development pipeline to researchers in academia, government, and industry. The CBC will be one entry point into the pipeline, and it will interface with other NCI programs that expedite new drugs from the laboratory to the bedside. Another critical component of NExT is phase 0 68clinical trials, first-in-human studies that aim to cut a year or more off the drug development process.
How does the CBC work?
The NExT program, including the CBC, is not a grant or contracts mechanism. Projects can enter the CBC based on favorable review of the application’s scientific merit. To be approved, applications must include a concept associated with a compelling hypothesis that warrants clinical evaluation; a concept that will enable clinical evaluation of a new, inadequately explored therapeutic approach; or a concept that is not likely to be explored without NExT assistance. How the project fits strategically within the NExT portfolio is also evaluated.
What does NCI hope to accomplish with the CBC?
The CBC will cause a paradigm shift in the use of public-private partnerships to translate knowledge from federal and nongovernmental institutions into ground-breaking new drug candidates. When fully operational, the consortium is expected to generate two to three new investigational drug applications per year.
When are the first and subsequent proposals due?
The first proposals to enter into the NExT program are due September 15, 2009. Subsequent proposals will have quarterly deadlines: November 15, February 15, May 15, and August 15. Proposals can be submitted through the
DCTD Web site 69.
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Dietary Supplements and Cancer Treatment: A Risky Mixture
Patients undergoing cancer treatment often experience not only pain and discomfort from their disease, but also the potentially debilitating side effects caused by their treatments.
Some patients who do not receive adequate palliative care 71 to lessen these side effects, or those driven to do anything possible to feel better while fighting their disease, may turn to dietary supplements advertised as having anticancer effects or being supportive of general health, frequently without consulting a health care professional.
Some herbal medicines and dietary supplements have negative interactions with prescribed cancer treatments.
These supplements are often herbs or other natural products. “A common, false belief is that ‘if it’s natural, it must be safe,’” said Dr. Barrie Cassileth, chief of the Integrative Medicine Service at the Memorial Sloan-Kettering Cancer Center. “But herbs and other dietary supplements are biologically active compounds, and they frequently have negative interactions with prescription pharmaceuticals.”
Furthermore, as a growing number of studies have shown, commonly used herbs and supplements can interact with cancer chemotherapy or radiation therapy, causing potentially life-threatening effects.
Widespread Use
In a systematic review 72 published by Dr. Cassileth and a colleague in 1998, the use of complementary and alternative medicine (CAM) by cancer patients, including herbs and other dietary supplements, ranged from 7 percent to 64 percent in 21 different studies, with the average being about 31 percent.
CAM use has most likely increased during the past 11 years. In a 2004 study 73 from the Mayo Clinic Comprehensive Cancer Center, more than 80 percent of patients enrolled in early phase chemotherapy trials concurrently used supplemental vitamins, herbs, or minerals, which were often explicitly not allowed as part of the trial protocols.
A study 74 from a Midwestern oncology clinic published in 2005 showed that 65 percent of patients receiving chemotherapy had also taken dietary supplements, not including vitamins. Twenty-five percent of these had used one or more herbal therapies that are thought to have negative interactions with chemotherapy drugs. The majority of the patients did not consult a health care professional prior to supplement use.
Dangerous Interactions
“We tell patients that if you are on any chemotherapy or undergoing radiation, or planning for it in the future: no herbs, no antioxidants, no dietary supplements, across the board. Particularly herbal agents, because they can interact with and decrease the level of chemotherapy or any medication that enters your body,” explained Dr. Cassileth.
Some Reliable Sources of Information on Natural Products
These effects are due to pharmacokinetic interactions—what happens when biologically active compounds in an herb alter the way a chemotherapy drug is absorbed, distributed in the body, metabolized, or eliminated. These interactions can happen for many reasons, including interference with the enzymes in the liver that normally break down the drugs, or interactions with the transporters that carry drugs across cell membranes. St. John’s Wort, garlic extract, and Echinacea are examples of commonly used herbal products thought to pharmacokinetically interact with chemotherapy drugs.
Pharmacokinetic interactions can have two potentially disastrous consequences. One is that less chemotherapy drug circulates in the bloodstream than is needed, leading to treatment failure. The other is the opposite effect: if the chemotherapy drugs are not broken down and removed from the body as expected, severe side effects can occur as a result of an overdose.
Unwanted Protection for Cancer Cells
Even antioxidant supplements such as vitamin E have the potential to interfere with treatment. Radiation therapy and some types of chemotherapy work by generating free radicals that damage cells’ DNA. Antioxidants can block this therapeutic effect.
