National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
March 8, 2011 • Volume 8 / Number 5

NEWS

Ovarian Cancer Study Raises Questions about Developing Markers for Early Detection


A long-awaited assessment of potential biomarkers for detecting early ovarian cancer shows that blood levels of the CA-125 protein remain the best predictor of the disease. But if there is to be any hope that screening will reduce deaths from this disease, then more accurate markers would have to be developed, researchers concluded in the March Cancer Prevention Research. Read more > >
Vials of blood

COMMENTARY

Reenergizing the Agenda for Cancer Communication

by Drs. Galen Cole, Barbara Powe, and Brad Hesse

Communication experts from the American Cancer Society, Centers for Disease Control and Prevention, and NCI discuss how to take advantage of new communication platforms to make progress against cancer. Read more > >

  

IN DEPTH

UPDATES

  • Legislative Update

    • Early Actions by the 112th Congress
  • Notes

    • President Appoints New Members to the National Cancer Advisory Board
    • Greenwald Named NCI Associate Director for Prevention
    • NCI Launches Interactive Cancer Control Community of Practice

Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

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Featured Article

Ovarian Cancer Study Raises Questions about Developing Markers for Early Detection

Vials of blood (Photograph by Daniel Sone) Researchers have strived to develop a blood test to detect early ovarian cancer for more than a decade. In a rigorous validation study of 28 potential markers, CA-125 remains the best predictor of disease. (Photograph by Daniel Sone)

A long-awaited assessment of potential biomarkers for detecting early ovarian cancer shows that blood levels of the CA-125 protein remain the best predictor of the disease. But if there is to be any hope that screening will reduce deaths from this disease, then more accurate markers would have to be developed, researchers concluded in the March Cancer Prevention Research.

None of the 28 potential serum markers tested in the study outperformed CA-125. But for screening, the researchers noted, doctors would need a test that could detect a signal from tumors more than 6 months before diagnosis; CA-125 had its strongest signal within 6 months of diagnosis.

Although the results may seem disappointing, the findings can inform future efforts to detect the disease early, the study authors wrote. This idea was echoed by several biomarker experts who were not involved in the work but who stressed the importance of the findings.

“This is a landmark study,” said Dr. Mark H. Greene of NCI’s Division of Cancer Epidemiology and Genetics, who co-authored an accompanying editorial. “For the first time, we have a rigorous analysis of years of ovarian cancer biomarker research to determine whether these markers represent an improvement over where the field began, with CA-125.”

The results, he continued, show that a new approach is needed to find an effective screening strategy for ovarian cancer. (Preliminary results from the study were presented in 2009.)

Accelerating the Search

Dozens of potential markers for ovarian cancer have been identified over the last decade, but most could not be validated and have been abandoned. To accelerate progress, leaders of NCI’s Early Detection Research Network (EDRN) and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial developed the current validation study. Investigators were granted access to high-quality blood samples from PLCO participants, including some rare prediagnostic samples from women who developed ovarian cancer during the trial.

The study assessed how well the ovarian cancer markers performed in prediagnostic specimens in asymptomatic women compared with how the markers performed in specimens obtained at diagnosis in a different group of women. Lead investigator Dr. Daniel Cramer of Brigham and Women’s Hospital predicted that there would be different interpretations of the findings, and he stressed the importance of learning more about CA-125.

First described 30 years ago, CA-125 is widely used to assess the effectiveness of treatment in patients with ovarian cancer, but the protein is less useful for screening. Blood levels are elevated in only about half the patients with early-stage ovarian cancer, and levels can rise for reasons other than this disease. Yet, CA-125 remains the best early-detection marker for ovarian cancer.

“If CA-125 is so important, as these results tell us, then I think we need to understand this protein better,” Dr. Cramer said. For instance, some women with advanced ovarian cancer have normal CA-125 levels, and understanding this phenomenon could potentially make the protein more useful for screening, he noted.

The primary interpretation of the current study will likely be that new markers are needed and that researchers should rethink the best way to discover and develop markers. To date, most potential markers have been identified in blood collected from women at the time of diagnosis, because these are the samples that researchers have available.

But these samples often reflect late-stage disease, and they may not be useful for early detection, as the new findings suggest.

“We need to think more about how to discover these markers,” said study co-author Dr. Claire Zhu of NCI’s Division of Cancer Prevention, who was also the first author of a companion report describing a framework for evaluating panels of markers. “And while we don’t know the best approach, we hope this study will encourage discussions within the field.”

