A new study led by Dr. Robin Yabroff of NCI’s Division of Cancer Control and Population Sciences indicates that the practice of cervical cancer screening using Pap tests varies by physician specialty. Published today in the Annals of Internal Medicine, the study involved a survey of more than 1,200 clinicians. While the large majority of physicians offered Pap tests to their eligible patients, the frequency of Pap tests recommended by physicians was often inconsistent with recommended national guidelines.
The slow but steady march toward more individualized care in cancer medicine has left pancreatic cancer behind. Patients diagnosed with this disease live no longer today than patients diagnosed 2 decades ago, despite more than a dozen large clinical trials. Even as many patients with other cancers have benefited from targeted drugs like imatinib (Gleevec) and trastuzumab (Herceptin), pancreatic cancer remains as deadly as ever. Read more > >
by Dr. Cathy Backinger
With the enactment of the Family Smoking Prevention and Tobacco Control Act on June 22, the United States entered a new era in tobacco control and prevention. While the importance of the new law cannot be overstated, it is only one component of a much larger, comprehensive tobacco control and prevention agenda, for which NCI-supported science is critically important. This issue of the NCI Cancer Bulletin highlights several important tobacco control research studies supported by NCI.
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.
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Pancreatic Cancer Report Urges Changes in Clinical Trials
The slow but steady march toward more individualized care in cancer medicine has left pancreatic cancer behind. Patients diagnosed with this disease live no longer today than patients diagnosed 2 decades ago, despite more than a dozen large clinical trials. Even as many patients with other cancers have benefited from targeted drugs like imatinib (Gleevec) and trastuzumab (Herceptin), pancreatic cancer remains as deadly as ever.
Recent advances in science and a new study may suggest a way forward. An expert panel convened by NCI has issued a consensus report that discusses many aspects of developing and testing treatments in this disease and charts a course for the next 5 years.
"This report is a call to action," said lead author Dr. Philip A. Philip of the Barbara Ann Karmanos Cancer Institute in Detroit, MI. "We need to do better clinical trials that are based on solid science, and patients need to be encouraged to participate in these studies."
A central recommendation is to design pilot studies that test potential treatments in smaller groups before proceeding to the kinds of large trials that have yielded disappointing results in the past. Decisions about which molecular targets and potential drugs to pursue will be made based on scientific evidence that will include preclinical and animal studies that better represent pancreatic cancer in humans.
"We have to be more thoughtful and innovative in bringing forward new targeted therapies and treatment combinations," said Dr. Philip. The hope is that the new strategy will ensure that precious resources and patient time are spent on the most promising treatments.
Often detected only after the disease has spread, pancreatic cancer is the fourth deadliest cancer in the United States, though it is not nearly as common as many other cancers. Most patients die within a year of diagnosis, and conventional chemotherapy has been notoriously unable to improve survival. With the exception of erlotinib (Tarceva), which has only a marginal benefit, the targeted drugs tested to date, including angiogenesis inhibitors, have not performed well.
The challenge for the field is to develop treatments when knowledge of pancreatic cancer biology is still limited. As the report notes, a better understanding of the complex signaling pathways in pancreatic tumors and the role of the local tumor environment are needed. More sophisticated modeling systems and repositories of high-quality biological samples that can be shared among preclinical researchers are also essential, noted Dr. Jack Welch, who oversees NCI's portfolio of gastrointestinal clinical trials in the Division of Cancer Treatment and Diagnosis.
"This is a difficult disease, and the scale of the challenge requires a broad-based and cooperative effort," Dr. Welch added. "To develop the kinds of combination treatments envisioned in the report, the pharmaceutical industry, researchers, and regulatory agencies will need to cooperate at an early stage and show flexibility."
The report stems from a 2007 meeting organized by the NCI Gastrointestinal Cancer Steering Committee, which brought together researchers, clinicians, patient advocates, and representatives from the pharmaceutical industry. The "Consensus Report of the National Cancer Institute Clinical Trials Planning Meeting on Pancreas Cancer Treatment" appeared online October 26 in the Journal of Clinical Oncology (JCO).
Also published in that issue of JCO was a study that provides an example of the kinds of trials many in the field hope to avoid in the future. As has been the pattern for these studies, patients saw little or no benefit from the experimental treatment, in this case a combination of gemcitabine (Gemzar) and capecitabine (Xeloda), as compared with gemcitabine alone.
The study, by the Medical Research Council in the United Kingdom, did not find an improvement in overall survival with the drug combination compared with gemcitabine alone. By another measure, however, there was a statistically significant difference: The combination delayed the time the disease took to progress by a little less than a month.
"You don't have to be a doctor to see that the difference between the two arms of this study is miniscule and of no real clinical benefit," commented Dr. Philip. "We need to make a distinction between what is statistically significant and what is meaningful for our patients."
According to an accompanying editorial in JCO, many groups involved in clinical trials for pancreatic cancer have learned the historic lessons of limited success in large trials and have already begun to adopt new ideas about developing and testing treatments. The authors stress that the report's recommendations be strongly considered in any clinical trial being planned for this disease.
Dr. Andrew Lowy, a surgical oncologist at the University of California, San Diego, and co-author of the report, is optimistic about the next few years. "We now have a greater understanding of this disease than ever before and more new agents directed at targets that have been rationally identified," he wrote in an e-mail.