“People are taking high-dose antioxidant supplements thinking they’re only going to protect normal cells, but both preclinical and clinical data show that they may protect both normal and tumor cells,” explained Dr. Brian Lawenda, a radiation oncologist from the Naval Medical Center in San Diego.
In 2008, Dr. Lawenda and his colleagues performed a review 78 of results from the published randomized clinical trials testing antioxidants with radiation therapy or chemotherapy, and they concluded that the use of high doses of “supplemental antioxidants during chemotherapy and radiation therapy should be discouraged because of the possibility of tumor protection and reduced survival.”
A Silver Lining?
Even though doctors now caution patients not to mix and match over-the-counter supplements with cancer treatment, the bioactivity of herbs and other natural products are of interest to some cancer researchers looking for ways to enhance chemotherapy. While many herbs have been shown to interfere with chemotherapy, some may actually improve its efficacy.
“The interaction between certain complementary approaches and conventional treatment is an area of special interest to the Office of Cancer Complementary and Alternative Medicine 79 (OCCAM),” said Dr. Jeffrey White, director of OCCAM. “We’re looking for ways to use natural products to improve the therapeutic index of conventional therapy.”
In addition to supporting ongoing clinical trials testing several traditional Chinese medicines in combination with the chemotherapy drugs
irinotecan 80,
capecitabine 81, and
gemcitabine 82, OCCAM recently released two program announcements (
PA-09-167 83 and
PA-09-168 84) that will provide funding for researchers interested in testing synergistic interactions between natural products and traditional therapies
— Sharon Reynolds
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UCSF Helen Diller Family Comprehensive Cancer Center
Director: Dr. Frank McCormick • 1600 Divisadero Street, San Francisco, CA 94115 •
Phone: 1-888-689-8273 • Web site: http://cancer.ucsf.edu
Background
The UCSF Helen Diller Family Comprehensive Cancer Center combines basic, clinical, and population-sciences research, along with cancer patient care, at the University of California, San Francisco.
UCSF Helen Diller Family Comprehensive Cancer Center (left) and the center's newly opened Helen Diller Family Cancer Research building (right)
It is the only NCI-designated comprehensive cancer center between Seattle and Los Angeles, and it ranks first among the 10 California centers in the size of its NCI center grant. (Annual NCI funding totals $71.5 million.) Dr. Frank McCormick has been center director since it received its designation as a comprehensive cancer center from NCI in 1999.
UCSF’s scientific leadership in cancer goes back to the late 1940s, when it established a Cancer Research Institute and collaborated with NCI and the Public Health Service to create the Laboratory of Experimental Oncology (LEO), one of the earliest postwar settings for clinical research in the United States. The LEO was a progenitor of the NCI clinical research center in Bethesda, where it moved in 1954.
The university’s contributions to cancer research and care are many. Research at UCSF in the 1970s led to the genetically engineered vaccine for hepatitis B, preventing thousands of deaths from liver cancer worldwide. Scientist and immediate past-UCSF chancellor Dr. J. Michael Bishop and colleague Dr. Harold Varmus received the Nobel Prize in 1989 for the discovery of oncogenes, a development that greatly expanded scientific knowledge of how cancers form. This discovery also formed the foundation for the field of targeted cancer therapy. The current UCSF Chancellor Dr. Susan Desmond-Hellmann, who assumed the post in August 2009, is also a cancer researcher and epidemiologist; previously, she was president of product development at Genentech, where she oversaw drug development for a number of cancer therapeutics.
Research
The center brings together nearly 400 investigators who collaborate across the cancer spectrum, from basic biology to risk factors and prevention and control strategies. Among the center’s 11 formal research programs, 6 are disease-focused (breast, prostate, hematopoietic, neurologic, pancreas, pediatric), and 5 address cross-cutting emphases (genetics, cancer and immunity, cell cycling/signaling, society/diversity/disparities, tobacco control). UCSF is also home to three SPOREs 85, focusing on breast, prostate, and brain cancers.
Laboratory-based research extends across five principal campuses. In addition to an 110,000-square-foot research building at UCSF Mount Zion, the new 162,000-square-foot Helen Diller Family Cancer Research Building (pictured) was inaugurated in June on the UCSF Mission Bay campus.
Patient Care
In 2007, 5,570 people were newly diagnosed with cancer at UCSF. Among the largest categories of diagnosis were digestive system, prostate, breast, brain, melanoma, respiratory system, and hematologic/lymphoid malignancies. Clinical areas of special and longstanding excellence at UCSF include breast, prostate, and central nervous system tumors, and neuroblastoma. Supportive care services include inpatient and outpatient palliative care and symptom management, along with a developing survivorship program.