PLCO is one of several large randomized studies that have made limited samples available for biomarker research in response to proposals from investigators. “Discovery should be done in prediagnostic samples because these samples are more reflective of the biology of the disease than other samples,” said Dr. Sudhir Srivastava, who heads the EDRN.

Many researchers have said that if no single marker could detect ovarian cancer, then panels of markers might get the job done. This idea was untested until now, and, at least in this case, panels added little value to CA-125.

“The panels that were tested just didn’t perform,” said co-author Dr. Eleftherios Diamandis, a researcher at the University of Toronto who has written about cancer biomarkers. “The message of this study, unfortunately, is that we have underestimated the difficulty of finding biomarkers.”

The field has learned, however, that the best way to do this research is through rigorous validation studies that use high-quality samples like those from PLCO, he added.

With Progress, New Questions

Moving forward, perhaps the biggest unknown is the biology of ovarian cancer. Even with better strategies for developing markers, no one knows whether markers are present in the blood that could be detected early enough to help save women’s lives.

“It’s very hard to do discovery on people who are asymptomatic, where there may not be a strong signal to pick up,” said co-author Dr. David Ransohoff of the University of North Carolina at Chapel Hill. “After all these studies, we don’t really know that good markers are really there.”

Some researchers are testing the rise in blood levels of markers over time for early detection. The idea behind longitudinal studies is that each person has a natural, or baseline, level for each marker, and that one or more of these markers will start rising above the baseline level when she develops ovarian cancer.

“The hope is that longitudinal information on biomarkers will be much more valuable than a biomarker at one point in time,” said co-author Dr. Steven Skates of Massachusetts General Hospital. “The thinking is that this rise over time may be the most sensitive flag for detecting the disease as early as possible, with a marker or collection of markers.” 

This approach—with CA-125 as the marker, followed by ultrasound if the blood test indicates that the woman has a high risk of ovarian cancer—is being tested in one arm of the UK Collaborative Trial of Ovarian Cancer Screening, a prospective study. “We’ll have to wait a few more years for the study’s results to see if this approach works,” Dr. Skates said.

The UK trial requires that both CA-125 and transvaginal ultrasound be positive before a woman is referred to surgery. The PLCO study, on the other hand, requires that one or the other be positive. The PLCO results are expected in the next few months.

In the meantime, the validation study provides an opportunity for the field to assess the last decade of study and how best to move forward.

“We need to know whether there are lessons to be learned about the process of biomarker discovery from these studies,” said Dr. Ransohoff. “It would also be useful to know why it has taken so long to get reliable results and how we can improve the process of discovery and validation.”

During the last decade, Dr. Ransohoff noted, some researchers made strong claims about potential markers for ovarian cancer based on preliminary data. And though the markers did not pan out, these claims were repeated by members of the media, raising false hopes about early detection.

“The new data speak for themselves, I’m afraid,” said Dr. Greene. “But this work really is a model for how these studies should be done.”  

Edward R. Winstead

Further Reading: Ovarian Cancer Study Tests Lead Time of Potential Biomarkers

Cancer Research Highlights

Surgical Biopsy Is Overused for Evaluating Suspicious Breast Imaging Findings

A comprehensive study of health care data from Florida shows that physicians are using surgical biopsy to investigate suspicious breast lesions much more often than is warranted, researchers reported in a study published online February 8 in the American Journal of Surgery. Medical guidelines recommend that in most cases doctors use a needle biopsy rather than more invasive open surgical biopsy to investigate suspicious lesions found during breast imaging exams such as mammography.

Dr. Stephen Grobmyer and his colleagues at the University of Florida examined records from the Florida Agency for Health Care Administration outpatient surgery and procedure database. Although the percentage of patients in Florida who had minimally invasive breast biopsy (MIBB), also known as percutaneous needle biopsy, increased over the 5-year study period (2003 to 2008), the rate of open surgical biopsy in 2008 was still around 30 percent. That rate was substantially higher than the 5 to 10 percent that a 2009 consensus panel suggested as an appropriate rate of open biopsy, the study authors noted. The use of MIBB was higher at academic medical centers than at nonacademic centers.

MIBB causes less scarring and fewer complications, such as infection and bruising, and is less expensive than open surgical biopsy. Most biopsied breast lesions turn out to be benign. And because MIBB is highly accurate, the authors noted, in most cases having a needle biopsy can prevent the need for a patient to have an open surgical biopsy procedure.