"Awareness of pancreatic cancer in the community is growing, and groundswells of public support generally lead to increases in funding for research," he continued. "This will only help our progress."
—Edward R. Winstead
Cancer Research Highlights
Even With Very Small Breast Tumors, Studies Find HER2 Status Matters
Two retrospective studies have found that women with HER2-positive breast tumors (that is, tumors that produce too much of the HER2 protein) that are 1 centimeter or smaller had a higher risk of their disease returning within 5 years than women with similarly small HER2-negative tumors. The findings, published online November 2 in the Journal of Clinical Oncology, may shed some light on an area of clinical uncertainty: Whether women with small, HER2-positive tumors should receive post-surgical, or adjuvant, treatment with the targeted agent trastuzumab (Herceptin). Few patients with these small tumors took part in the large clinical trials that established adjuvant trastuzumab in combination with chemotherapy as a standard treatment for women with HER2-positive, early stage breast cancer.
The studies included women treated at the University of Texas M.D. Anderson Cancer Center and the European Institute of Oncology in Milan, respectively. In each study, the researchers reviewed the medical records of women with these small tumors treated at their respective institutions. Although the researchers excluded patients who had received adjuvant trastuzumab, some patients included in the analyses had received other adjuvant treatments, particularly those in the Milan group. Both studies found an approximately 2.5-fold higher risk of recurrence in women with small, HER2-positive tumors than in women with small, HER2-negative tumors, and the M.D. Anderson study showed a more than 5-fold increase in risk of developing metastatic disease.
The findings echo those of two earlier studies, noted Drs. Harold Burstein and Eric Winer of Dana-Farber Cancer Institute, in an accompanying editorial. And the findings add to the mounting evidence that, while women with small HER2-positive breast tumors still have a good prognosis, they may benefit from adjuvant treatment with chemotherapy and trastuzumab.
Given the lack of data from randomized clinical trials on the effect of trastuzumab on outcomes in women with small, HER2-positive tumors, Drs. Burstein and Winer caution that “treatment options should still be tailored to the underlying risk of recurrence.” This is particularly true for women with the smallest of these tumors, 5 mm or less, for whom the recurrence risk is “still uncharacterized.” In these patients “it seems hard to justify the rare but potentially serious risks of adjuvant chemotherapy and trastuzumab,” they wrote. In women for whom adjuvant treatment is being considered, they concluded, “Given the potency of trastuzumab-chemotherapy combinations, it seems likely that abbreviated courses of treatment might suffice.”
Risk of Contralateral Breast Cancer Estimated for BRCA Families
Women with inherited forms of breast cancer are at an increased risk of developing a second cancer later in life, often in the opposite (contralateral) breast. German researchers have now estimated the risk of contralateral breast cancer for these women and identified two factors that are associated with risk: a woman’s age when she was first diagnosed with breast cancer, and whether she has inherited a mutation in the BRCA1 or BRCA2 genes. The findings were reported online in the October 26 Journal of Clinical Oncology.
In a retrospective analysis of 2,020 German women with known or suspected BRCA1/2 mutations, the risk of contralateral breast cancer was highest among women with mutations in the BRCA1 gene who were initially diagnosed before the age of 40. For this group, the cumulative contralateral breast cancer risk after 25 years was nearly 63 percent, the researchers found.
Older age at the diagnosis of first breast cancer was associated with a smaller increase in risk. For those with BRCA1 mutations whose first cancer was diagnosed after age 50, the cumulative contralateral breast cancer risk after 25 years was 19.6 percent, and for their BRCA2 mutation-carrying counterparts, it was 16.7 percent, approximately the same as the risk among women from the general population.
For all women in the study, however, the overall risk of contralateral breast cancer at 25 years after a breast cancer diagnosis was nearly 50 percent and continued to rise thereafter. Though the risk estimates are lower than reported previously for this group, the findings suggest that “contralateral breast cancer risk is relevant even a long time after diagnosis of first breast cancer,” the researchers wrote.
Many high-risk women are seeking genetic counseling and BRCA1/2 mutation testing prior to diagnosis or at the time of diagnosis, in the hope that knowledge of their mutation status will improve their medical care. Although the findings need to be confirmed, they could potentially inform decisions about treatment, the authors said. This study may be the first to show that patients from families with BRCA1 mutations face a significantly higher risk of contralateral breast cancer than patients with BRCA2 mutations.
In an accompanying editorial, Drs. Judy Garber and Mehra Golshan of Brigham and Women’s Hospital said that for high-risk women diagnosed at a young age, the estimates “provide powerful figures that should compel the breast cancer care team to consider the issue of management of the opposite breast.” Equally important, the risk of contralateral breast cancer is “less compelling” for BRCA1/2 carriers who are older (i.e., over age 50) at diagnosis, they wrote.
Lower Total Blood Cholesterol Levels Are Not Linked to Higher Cancer Risk
A study published November 2 in Cancer Epidemiology, Biomarkers & Prevention has yielded new insight into the relationship between cholesterol and cancer. Previous studies have suggested that lower total blood cholesterol levels are associated with increased cancer incidence and mortality, but it has been unclear whether these studies observed a cause-and-effect association or if lower cholesterol can in some cases be a product of metabolic changes caused by very early cancer.