Clinical research investigators in 2008 led more than 400 therapeutic protocols, which included some 600 newly enrolled cancer patients.
UCSF is in the planning phase for a new integrated medical center which will include three specialty hospitals—one for cancer patients, one for women, and one for children—at the UCSF Mission Bay campus, slated to open in 2014.
Other Notable Programs
A cancer risk program provides genetic counseling, risk assessment, and genetic testing for individuals from families with a high risk of heritable cancer. The program focuses primarily on breast/ovarian cancer syndromes, hereditary non-polyposis colorectal cancer, and related malignancies. The center’s nationally recognized Art For Recovery 86 program provides a creative avenue for patients to deal with the emotional aspects of their disease.
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Refining Treatment for High-risk Early Stage Endometrial Cancer
Name of the Trial
Phase III Randomized Study of Pelvic Radiotherapy Versus Vaginal Cuff Brachytherapy, Paclitaxel, and Carboplatin in Patients with High-Risk Stage I or II Endometrial Carcinoma (GOG-0249). See the protocol summary 87.
Dr. Scott McMeekin
Principal Investigators
Dr. D. Scott McMeekin and Dr. Marcus Randall, Gynecologic Oncology Group
Why This Trial Is Important
Endometrial carcinoma is cancer that starts in the tissue lining the uterus 88 called the endometrium. Women with early stage endometrial cancer are usually treated with surgery to remove the uterus (hysterectomy 89) and the ovaries and fallopian tubes (bilateral salpingo-oophorectomy 90). Although these surgical procedures cure most women with early stage disease, as many as 25 percent will have their cancer recur 91. Previous research has identified several risk factors 92 that are associated with a likelihood for recurrence, including grade 93 II or III tumors, deep invasion of the uterine muscle, spread of the tumor outside the uterus, and evidence of cancer in the surrounding lymph nodes 94 or blood vessels.
Currently, patients with high-risk early stage endometrial cancer are treated with adjuvant 95 external-beam radiation therapy 96 to the pelvis 97 to help prevent recurrence. Although often effective, this type of radiotherapy carries the risk of potentially severe side effects 98 that can substantially limit quality of life 99. Consequently, researchers are eager to find better ways to prevent or delay the return of cancer in these patients.
Most recurrences in women with high-risk early stage endometrial cancer occur either in the vaginal cuff (the upper part of the vagina that connected to the cervix before the uterus was removed) or at distant sites throughout the body. Some researchers have suggested, therefore, that post-surgical treatment may be made safer by targeting only the vaginal cuff with radiotherapy and more effective by adding chemotherapy 100 to help prevent systemic disease 101.
In this clinical trial, women with high-risk early stage endometrial cancer will be randomly assigned following surgery to receive one of two types of adjuvant therapy: brachytherapy 102 targeted to the vaginal cuff in combination with chemotherapy or standard pelvic external-beam radiotherapy. Brachytherapy involves implanting radioactive seeds in the area where cancer cells may be present or where recurrence is likely to happen.
“A variety of trials have shown the value of radiotherapy for women with high-risk early stage endometrial cancer, so this study is really building on our previous experiences and evaluating the possible benefits of adding chemotherapy to radiotherapy in this subset of patients,” said Dr. McMeekin. “This large study should reveal whether there is a benefit from the addition of chemotherapy and clarify the best way to improve care for a substantial portion of women with early stage endometrial cancer,” he added.
For More Information
See the lists of entry criteria 103 and trial contact information 104 or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.
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NCI Plans to Expand Outreach through Community-based Research Programs
NCI recently announced plans to incorporate its community outreach and cancer information dissemination activities as a key component in all of the institute’s community-based research programs, creating an enhanced National Outreach Network.
“NCI is committed to the effective dissemination of cancer information, particularly to underserved communities, and we believe it is a responsibility that should be met by all of our community-based research initiatives,” explained Dr. Sanya Springfield, director of NCI’s Center to Reduce Cancer Health Disparities (CRCHD) 106 during her July 29 presentation at NCI’s Cancer Information Service (CIS) Partnership Program meeting.
“We anticipate expanding NCI’s outreach capacity through several entities,” Dr. Springfield said. These include the Community Networks Program (CNP) 107, Minority Institution/Cancer Center Partnerships (MI/CCP) 108, Patient Navigation Research Program (PNRP) 109, Minority Based Community Clinical Oncology Program (MB-CCOP) 110, NCI Community Cancer Centers Program (NCCCP) 111, and the NCI-designated Cancer Centers 112—all programs with a proven track record for community-based research, Dr. Springfield explained.