“These findings suggest the need for further efforts to educate practitioners and patients about the numerous advantages of MIBB for the evaluation of suspicious image-detected breast lesions,” the authors wrote. “Achieving a reduction in the rate of open surgical biopsy should remain a priority.”

AddingRadiation to Chemotherapy Improves Outcomes in Early-Stage Hodgkin Lymphoma

Combined data from five randomized clinical trials indicate that patients with early-stage Hodgkin lymphoma should receive radiation therapy in addition to chemotherapy. The combination of the two therapies is currently the standard treatment for Hodgkin lymphoma.

However, some researchers have suggested that forgoing radiation therapy may not lower survival for patients with early-stage disease. Radiation therapy can cause late side effects in survivors, who tend to be young at the time of treatment. These side effects include second cancers, most commonly breast cancer in young women who receive radiation therapy to the chest.

Researchers from the Cochrane Collaboration performed a meta-analysis using data from 1,245 patients enrolled in the five trials. Each trial compared outcomes among patients treated with six cycles of chemotherapy alone with those among patients treated with six cycles of chemotherapy plus radiation therapy. Patients had stage I or stage II disease and either a favorable or unfavorable prognosis. Median follow-up for the trials ranged between 2 and 11.4 years.

Patients who received the combination of radiation therapy and chemotherapy lived longer than patients who received chemotherapy alone. The authors estimated that one life would be saved for every 11 to 55 patients treated with combination therapy instead of chemotherapy alone. Patients who received combination therapy also had a lower risk of relapse. For every six patients treated with combination therapy instead of chemotherapy alone, the authors estimated, one relapse would be prevented.

Patients receiving either treatment experienced similar side effects during the trials. However, “long-term adverse effects such as secondary malignancies…can occur later than the reported observation times of the discussed trials,” explained the authors. This long lag time makes it impossible to determine from the available data if deaths due to late side effects differ between the two groups.

Two ongoing clinical trials are testing whether positron emission tomography (PET) scans can be used to determine if some patients with early-stage Hodgkin lymphoma can safely skip radiation therapy. (Descriptions of those trials can be found here and here.)

Trastuzumabafter Chemotherapy Is Effective in HER2-Positive Breast Cancer

Treatment with trastuzumab (Herceptin) for 1 year following standard chemotherapy improved disease-free survival in women with HER2-positive early breast cancer. The finding comes from the third analysis of the Herceptin Adjuvant (HERA) trial, a large multicenter study that compared outcomes in patients randomly assigned to receive standard chemotherapy followed by trastuzumab with those in patients randomly assigned to receive chemotherapy alone (the observation group). The 4-year follow-up results were reported February 25 in Lancet Oncology.

Dr. Luca Gianni of the San Raffaele Institute in Milan, Italy, and his colleagues randomly assigned 1,703 women to receive 1 year of adjuvant therapy with trastuzumab and 1,698 women to the observation group. (A third group, not included in this analysis, received 2 years of trastuzumab.) After a median follow-up of 4 years, 79 percent of women in the trastuzumab group were disease free, compared with 72 percent in the observation group. Patients in the trastuzumab group had a roughly 24 percent lower risk of disease [than those in the observation group], and the difference between groups was highly statistically significant

Trastuzumab is a monoclonal antibody that targets tumor cells that overproduce a protein called HER2 and interferes with their growth. HER2-positive cancers, which make up about 20 percent of all breast cancers, are more aggressive and women with this form of breast cancer have a higher risk of disease recurrence and death. Trastuzumab extends survival of women with HER2-overexpressing metastatic breast cancer, and the HERA trial is one of several trials that were initiated to determine whether this treatment would benefit patients with early-stage disease as well.

Unlike results from an earlier analysis of the HERA trial, the 4-year follow-up results do not show a statistically significant difference in overall survival between the two groups. “These results are probably heavily influenced by the 52 percent of patients who crossed over from the observation group to the trastuzumab group,” noted Dr. Heikki Joensuu of Helsinki University Central Hospital in an accompanying editorial. Patients in the observation group who were disease free and did not have heart problems (a possible side effect of trastuzumab) were given the option of crossing over to receive trastuzumab because initial results of the HERA trial had shown a clear benefit in terms of reducing recurrence risk with 1 year of trastuzumab.