To better understand the associations between blood cholesterol and cancer risk, researchers from NCI’s Division of Cancer Epidemiology and Genetics examined prospective data from 29,093 male smokers who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Total blood cholesterol levels and HDL (so-called good cholesterol) levels were measured at the beginning of the study and 3 years later. The participants were followed for 18 years, during which time 7,545 cases of cancer occurred.
The researchers observed an overall association between higher blood cholesterol and decreased overall cancer incidence; however, when cancer cases diagnosed during the first 9 years of the study were excluded, this association disappeared, indicating that the association is not causative and was more likely due to existing early cancers in many cases. “Our data come down very strongly in support of low cholesterol not being a risk factor for cancer,” said Dr. Demetrius Albanes, senior author of the study.
The researchers also saw an association between higher levels of HDL and a lower risk of cancer overall. Unlike for total cholesterol, this association was slightly stronger when cases diagnosed through the first 9 years of follow-up were excluded. “We saw an 11 percent lower risk for all cancers over the entire observation period for the highest HDL levels,” said Dr. Albanes. “That became a 15 percent lower risk after excluding cases diagnosed during the first 9 and even 12 years of follow-up. If these new findings are confirmed by other researchers, higher HDL levels may be beneficial not only for preventing cardiovascular disease but also for inhibiting cancer,” he concluded.
Tests for Catching Cervical Precancers Show Equivalent Accuracy
The two most common methods for identifying cervical cancer precursors are equally accurate, according to the results of the largest randomized study ever comparing the two tests. The study found that liquid-based cytology, now the most commonly used approach for cervical cancer screening in the United States, was not superior to the conventional Pap test for the detection of abnormal cells that can precede cancer development. The results were published in the October 28 Journal of the American Medical Association.
The trial included approximately 90,000 women aged 30 to 60 who were screened at nearly 250 medical practices in the Netherlands that participate in the Dutch cervical cancer screening program. The medical practices were randomly assigned to use one of the two tests; physicians who followed up on women with positive test results were blinded to the type of test used and the test result. Both tests had nearly equivalent rates of detecting precancerous lesions—called cervical intraepithelial neoplasia—and had equivalent positive predictive value, which is the likelihood of precancerous cells being present following a positive test.
The liquid-based test is more expensive than a conventional Pap test, wrote the study’s lead author, Dr. Albertus G. Siebers, and colleagues. “But in equivocal cases it has the possibility of concomitant testing on the residual material for the presence of [HPV DNA] or other molecular cell cycle-related biomarkers,” the authors noted.
The trial results “are unlikely to have a major effect on cytology screening in the United States,” wrote Dr. Mark Schiffman of NCI’s Division of Cancer Epidemiology and Genetics and Dr. Diane Solomon of NCI’s Division of Cancer Prevention in an accompanying editorial. Liquid-based cytology is preferred by most laboratories because the specimen is easier and quicker to scan under the microscope. And, as the study found, there are fewer unsatisfactory specimens with liquid-based cytology.
“Cytology is now competing against primary and other secondary cervical cancer preventive strategies,” they wrote, including the HPV vaccine and HPV DNA testing. “Even though an increasingly powerful set of prevention tools is available, no combination of vaccination, cytology, HPV testing, colposcopy, and novel methods will be suitable for all settings.”
Nicotine Patch and Lozenge Combination Helps Smokers Quit for Longer
In a comparative effectiveness study testing five different smoking-cessation aids, researchers found that a combination of the nicotine patch plus the nicotine lozenge was most effective at increasing smoking abstinence. The results appeared yesterday in the Archives of General Psychiatry.
Clinical trials have shown that a variety of smoking cessation aids, including nicotine replacement products (such as the nicotine patch) and non-nicotine medications (such as bupropion), can help people quit smoking. However, the lack of research directly comparing the efficacy of these products has made it difficult for smokers to choose and doctors to recommend one aid over another.
The trial, led by Dr. Megan Piper of the Center for Tobacco Research and Intervention at the University of Wisconsin, enrolled 1,504 smokers and randomly assigned them to one of 10 treatment groups: the nicotine lozenge, nicotine patch, a combination of the nicotine lozenge and patch, bupropion, bupropion plus the lozenge, or a placebo for one of the five active treatments. All patients, including those in the placebo groups, received intensive smoking-cessation counseling.
Although all five active regimens helped people immediately quit smoking compared with their placebo controls, only three—the nicotine patch and the two combination regimens—increased abstinence at 1 week after quitting, and only the patch plus the lozenge was effective relative to its placebo 6 months after quitting. People who used this combination during the trial were more than twice as likely to remain abstinent at 6 months than those who received the placebo.
While the patch-plus-lozenge combination was the most effective therapy compared with its placebo, the authors caution that when compared head-to-head (instead of against their placebo controls), the five active cessation treatments all provided a relatively similar benefit for sustaining abstinence 6 months after quitting. In addition, the placebo groups all achieved an unusually high rate of success in quitting, perhaps due to the intensive counseling provided.