NCI will incorporate the 33 years of experience it has gained from the CIS Partnership Program, which will end in January 2010, into the institute’s disparities research programs, she continued, “and we will create and maintain a sustainable National Outreach Network within medically underserved communities.” Through integration of community outreach and education activities into its disparities research programs, the institute will be better positioned to more effectively reach communities in need.
The new outreach network will be established in several phases, beginning in September with the hiring of community health educators by organizations involved in NCI’s community-based research programs. “Once implemented, this network of community outreach activities will represent a total of 66 sites across the United States and will ensure broad coverage for NCI’s community outreach effort to some of our most vulnerable populations,” Dr. Springfield said.
NCI will also incorporate Community Outreach Cores within the community-based research programs to fully integrate and sustain the community health educators in the National Outreach Network. “These new cores will provide continued staff and resources for outreach, education, and dissemination, and will support NCI in meeting the cancer control needs of communities,” Dr. Springfield added.
Staff from CRCHD and NCI’s Office of Communications and Education (OCE) will continue to assist community partners with ongoing activities, such as training and technical assistance, explained OCE Director Lenora Johnson. “NCI looks forward to continuing to engage our public and private national partners, current and new, to develop collaborations that effectively address cancer health disparities in our communities,” she said.
—Bill Robinson
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Senate Confirms Dr. Francis Collins as NIH Director
Dr. Francis Collins
On August 7, the U.S. Senate unanimously confirmed Dr. Francis Collins as the 16th director of the National Institutes of Health 113. Dr. Collins is a physician-geneticist known for his landmark discoveries of disease-causing genes and for spearheading the Human Genome Project. He served as director of NIH’s National Human Genome Research Institute 114 (NHGRI) from 1993 to 2008.
Under the leadership of Dr. Collins, the Human Genome Project was completed in April 2003 after deciphering the human genetic code. Dr. Collins’ own research laboratory has been involved in the discovery of a number of genes, including those associated with cystic fibrosis, neurofibromatosis, Huntington’s disease, type-2 diabetes, and Hutchinson-Gilford progeria syndrome.
Dr. Collins received a B.S. in chemistry from the University of Virginia, a Ph.D. in physical chemistry from Yale University, and an M.D. with honors from the University of North Carolina. Prior to coming to NIH in 1993, he spent 9 years on the faculty of the University of Michigan, where he was an investigator of the Howard Hughes Medical Institute. He has been elected to the Institute of Medicine and the National Academy of Sciences, and was awarded the Presidential Medal of Freedom in November 2007.
When President Obama nominated Dr. Collins on July 8, he said, “The National Institutes of Health stands as a model when it comes to science and research. My administration is committed to promoting scientific integrity and pioneering scientific research, and I am confident that Dr. Francis Collins will lead the NIH to achieve these goals. Dr. Collins is one of the top scientists in the world, and his groundbreaking work has changed the very ways we consider our health and examine disease. I look forward to working with him in the months and years ahead.”
“Dr. Collins has the all-important vision of how to use new knowledge about the molecular basis of disease to transform the delivery of health care,” said NCI Director Dr. John E. Niederhuber. “Indeed, NCI shares that vision of personalized medical solutions with interventions designed around the unique biology of the individual. The collaboration between NCI and NHGRI on The Cancer Genome Atlas 115, in just 3 years, has significantly advanced our understanding of two cancers and, more importantly, demonstrated that it is possible to develop a high-throughput approach to cataloging the genetic alterations that drive the initiation and progression of cancer.”
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Bevacizumab Approved to Treat Metastatic Kidney Cancer
The FDA has approved bevacizumab 116 (Avastin), in combination with interferon alpha, for the treatment of kidney cancer that has spread to other parts of the body. Bevacizumab is now approved for the treatment of five different types of cancer.
This most recent approval is based on the results of the AVOREN trial 117, an international phase III clinical trial of approximately 650 patients with previously untreated metastatic renal cell carcinoma. Patients in the trial, all of who had undergone a complete or partial removal of the kidney (nephrectomy) and whose cancer was of the clear-cell type, were randomly assigned to receive bevacizumab and interferon alpha or interferon alpha and placebo. There was a nearly twofold improvement in progression-free survival (PFS) in patients in the bevacizumab arm compared with patients in the placebo arm, 10.4 months versus 5.5 months, and a nearly threefold improvement in response rate (measured as tumor shrinkage), 31 percent versus 12 percent. There was a trend toward improved overall survival in the bevacizumab arm, but it was not statistically significant.
The original primary endpoint of the AVOREN trial was overall survival. In a news release, however, Roche, which manufactures bevacizumab, explained that “in prior consultation with the U.S. FDA and European regulatory authorities, the PFS endpoint was accepted as the basis for regulatory approval.”