The latest analysis “provides further assurance” that giving trastuzumab after standard chemotherapy is effective for treatment of early HER2-positive breast cancer and that such treatment “continues to show a generally favorable safety profile with a low rate of congestive heart failure,” Dr. Joensuu wrote. Questions still remain about whether it’s best to give trastuzumab with chemotherapy or after chemotherapy (the risk for heart complications increases when trastuzumab is combined with some chemotherapy drugs), and how long to treat with trastuzumab, he noted. 

DenosumabReduces Risk of Bone Side Effects in Advanced Prostate Cancer

Also in the Journals: Denosumab Also Effective for Multiple Myeloma and Solid Tumors

Results from another randomized phase III trial of denosumab for cancer were published online February 22 in the Journal of Clinical Oncology (JCO). FDA approval of denosumab for the reduction of skeletal-related events (SREs) was based in part on this study as well. The nearly 1,800-patient trial had a design similar to that of the prostate cancer trial and included patients with multiple myeloma and a variety of advanced solid tumors (but specifically excluded patients with prostate and breast cancer). Patients who received denosumab had a reduced risk of SREs compared with patients who received zoledronic acid, although the reduction did not reach statistical significance. In an accompanying commentary in JCO, Dr. Howard West of the Swedish Cancer Institute in Seattle also addressed the economic implications of denosumab treatment, as well as a potential biomarker-driven approach to its use in patients with metastatic cancer.

The biological agent denosumab (Xgeva) is more effective than zoledronic acid at decreasing the risk of bone fractures and other skeletal-related events (SRE) in men with castration-resistant metastatic prostate cancer, according to results from a 1,904-patient phase III randomized clinical trial. The findings, in part, led to the FDA's 2010 approval of denosumab to reduce the risk of SREs in patients with solid tumors. (Denosumab is also approved to treat osteoporosis in postmenopausal women at increased risk of bone fractures and SREs and is sold under the trade name Prolia for that indication). Results from the trial, which was funded by denosumab’s manufacturer, Amgen, were reported online February 25 in The Lancet.

Participants in the trial had never received treatment with bisphosphonates, a class of drugs that includes zoledronic acid, the current standard of care to prevent SREs in men with advanced prostate cancer. SREs were defined as the first incidence of a bone fracture, spinal cord compression, or the use of radiation or surgery to alleviate bone pain. Men who received denosumab had an 18 percent increase in median time before a first SRE compared with men who received zoledronic acid (20.7 months versus 17.1 months), the trial’s lead investigator Dr. Karim Fizazi and colleagues reported. Denosumab treatment was not associated with improvements in either progression-free or overall survival.

The rate and type of side effects were similar in both treatment groups. Break down and death of bone in the jaw (osteonecrosis) was more common in the denosumab group, but the increased risk was not statistically significant.

Zoledronic acid must be delivered intravenously and can have serious side effects, including acute allergic reactions and damage to kidney function, the researchers explained. “These limitations do not apply to denosumab,” they wrote.

The trial results are “yet another milestone in the treatment of men with metastatic, castrate-resistant prostate cancer,” wrote Dr. Jeanny B. Aragon-Ching of George Washington University in a related commentary. But the results, she continued, raise “several issues” about the clinical use and impact of denosumab in cancer treatment. Because denosumab is more expensive than zoledronic acid, for example, Dr. Aragon-Ching posed the question of whether the modest delay in time to first SRE compared with zoledronic acid is “clinically significant enough to justify the choice of denosumab over zoledronic acid…especially in the absence of survival or progression benefit.”

HighRates of Human Papillomavirus Infection Found in Men

A study of the incidence of genital human papillomavirus (HPV) infections in men has found that half of the participants were infected with at least one type of the virus, including types that can cause genital warts and cancer. The incidence of infection was both high and relatively constant across age groups (from 18 to 70 years of age), Dr. Anna Giuliano of the H. Lee Moffitt Cancer Center and Research Institute and her colleagues reported in a study published online February 28 in The Lancet.

Approximately 40 HPV types can be transmitted sexually. Some of these HPV types cause genital warts, and others (so-called high-risk or oncogenic types) can cause cancer. In men, HPV-related cancers include cancers of the penis, oral cavity, oropharynx (a subset of the head and neck that includes the tonsils), and anal canal.

Two vaccines that prevent persistent infections with the two high-risk types of HPV responsible for 70 percent of cervical cancers have been approved by the FDA for use in young women for the prevention of cervical cancer and some vulvar and vaginal cancers. One of these vaccines, Gardasil, also protects against infection with the two HPV types that cause 90 percent of genital warts and has been approved for use in young men and women for prevention of genital warts. And last December, Gardasil was approved for use in young men and women for the prevention of anal cancer. The new findings about the natural history of HPV infections in men provide much-needed information for developing realistic cost-effectiveness models about the use of HPV vaccinations in males internationally, the researchers said.