Personalized Phone Counseling Helps Teens Quit Smoking
In the largest clinical trial of its kind, researchers from the Fred Hutchinson Cancer Research Center have shown that telephone-based counseling that includes motivational interviewing and cognitive behavioral approaches helps older teens quit smoking. The trial is the first to demonstrate a prolonged effect—defined in the trial as lasting at least 6 months—on smoking cessation among adolescent smokers. This finding is consistent with the recommendation in the U.S. Public Health Service’s 2008 Clinical Practice Guidelines, which indicate that counseling can be an effective treatment to help youth quit smoking.
“These results are critically important for supporting and stimulating our nation’s search to find successful ways to help reduce smoking by teens and young adults,” said the study’s lead investigator, Dr. Arthur V. Peterson, Jr., in a press release. The study was published online October 12 in the Journal of the National Cancer Institute (JNCI).
The NCI-funded trial enrolled 2,151 older teenage smokers (identified through surveys) from 50 high schools in Washington State. Half of the schools were randomly assigned to receive confidential counseling, while student participants in the remaining 25 schools received no counseling. A large group of nonsmokers was also enrolled in the trial to mask participants’ smoking status.
Nearly two-thirds of the participants in the counseling group took part in at least one counseling call. The counseling, the research team explained, centered on two techniques: motivational interviewing, which helps give participants the motivation and confidence to quit, and cognitive behavioral skills training, which provides the tools for learning how to quit.
Among all smokers, 6-month quit rates were higher in participants who received the counseling compared with those who did not (21.8 percent versus 17.7 percent). Daily smokers who received the counseling were nearly twice as likely to report 6-month abstinence rates compared with daily smokers who did not receive counseling (10.1 percent versus 5.9 percent). The counseling intervention effects differed for male and female daily smokers. Male daily smokers who received counseling were more likely than male daily smokers who did not receive the intervention to sustain 6-month abstinence rates. However, this was not true for female adolescent smokers.
In an accompanying editorial in JNCI, Dr. Scott Leischow and Eva Matthews of the Arizona Cancer Center praised the trial and called for “encouraging in the strongest possible way” state tobacco quitlines “to implement the intervention…to the extent feasible.”
Guest Director's Update
Entering a New Era in Tobacco Control Research
With the enactment of the Family Smoking Prevention and Tobacco Control Act on June 22, the United States entered a new era in tobacco control and prevention. The act, which gives the FDA the authority to regulate tobacco products, means that the tobacco industry will no longer have free reign to market tobacco products to youth, promote so-called “light” cigarettes as less harmful than others, keep scientists and the public in the dark about ingredients and design features of cigarettes, and make unproven health claims for modified tobacco products. Already, the FDA has shown that it intends to act aggressively to implement the new law; on September 22, the agency announced a ban on fruit- and candy-flavored cigarettes.
While the importance of the new law cannot be overstated, it is only one part of a much larger, comprehensive tobacco control and prevention agenda, for which NCI-supported science is critically important. Most recently, NCI funded 15 new grants under two new Requests for Applications (RFAs), jump-starting research in two important areas: improving effectiveness of smoking cessation interventions among low-income adults, and preventing and reducing smokeless tobacco use. In 2010, we expect to fund grants in a third area, targeting state and community tobacco control and media research.
This issue of the NCI Cancer Bulletin highlights several important tobacco control research studies supported by NCI. In the largest trial of its kind to date, researchers from the Fred Hutchinson Cancer Research Center found that telephone counseling using motivational interviewing and cognitive behavioral approaches significantly improved 6-month cessation rates in older teens. Given that 20 percent of American high school seniors smoke cigarettes, and that few strategies have been effective at promoting cessation among teen smokers, this finding is very significant. This issue also highlights a study of mobile phone technology provided to DC Tobacco Quitline callers and the expansion of Smokefree.gov, including new links to social media, such as Facebook, that take advantage of interactive Web technologies to reach new audiences for smoking cessation.
NCI’s tobacco control research cannot be limited to the United States, where, as in most high-income countries, tobacco use is slowly declining. By 2030, global mortality from tobacco use is expected to rise to 8 million deaths per year. About 80 percent of those deaths will occur in low- and middle-income countries, where tobacco use is still increasing. Research will be critical to averting this global epidemic, which threatens to reverse hard-won improvements in global health and which economically developing countries with overburdened health care systems can ill afford.
NCI supports a number of critically important international research projects, including the International Tobacco Control Policy Evaluation Project, which evaluates policies being enacted around the world in response to the World Health Organization’s Framework Convention for Tobacco Control. We are also a co-funder of the Fogarty International Center’s International Tobacco and Health Research and Capacity Building Program, which has galvanized tobacco control research in low- and middle-income countries.
Tobacco use remains the country’s leading cause of premature, preventable death—including an estimated one-third of all cancer deaths—and it is an important contributor to health disparities. But sustained research, comprehensive state-based tobacco control programs, and the FDA’s new authority to regulate tobacco products have put us on the road to a new future. Decades of scientific research supported by NCI and other NIH institutes have provided the foundation for the FDA’s new authority. NCI is committed to working with the FDA and other partners to ensure that scientific research continues to inform and advance tobacco control policies and interventions.