Warning Labels on TNF Blockers Cite Cancer Risk
New warning labels that highlight the increased risk of lymphomas and other cancers will be required for a class of drugs known as tumor necrosis factor 118 (TNF) blockers, the FDA announced last week. TNF blockers are used to treat a number of immune system diseases, including juvenile rheumatoid arthritis 119, Crohn disease 120, and several other inflammatory diseases. The drugs in this class include infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi).
The warnings are the result of a safety review initiated earlier this year 121 by the FDA in response to reports to the agency’s adverse event reporting system of malignancies in patients treated with TNF blockers. The analysis, the agency reported 122, showed an increased risk of cancer “occurring after 30 months of treatment on average.” Approximately half of the cancers identified in the review were lymphomas, including Hodgkin and non-Hodgkin lymphoma. Other malignancies included leukemia, melanoma, and solid organ cancers.
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Dr. William Klein to Lead NCI's Behavioral Research Program
Dr. William Klein
Dr. William Klein has been named associate director of NCI’s Behavioral Research Program 123 in the Division of Cancer Control and Population Science, which includes five branches—Applied Cancer Screening Research, Basic and Biobehavioral Research, Health Communication and Informatics Research, Health Promotion Research, and Tobacco Control Research.
Dr. Klein received his bachelor’s degree in psychology and mathematical methods in the social sciences at Northwestern University and his M.A. and Ph.D. in social psychology at Princeton University. Most recently, he was a faculty member in the Social Psychology and Biological and Health Psychology graduate programs at the University of Pittsburgh, where he also served as director of undergraduate studies. Dr. Klein’s research interests fall largely under the areas of self-judgment, risk perception, and risk communication.
Deadline for Immune Response Modifiers RFI is August 24
The NCI Coordinating Center for Clinical Trials 124 (CCCT) is gathering input through a Request for Information (RFI) on translational research opportunities focused on cancer immunotherapy and immunoprevention. Members of the scientific community, including clinical oncologists and investigators from academia and the pharmaceutical industry, are encouraged to respond to this new approach to accelerate translational research.
The RFI is in response to the Translational Research Working Group’s 125 (TRWG) recommendation to set up a process to accelerate translational science; one that identifies promising translational projects and provides the resources and coordinated management required to rapidly advance those projects to phase I and II clinical testing. NCI may use the information gathered to develop requests for proposals, requests for applications, program announcements, cooperative research and development agreements, and other cooperative agreements; or advance intramural research by NCI staff and intramural mechanisms.
The RFI can be found online 126 and responses will be accepted through August 24, 2009.
NCI to Host Conference on Emerging Technologies for Circulating Tumor Cells
On September 10–11, NCI will host a conference titled, “Circulating Tumor Cells (CTC): Emerging Technologies for Detection, Diagnosis, and Treatment.” Attendees will gather on the NIH campus in Bethesda, MD, to learn about technologies for CTC-based cancer detection and treatment; meet with leaders, experts, and investors in the field; and hear about funding opportunities for CTC research and technology development. NCI’s Division of Cancer Treatment and Diagnosis 64, Small Business Innovation Research Development Center 127, and Division of Cancer Prevention 52 are hosting this conference to build new scientific collaborations and promote innovative research programs that translate basic research to product development and commercialization.
Participation is free, but space is limited. Go online 128 for more information and to register.
Registration Open for February State-of-the-Science Conference on Colorectal Cancer Screening
On February 2–4, 2010, NCI and the NIH Office of Medical Applications of Research 129 will convene a state-of-the-science conference on enhancing the use and quality of colorectal cancer screening. The conference will be held at the Natcher Conference Center on the NIH campus and will address the following key questions:
- What are the recent trends in the use and quality of colorectal cancer screening?
- Which factors influence the use of colorectal cancer screening?
- Which strategies are effective in increasing the appropriate use of colorectal cancer screening and follow up?
- What are the current and projected capacities to deliver colorectal cancer screening and surveillance at the population level?
- What are the effective approaches for monitoring the use and quality of colorectal cancer screening?
- What research is needed to make the most progress and have the greatest public health impact in promoting the appropriate use of colorectal cancer screening?
Invited experts will present information pertinent to these questions, and a systematic literature review will be summarized. Conference attendees will have the opportunity to ask questions and provide statements during open discussion periods. After weighing the scientific evidence, an independent panel will prepare and present a consensus statement addressing the key conference questions.
The conference is free and open to the public but advance registration is recommended. Go online 130 to find more information and register.
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