The cohort study enrolled 1,159 men from Brazil, Mexico, and the United States to investigate the prevalence and clearance of HPV in men. The acquisition of new infections was strongly associated with sexual behavior, as was the likelihood of clearing an infection. The median duration of infection with any HPV type was about 7 months, and for HPV 16, an oncogenic type, it was about 12 months. By the end of the 3-year study period, the majority of men had cleared their HPV infection.

In women, the risk of HPV infection is known to decline with increasing age. But this study found that in men, by contrast, the risk of infection appears to be stable throughout their lives. “If indeed men remain at high risk of acquiring new HPV infections throughout their lives, then vaccination of older men might be warranted,” the researchers said.

Because of strict criteria used for enrollment, the estimates of HPV incidence cannot be generalized to all men in the three countries, the researchers noted. They also cautioned against drawing conclusions about infection rates in other populations based on these results, although they noted that all studies to date have found high acquisition rates of HPV infection in men.

For more see: Human Papillomaviruses and Cancer

Also in the Journals: 2006 Lung Cancer Study Retracted

The authors of a study published in the New England Journal of Medicine—and reported in the August 15, 2006, issue of the NCI Cancer Bulletin—have retracted their research article. Dr. Anil Potti and his colleagues requested a retraction of their article on a genomic model to refine the prognosis of early-stage non-small cell lung cancer because they “tried and failed to reproduce results supporting the validation of the lung metagene model” using data from studies conducted by the American College of Surgeons Oncology Group and the Cancer and Leukemia Group B cooperative groups. A note about the retraction has been added to the NCI Cancer Bulletin article on this study.

Guest Commentary by Drs. Galen Cole, Barbara Powe, and Brad Hesse

Communications
This is the sixth article in a series of stories related to cancer communications. You can read more articles in the series here.

Reenergizing the Agenda for Cancer Communication

Drs. Galen Cole, Barbara Powe, and Brad Hesse Drs. Galen Cole of the CDC, Barbara Powe of the American Cancer Society, and Brad Hesse of NCI.

“All we have to do is mention Egypt,” said a presenter at a recent conference on cancer communication, “and everyone knows that we have reached an inflection point in the communication environment.” What the speaker was describing, of course, was the historic revolution that ousted the 30-year Mubarak regime in Egypt.

Facilitated largely by social media sites such as Facebook and Twitter, these recent political events are being referred to by some as the “Facebook Revolution,” and they illustrate the massively influential ways in which participative media can be used to mobilize social forces. Now, the question for the National Cancer Program is how to take advantage of new communication platforms to make similarly historic progress against the burden of cancer.

To address such issues, the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), and NCI convened a state-of-the-science-and-practice meeting in Atlanta, Georgia, on February 14 and 15. True to its theme, the meeting was opened to the public through a live video feed and invited discussions through Twitter and by e-mail. (View the archived video feed on the meeting Web site.)

Scientific leaders from our organizations participated in the event. The meeting was also attended by leading scholars in cancer communication science and leading practitioners of cancer-related communication activity. Some of these experts participated in a panel and shared their synopses of the most substantial research in this field during the last decade, as well as where the translation of this research into practice could take us in the decade to come.

To be sure, communication science and practice have already produced a strong influence on national cancer control objectives. Public health efforts aimed at reducing addiction to tobacco products and at eliminating exposure to secondhand tobacco smoke have spurred some of the most notable reductions in age-adjusted deaths from cancer observed over the past century.

Similarly, efforts to disseminate early detection techniques through clinical practice and to encourage public acceptance of screening tests through mass media have led to substantial decreases in mortality from cervical, breast, and colorectal cancers. After television celebrity Katie Couric underwent a televised colonoscopy, for example, there was a noticeable bump in the public’s use of colorectal cancer screening tests. Epidemiologists subsequently referred to this phenomenon as the “Katie Couric effect.”

The Internet is enabling a new kind of communication environment in which citizens and governments, and patients and physicians, are becoming engaged in “co-creating” health through participative media. At our meeting, we discussed how this promise of co-created health can be catalyzed by Congressional efforts, including provisions of the Health Information Technology for Economic and Clinical Health Act of 2009.