Dr. Cathy L. Backinger
Chief, Tobacco Control Research Branch
NCI Division of Cancer Control and Population Sciences
How Gene Fusions May Occur in Prostate Cancer
Four years ago, researchers at the University of Michigan Medical School uncovered a common genetic change in prostate cancer—fused genes. These mutant genes, which have since been found in other common cancers, form when DNA from different parts of the genome merge. The mechanisms underlying these changes are poorly understood.
Now, the Michigan team, led by Dr. Arul Chinnaiyan and supported in part by NCI’s Early Detection Research Network, has recreated gene fusions in the laboratory. They show that exposure to male hormones called androgens can cause chromosomes to change their three-dimensional positions in a cell, bringing into proximity genes that are normally far apart. When this occurs in a cell that experiences DNA damage, genes from different chromosome regions may fuse together.
Gene fusions may therefore be the product of a two-step process, the researchers reported online October 30 in Science. The study was done using prostate cancer cells that lacked gene fusions but were sensitive to androgens, which play a role in some prostate cancers. The cells were exposed to dihydrotestosterone, a modified version of testosterone, and then to radiation. Higher doses of radiation were associated with more fusion events.
“Gene fusions in prostate cancer are caused by a combination of androgen signaling and DNA-damaging agents,” said Dr. Chinnaiyan. While the researchers had thought that these events could occur by chance, this study suggests that androgens may set the stage for at least some types of fusions.
A study last year reported that the hormone estrogen could induce positional changes in chromosomes and bring together genes that were normally far apart. Because of the similarities between androgen and estrogen signaling in cells, the researchers hypothesized that androgens may induce chromosomal movements in prostate cancer.
“We have known that androgens can regulate genes, and it now appears that the hormones can induce intra-chromosomal movements,” said Dr. Ram-Shankar Mani, the study’s first author. Future studies are needed to unravel the molecular mechanisms underlying the chromosomal changes and fusion events.
The researchers focused on the fusion of two genes on chromosome 21 that normally reside far apart, TMPRSS2 and ERG. This fusion occurs in approximately half of prostate cancers and may drive the disease.
The Michigan group plans to investigate other fusions, as well. “We focused on the most common gene fusion associated with prostate cancer, but we believe that many genes will come into proximity because of androgen signaling,” said Dr. Chinnaiyan.
These findings have important implications for understanding the cell type-specific three-dimensional architecture of the nucleus, commented Dr. Steven Smith, Professor of Molecular Science at City of Hope in Duarte, CA, who was not involved in the research.
“This study really highlights the cross-fertilization between cancer biomarker research and basic biology,” Dr. Smith wrote in an e-mail message. “One usually thinks that basic science drives cancer research but often, as in this study, it can be the other way around.”
—Edward R. Winstead
Profiles in Cancer Research
Dr. Marcia R. Cruz-Correa
Director, Gastrointestinal Oncology Program, University of Puerto Rico Comprehensive Cancer Center
As you walk down the halls of the new comprehensive cancer center at the University of Puerto Rico (UPR) Medical Sciences Campus in San Juan, keep an eye out. The woman bustling by could be Dr. Marcia Roxana Cruz-Correa, and she’s not someone you want to miss.
“She knows where she’s going, and before you quite realize it, you’re shaking your head with a bemused smile and pretty much wanting to go along with her,” said Dr. Francis Giardiello, gastroenterologist and clinical researcher at the Johns Hopkins School of Medicine and Dr. Cruz-Correa’s clinical mentor. “Marcia is definitely running a 3- or 4-ring circus,” he added.
In addition to clinical and academic research, she is a physician-scientist committed to seeing patients in the clinic. When she was a kid, she said, “My mom tells me that I was prowling around the house looking for things to fix. I like taking care of patients and people, and endoscopy is one way of ‘fixing stuff.’ It’s really satisfying for me.”
She was well-served by the pre-med undergraduate program at UPR, where she also attended medical school. To help pay her way through, Dr. Cruz-Correa joined the U.S. Army Reserve—another ring in the circus.
“I married my high school sweetheart when I was 23, which seemed pretty natural, unless you were in your first year of med school,” she said. “Two years later I got pregnant, so before I was putting Dr. in front of my name I was a mom. Estefania Jordan was born in 1993.
“But I always knew I wanted to do clinical research, which definitely meant leaving the island. I did my internal medicine residency in Puerto Rico, but since Estefania was no longer a baby, you know, I decided to just go for it.” Fifteen fellowship applications later, toddler and husband in tow, she found herself a first-year fellow in gastroenterology at Hopkins and a Ph.D. student in the Johns Hopkins Bloomberg School of Public Health.
The Baltimore Years
Loss of Gene Imprinting and Cancer Risk
Most genes come in pairs, one inherited from the mother and one from the father. In most cases, both copies, or alleles, of the gene are expressed or “switched on.” But for some genes, only one of the two alleles is expressed. The other is silenced or “switched off” through a process known as “imprinting.” When a normally silenced gene loses its imprinting and is expressed from both alleles, disease can follow.
In humans, the IGF2 gene is normally imprinted, with only the paternal allele expressed. Dr. Feinberg’s lab at the Johns Hopkins University School of Medicine discovered that the normally silenced maternal IGF2 allele can undergo loss of imprinting. IGF2 is a growth promoting gene, and evidence is mounting that individuals with loss of imprinting of IGF2 may be at increased risk for developing several cancers, including colorectal.
Dr. Giardiello became her clinical mentor and referred her to Dr. Andrew P. Feinberg, now the King Fahd Professor of Molecular Medicine and a pioneer in the study of methylation and other epigenetic aspects of cancer. His laboratory had discovered loss of imprinting of the insulin-like growth factor II (IGF2) gene in Wilms tumor and had been doing work to extend the connection to colorectal cancer, which might have bigger clinical implications. (See the sidebar for further explanation.)
“People are familiar with the IGF1 gene for its role in diabetes, but IGF2 has kind of been overlooked,” Dr. Cruz-Correa explained. Overexpression of this gene may help tumors grow, and Dr. Feinberg’s group had found the gene not only in the tumors but also in the normal tissue of patients who developed colorectal cancer. The overexpression of IGF2 is very unusual among the general population and might one day lead to a way of identifying those at higher risk for developing the disease.
Dr. Cruz-Correa worked with Dr. Feinberg’s team on designing a clinical study to learn how common loss of imprinting of IGF2 might be. She persuaded the private practice physicians affiliated with Hopkins to join her network and provide a ready stream of colonoscopy patients. But she also had to convince the patients to join the trial, and historically fewer than 4 percent of cancer patients do so.
“Practically none of these patients refused to join,” recollected Dr. Giardiello. “I think she recruited about 390 out of 400 patients she approached. She is unique, a special person,” he explained. “If she wants your help, she makes it almost irresistible with her sincerity and her personal appeal to bring you along. That’s her special quality.”
As Dr. Feinberg puts it, “Preserving the sense of wonder and joy in discovery is one of the keys to succeeding in science or medicine. It is most unusual to find people like Marcia; she has that quality and she brings it to the laboratory, the public health arena, and also to the one-on-one experience with her clinical patients. It makes her a most extraordinary exemplar of what we aim for in translational investigators.”
After finishing her fellowship, Dr. Cruz-Correa has continued her connection with Hopkins as a visiting associate professor of medicine and has been the lead author on several studies coming from the Feinberg lab.
Navigating the Landscape of Opportunity
Like most successful researchers, Dr. Cruz-Correa has learned how to navigate the landscape of programs and opportunities at NIH. She received K07 and K22 awards from NCI, and with her R03 grant she helped to develop the first Familial Colorectal Cancer Registry in Puerto Rico. (As patients diagnosed with colorectal cancer join this group, investigators gather important information on their medical history, diet, and other lifestyle factors that may have contributed to their cancer.)
The UPR hospital she bustles through would not exist without the help of NCI and the Center to Reduce Cancer Health Disparities. The U-54 Minority Institution/Cancer Center Partnership program (MI/CCP) helped the UPR Medical School to develop a comprehensive cancer center by establishing a working relationship with the University of Texas M.D. Anderson Cancer Center in Houston, where Dr. Cruz-Correa remains an adjunct associate professor of surgical oncology.
“When we got the planning grant in 2002,” she said, “we went from having no building and a few investigators to this beautiful facility with state-of-the-art laboratory facilities and more than 60,000 square feet of bench space. We’re still recruiting, but our faculty is already at 14 or 15, each one of us with our own team of people. So it’s growing, and it shows what federal support can accomplish.”
Biomedical research isn’t for the faint hearted, she believes. “Sometimes the most difficult thing is to get people to believe in themselves. Then you need to know what opportunities exist. I am so grateful to NCI. Over the years I’ve worked with many people at NIH, and they are unfailingly eager to provide good advice, nurture hope, and really often inspire people. I’m their biggest fan.”
“Pass it Forward”
Dr. Cruz-Correa thinks that more minority women can and should join the ranks of cancer researchers. There are disparities, she admits, but she believes that “this is a field for anyone who has the desire, the energy, and the passion. The help I’ve gotten, I want to pass it forward, and I consider mentoring a privilege. Of course we all work very hard. But anyone who is willing to do that, and wants advice, I’m delighted to help them. What matters isn’t your background, it’s your attitude.” Although she serves just 2 weeks of active duty each summer, her own attitude, energy, and passion have taken her to the rank of lieutenant colonel in the U.S. Army Reserve.
Certainly her most treasured mentoring project is Estefania, who has been attending conferences and meetings with her recently. At the age of 16, Estefania says that she wants to become a doctor, like her mom. “I wanted her to know her mom was more than just the person she saw at home. That often when I’m away, it’s because I’m at the clinic helping other people,” said Dr. Cruz-Correa. “She sees her mom as a speaker and active part of this cancer research world.”
Featured Clinical Trial
Combining Chemotherapy and a PARP Inhibitor for Advanced Solid Tumors
Name of the Trial
Phase I Study of PARP Inhibitor AZD2281 in Combination with Cisplatin and Gemcitabine Hydrochloride in Patients with Unresectable or Metastatic Solid Tumors (NCI-08-C-0128). See the protocol summary.
Dr. Giuseppe Giaccone, NCI Center for Cancer Research
Why This Trial Is Important
Over the past decade, new drugs and biological agents have been developed that fight cancer by targeting certain proteins thought to be involved in promoting cancer cell growth and survival. These new treatments are commonly referred to as targeted therapies. In contrast, traditional chemotherapy drugs and radiation therapy attack cancer by preferentially killing rapidly dividing cells.