The promise can also be achieved by using advances in communication science to improve the diffusion of evidence-based practices into clinical and public use. Small advances in communication practice could “bend the curve” and reduce costs and save the lives of people who have been affected by cancer. To help make these advances, we are developing a report that outlines what was discussed at the conference last month, as well as the action plan that our three organizations will follow to establish priorities and coordinate our efforts going forward.

We cannot forget, however, that, even with the phenomenal reach of technology, human touch and face-to-face communication will always play a crucial role in effectively communicating information that ultimately improves people’s health. This is particularly true for those who are still separated by a digital divide.

Dr. Bradford Hesse 
Chief of the Health Communication and Informatics Research Branch
NCI’s Division of Cancer Control and Population Sciences

Dr. Barbara Powe 
Director of Cancer Communication Science
American Cancer Society

Dr. Galen Cole
Associate Director for Communication Science
U.S. Centers for Disease Control and Prevention

Special Report

PSA Velocity Does Not Improve Prostate Cancer Detection

A rapid increase in prostate-specific antigen (PSA) levels is not grounds for automatically recommending a prostate biopsy, according to a study published online February 24 in the Journal of the National Cancer Institute.

The rate of change in PSA levels, referred to as PSA velocity, has been studied as a marker for the presence of prostate cancer. Clinical recommendations from two organizations, the National Comprehensive Cancer Network (NCCN) and the American Urology Association (AUA), suggest that men with a PSA velocity that exceeds a certain threshold (0.35 ng/ml per year) should consider having a needle biopsy, even if their overall PSA levels are below the standard cutoff for the procedure and they have a normal result on a digital rectal examination (DRE).

The findings from this new study indicate that these recommendations should be revised, the authors concluded.

We found no reason to believe that [recommending a needle biopsy for men with a PSA velocity above a certain threshold] would improve patient outcomes; indeed, its use would lead to a large number of unnecessary biopsies.

—Dr. Andrew Vickers and his colleagues

“Overall, PSA velocity did not importantly add predictive accuracy to a standard predictive model or to just PSA alone,” wrote Dr. Andrew Vickers and his colleagues from Memorial Sloan-Kettering Cancer Center (MSKCC). “We found no reason to believe that implementation of the guideline would improve patient outcomes; indeed, its use would lead to a large number of unnecessary biopsies.”

PSA velocity falls under the general umbrella of what is often called PSA kinetics—assessing PSA levels dynamically over time, explained Dr. Howard Parnes of NCI’s Division of Cancer Prevention. In addition to PSA velocity, PSA kinetics also includes measures such as how long it takes for PSA levels to double.

“Intuitively, you would think you could get more useful information by looking at a change in a biomarker over time,” Dr. Parnes said. The study results indicate that this is not the case with PSA velocity. “You can understand why urologists feel that if the PSA is going up, a biopsy should be offered, because they don’t want to miss a cancer,” he added.

To conduct the study, the researchers used data from more than 5,500 men in the placebo arm of the NCI-funded Prostate Cancer Prevention Trial (PCPT). In that clinical trial, men ages 55 or older with a PSA level below 3.0 ng/ml and a normal DRE result at study entry were randomly assigned to receive either the drug finasteride or a placebo.  

In addition to receiving regular PSA tests and a prostate biopsy recommendation for PSA levels of 4.0 ng/ml or higher, the majority of these men also underwent end-of-study biopsies irrespective of PSA levels. As a result, the study authors wrote, “the PCPT provides a perfect test case for PSA velocity” throughout the entire range of PSA values.

Researchers looked at whether a PSA velocity above the 0.35 ng/ml per year threshold—when added to a standard risk model that includes age, PSA level, DRE result, family history of prostate cancer, and history of a prior prostate biopsy—improved the model’s predictive accuracy. The analysis was broken out by different methods for measuring PSA velocity as well as by whether PSA velocity might improve the detection of more aggressive cancers (defined as those with a Gleason score of 7 or higher) and “clinically significant” cancers (defined by the commonly used Epstein criteria). 

In all cases, the addition of PSA velocity yielded only a slight difference in the model’s predictive accuracy. In fact, the analysis indicated that lowering the PSA threshold for a biopsy from 4.0 ng/ml to 2.5 ng/ml would be a more effective means of directing prostate biopsies.

Adding PSA velocity to the model would have identified 115 additional cancers (although not necessarily fatal cancers) but also resulted in 433 “unnecessary biopsies” that would have shown no cancer. Lowering the PSA threshold for biopsy to 2.5 ng/ml would have led to nearly the same number of unnecessary biopsies but identified 24 more cancers.

“The decision to proceed to prostate biopsy should be based not only on an abnormal PSA and/or digital rectal examination results, but should take into account multiple factors,” said Dr. Peter Carroll, chair of the Department of Urology at the University of California School of Medicine, in a statement from the AUA on the study findings. PSA velocity can “on occasion” be one of those factors, he said.

In clinical practice, for men who have previously had a prostate biopsy, an increase in PSA velocity often leads to a repeat biopsy, Dr. Parnes explained. In such situations, he recommended using the risk calculator developed by PCPT investigators using data from the trial. (The risk model used in the JNCI study was based on that tool.) The online calculator estimates the likelihood that a biopsy will detect prostate cancer in general and high-grade prostate cancer in particular.

The study’s findings are helpful, Dr. Parnes said, because it’s clear that PSA velocity is actively being used to guide biopsy decisions. “They allow for discussions between doctors and patients that are based on data,” he continued, “and an understanding that we’re dealing with risk estimates.”

Carmen Phillips

Further reading: Testing a "Smarter" Biopsy for Prostate Cancer.

A Closer Look

The Epithelial-Mesenchymal Transition in Cancer: A Potentially Fatal Transformation?

The question remains one of cancer biology’s most perplexing: How do cancer cells from a primary tumor navigate to other parts of the body to form metastatic tumors?

Most solid tumors arise from epithelial cells, which normally stick together in tightly bound sheets to provide the structural foundations of many organs. In principle, epithelial cells lack the ability to escape those bonds and wiggle and jostle their way into nearby tissues, other organs, or the circulatory system. Yet, somehow cancerous epithelial cells—also known as carcinoma cells—do end up in other areas of the body, and the outcome is often dire: metastatic tumors are responsible for the vast majority of cancer-associated deaths.

Tumor cells from a highly aggressive ovarian cancer cell line before and after researchers introduced microRNA-429 (Images courtesy of Dr. John McDonald, Georgia Institute of Technology) Tumor cells from a highly aggressive ovarian cancer cell line are shown on the left. They have a mesenchymal shape (spindle-like) and express typical mesenchymal markers. On the right, cells from the same cell line reverted to an epithelial shape (rounded) and expressed epithelial cell markers after researchers introduced microRNA-429. (Images courtesy of Dr. John McDonald, Georgia Institute of Technology)

Over the past decade, accumulating evidence has shown that epithelial tumor cells can undergo an important change that transforms them into migratory mesenchymal cells. Some researchers now believe this conversion, known as the epithelial-to-mesenchymal transition, or EMT, can explain how epithelial tumor cells escape their primary residence in the breast, for instance, and travel to the liver, lungs, or bone marrow.

Recently, the role of EMT in cancer has come under even greater scrutiny because of evidence linking the process to the formation of so-called cancer stem cells, explained Dr. Suresh Mohla, associate director of NCI’s Division of Cancer Biology and program director of DCB’s Tumor Microenvironment Network (TMEN) program. Cancer stem cells, he noted, have been strongly associated with resistance to treatment and disease recurrence.

Although the evidence to support a role for EMT in cancer comes mostly from cell-line and animal-model studies, the evidence so far has been consistent with what’s been observed in human cancers, argued Dr. Jean-Paul Thiery, of the A*STAR Institute of Cellular and Molecular Biology in Singapore. A better understanding of EMT, he believes, could lead to an “improved rationale for effectively treating cancer.”

Gathering the Evidence

EMT is best known for its role in embryonic development, a time when epithelial cells readily bounce back and forth between epithelial and mesenchymal states as part of organ development. After the completion of embryogenesis, it was widely assumed that there was little biological use for EMT; that it was switched off and put to rest, perhaps permanently. At most, it appeared, EMT might be reactivated briefly during wound healing.

Over the last decade, however, researchers have found evidence that cancer cells reactivate EMT in an effort to escape their normal confines. For a carcinoma cell to escape and eventually form a micrometastasis in a distant tissue EMT may even be essential, explained Dr. Robert Weinberg, of the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology, who is a TMEN investigator.

“If a carcinoma cell were still fully epithelial, to my mind it would be incapable of executing a number of the steps required for its physical dissemination from the primary tumor to a distant tissue site,” Dr. Weinberg said.