AZD2281 (olaparib) is a new type of targeted therapy that blocks the activity of proteins called PARP1 and PARP2, which help cells repair damaged DNA. Researchers hope that combining a PARP inhibitor like AZD2281 with traditional chemotherapy drugs, which work by damaging DNA, will produce greater anticancer effects than either chemotherapy or a PARP inhibitor alone. This approach is based on the observation that cells are unable to survive if they accumulate high levels of DNA damage.
In this clinical trial, patients who have solid tumors that cannot be removed by surgery or that have spread to other areas of the body will be treated with AZD2281 and the chemotherapy drugs cisplatin and gemcitabine. Doctors will assess the safety of this regimen, determine the maximum tolerated dose, and examine the effects of treatment on specific molecular markers in tumor biopsy specimens and blood samples taken from the patients.
“Preclinical models show synergy between PARP inhibitors and drugs that work by damaging DNA,” said Dr. Giaccone. “Non-small cell lung, bladder, and pancreatic cancers may be particularly interesting cancers in which to study this regimen, because the combination of cisplatin and gemcitabine is already used as a standard treatment in these tumor types.
“In previous clinical studies, olaparib [AZD2281] has demonstrated antitumor activity as a single agent against some breast, ovarian, and prostate cancers associated with BRCA1 or BRCA2 gene mutations,” continued Dr. Giaccone. “Many of the patients in those studies experienced clinical benefit without substantial adverse effects.”
Local Partners Study Mobile Support for DC Tobacco Quitline
A partnership of organizations in Washington, DC, will explore how effectively new media tools help District residents quit smoking. The American Legacy Foundation’s Schroeder Institute for Tobacco Research and Policy Studies received nearly $980,000 in American Recovery and Reinvestment Act (ARRA) funds from the National Institute on Drug Abuse to carry out a randomized controlled trial to study the effectiveness of Mobile Quitline Enhancement (MQE), an Internet-based mobile phone technology to be provided through the DC Tobacco Quitline.
The quitline provides free support to those who want to stop smoking and are motivated to seek cessation services. Currently, resources include a series of five phone counseling sessions and an 8-week course of nicotine replacement therapy (NRT), in either lozenge or patch form. MQE services are designed to assist quitline counselors, giving users the opportunity to share real-time information about their quit attempt through daily assessments. This provides counselors with accurate and timely data between phone sessions, allowing them to tailor their intervention.
Approximately 800 quitline callers will be selected to take part in the trial. Of these, 500 participants will be randomly assigned to receive mobile phones equipped with MQE software and Internet access, allowing them to send updates on factors such as cravings and potential lapses directly to a quitline database. The other 300 participants will receive standard quitline services.
The study will compare the two groups to evaluate MQE’s impact on cessation rates. It will also examine whether MQE users choose to use cessation support resources more often than MQE nonusers, and whether differences in NRT use impact overall cessation outcomes.
MQE will allow counselors to save time spent on detailed discussions of users’ smoking behavior during the weeks between calls to the quitline, since the system provides counselors with specific information about their clients’ ongoing progress with cessation. It will also allow counselors to provide customized support based on each participant’s behavior.
Dr. Thomas Kirchner, an investigator at the Schroeder Institute for Tobacco Research and Policy Studies, will lead the initiative. He points out that Web-based mobile technologies hold tremendous potential to address the challenges quitters face during smoking cessation.
“It is important for cessation-support services to take situational circumstances into account. Mobile devices enable existing systems to do precisely that—to consider momentary circumstances,” Dr. Kirchner said. “They provide tailored relapse prevention support wherever and whenever it happens. One way to think about these devices is that they are a distress beacon the user can activate to receive support.”
The American Legacy Foundation will collaborate on this project with the DC Department of Health, DC Cancer Consortium, American Lung Association of DC Tobacco Free Families Initiative, and the Georgetown University Lombardi Health Disparities Initiative.
“This project spearheads a new local partnership that is totally focused on improving health outcomes among underserved DC residents,” said Dr. Kirchner. “We’re excited to work hand-in-hand with local partners. We are all working to sustain these systems well past the ARRA window,” he explained.
Ashley Ross, tobacco control program manager at the DC Department of Health, agreed. “We’re excited about this opportunity on a number of levels. Any opportunity to increase effectiveness and help more people quit is something we want to do. It really helps us crack the code for how we can continue to offer effective, sustainable cessation services,” Ms. Ross said.
“[MQE] provides a unique protocol for the underserved smoker,” said Debra Annand, lead advisor for the American Lung Association of DC and for the quitline. “We plan to assess how these extra interventions can improve quit attempts for underserved and underinsured smokers.”
Smoking prevalence varies across the city—from as low as 10 percent in Ward 3 to as high as 26 percent in Ward 8. Overall, smoking prevalence is much higher in Wards 5 through 8; and it is here where the majority of the quitline’s outreach is focused, and where residents also generally have lower socioeconomic status. The quitline addresses this disparity and tailors services to meet the needs of those individuals.
Ms. Ross notes that MQE technology could have implications for these communities beyond this study. “We can start to think about the quitline less as a destination, and more as a vehicle. We are reaching communities most in need, connecting with them and helping them build their own capacity—not just with cessation but also with other risk behaviors.”
—Holly Aprea Gibbons
Adolescent and Young Adult Cancer Portal Launched
NCI has launched a new Web portal that provides a single access point to information for adolescent and young adult (AYA) cancer patients aged 15 to 39. About 70,000 AYAs are diagnosed with cancer each year in the United States.
Cancer is the second leading cause of death in this age group. Yet, substantially less attention has been given to young adults with cancer than to children and older adults, and improvement in the survival rate of young adults has not kept pace with that achieved in other patient groups. Reasons for this lack of progress include issues specific to this age group: differences in biology or intolerance of therapy, delay in diagnosis, physicians unfamiliar with the disease, a lack of both available clinical trials and access to these trials, and, often, the psychosocial condition of the patient. Additionally, AYA patients often have special concerns that differ from those of older cancer patients, such as preserving fertility, being able to obtain health insurance and access health care following a cancer diagnosis, and feeling isolated because of a lack of peers who can relate to fighting cancer at their age.
The portal was developed in response to a report by the Adolescent and Young Adult Oncology Progress Review Group (PRG). This PRG, a collaborative effort between NCI and the Lance Armstrong Foundation, was followed by Closing the Gap: A Strategic Plan, developed to address recommendations in the PRG report. The AYA cancer portal is designed to reach newly diagnosed AYA patients with evidence-based information that will help them learn more about their treatment options and participate in treatment-related decisions, explore clinical trial options, get emotional/coping support, and learn about organizations that provide information and support to AYAs.
The portal can be accessed at http://www.cancer.gov/cancertopics/aya.
A New Face for Smokefree.gov
The update includes bold colors, new images, and a poll on the homepage to engage users, as well as expanded content and new topic areas inspired by questions commonly asked by site visitors. Expanded topics include the benefits of quitting, secondhand smoke, and medications to help smokers through the quitting process. Users will find two new sections, on stress and depression. Both sections contain online quizzes that can help users evaluate feelings of depression, with general treatment recommendations and a list of resources to help them seek professional help for stronger feelings of depression.
NCI plans to expand the site to include a presence on Facebook—much like Smokefree Women—to increase social support for smokers who are trying to quit.
NCI Launches Physical Sciences-Oncology Centers
On October 26, NCI awarded institutional grants establishing 12 Physical Science-Oncology Centers (PS-OC) as part of its Physical Sciences in Oncology initiative to better understand the laws and principles that shape and govern the emergence and behavior of cancer. The goal of the 5-year initiative is to engage transdisciplinary scientific teams from physics, mathematics, chemistry, and engineering to examine new, nontraditional approaches to cancer research.
Researchers will explore the physical laws and principles of cancer; evolution and evolutionary theory of cancer; information coding, decoding, transfer, and translation in cancer; and cancer’s complexity. These ongoing efforts will enable experts to explore innovative approaches to better understand, diagnose, treat, and control cancer.
The PS-OCs are based at:
- Arizona State University
- Cornell University
- H. Lee Moffitt Cancer Center & Research Institute
- Johns Hopkins University
- Massachusetts Institute of Technology
- Memorial Sloan-Kettering Cancer Center
- Northwestern University
- Princeton University
- Scripps Research Institute
- University of California, Berkeley
- University of Southern California
- University of Texas Health Science Center at Houston
Each of the PS-OCs has convened groups of experts that will support a transdisciplinary environment and promote research that: originates and tests novel, non-traditional physical sciences-based approaches to understand and control cancer; generates independent sets of physical measurements and integrates them with existing knowledge of cancer; and develops and evaluates approaches from the physical sciences to provide a comprehensive and dynamic picture of cancer.
Through coordinated development and testing of these approaches to studying cancer processes, the PS-OCs are expected to generate new bodies of knowledge in order to identify and define critical aspects of physics, chemistry, and engineering that operate at all levels in cancer processes.
“I truly believe the initiative’s objective of applying physical sciences and engineering perspectives and principles to cancer will lead to paradigm-shifting science toward understanding and, ultimately, treating the disease,” said Dr. Larry Nagahara, NCI PS-OC program director. “I’m very excited about the team of world-class researchers assembled in these centers and the fact that they will be working together as a collaborative network.”
Learn more about the PS-OCs online.
Spanish Clinical Trials Promotional Tools Available from NCI
NCI recently made available Spanish-language promotional posters and pins to increase awareness about clinical trials. The tools are intended to spark 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.
Meet NCI Experts at APHA
Learn about NCI’s programs and Web sites by visiting booth #1113 in the exhibit hall during the American Public Health Association Annual Meeting in Philadelphia, PA. NCI experts will be available to talk about a wide range of topics. See the schedule below.
Sunday, November 8
NCI Cancer Bulletin
NCI Research Funding Opportunities in Cancer Complementary and Alternative Medicine
Public Health Genomics at NCI
Designing for Dissemination
Results and Opportunities in Energy Balance Research
Applied Cancer Screening
Meet & Greet with Office of Communications and Education Director
State Cancer Legislative Database
New Media at NCI
Health Communications Internship Program
NCI Cancer Bulletin
State Cancer Legislative Database
Cancer Prevention Fellowship Program