Cells that have undergone some degree of EMT are typically identified by the excess presence of certain molecules, such as vimentin and fibronectin, that promote a flexible structure and the ability to move, as well as by their shape, which is more spindle- and amoeboid-like than the typically rounded epithelial cell. Studies have also linked the activation of EMT to an overabundance of certain proteins and microRNAs. In some human tumors, an excess of these same proteins and microRNAs has been associated with more aggressive, metastatic disease.

Additional evidence of EMT-induced tumor cell migration in cancer has come from NCI-supported studies of mice in which an “imaging window” has been implanted in the skin above mammary tumors. In these studies, individual cells can be tracked over time with the use of light-sensitive proteins.

Digging Deeper into the Tumor Microenvironment

NCI is funding many research projects focused on learning more about the role of the epithelial-to-mesenchymal transition in cancer and, more generally, how the tumor microenvironment contributes to cancer initiation, progression, and metastasis.

A key component of this effort is NCI’s Tumor Microenvironment Network (TMEN) program. Launched in 2006, TMEN is composed of 10 research programs that are collectively working to better delineate the biological mechanisms that govern the interactions between a tumor and its microenvironment. Much of this work is focused on specific tumor sites, using human cancer tissues and models.

Fostering collaboration is a critical aspect of the TMEN program, explained Dr. Suresh Mohla, program director of TMEN. Research teams supported by the program are identifying and developing tools and resources, such as critical reagents and new cancer models, for use by the research community. Seven working groups help to facilitate the efforts of the 10 TMEN-funded programs.

One NCI-supported study found that cancer cells only traveled in certain areas of the tumor, depending on the makeup of the surrounding microenvironment, including the presence of blood vessels and tumor-infiltrating cells such as macrophages. The migrating tumor cells lacked the traditional symmetrical structure and shape of epithelial cells and thus appeared to have undergone EMT, said Dr. John Condeelis, also a TMEN-supported investigator whose lab at the Albert Einstein College of Medicine developed the mouse model.

The microenvironment surrounding cancer cells within a tissue is a critical component in the EMT, Dr. Condeelis explained. Signals from the microenvironment, in some cases caused by inflammation or perhaps in response to oxygen depletion in the tumor itself, may trigger the process of EMT and tumor cell migration. High-resolution imaging of this type, he continued, makes it easy “to believe in microenvironment-dependent tumor cell dissemination, because that’s what we see.”

Evidence of EMT and cell migration in human tumors has, however, been tough to come by. Studies suggest that mesenchymal tumor cells are not common and that they probably form only “at the [tumor’s] leading edge,” where the tumor interacts with its microenvironment, said Dr. Mohla. “Unless you are specifically looking for them, you’re probably not going to find them.”

Dr. Thiery pointed out that tumor cells that have undergone a complete EMT are hard to differentiate from other mesenchymal cells, such as fibroblasts, which are critical components of normal connective tissue. And Drs. Weinberg and Thiery both stressed that cancer cells may be in a mesenchymal state for only a short time before they revert to an epithelial state.

But some human evidence is beginning to emerge. In colorectal tumor samples, histopathology studies have identified “tumor budding,” small bunches of loosely grouped cancer cells at a tumor’s invading front. And recently published data from The Cancer Genome Atlas (TCGA) identified four distinct subtypes of glioblastoma, including a “mesenchymal type” that is highly aggressive and expresses markers indicative of EMT. In unpublished work, Dr. Thiery’s lab, using ovarian cancer samples acquired via TCGA, found that 45 percent of the tumors they analyzed had cells that expressed classic EMT markers.

A Transition to Treatment

Although there remain many unknowns about EMT’s significance in cancer, the phenomenon is already being used to guide new treatment approaches. OSI Pharmaceuticals, for example, is pursuing treatment approaches that are driven by EMT markers, explained Dr. David Epstein, the company’s chief scientific officer.

Retrospective analyses from two clinical trials involving the targeted therapy erlotinib (Tarceva) in patients with advanced non-small cell lung cancer (NSCLC) showed that responders had increased expression of the classic epithelial cell marker, E-cadherin. However, patients with low E-cadherin expression appeared to be less responsive to the drug. Further studies in cell lines, Dr. Epstein said, have indicated that mesenchymal-like NSCLC cells lose their reliance on erlotinib’s molecular target, the epidermal growth factor receptor.

“When we…think about EMT, we think about the rewiring that occurs as a function of that transition,” Dr. Epstein said. “That’s what’s kept us looking at the pharmacology, how we can use this to better design combination therapies and better delineate response markers in the clinical setting.”

Dr. Thiery believes EMT can also be exploited by forcing tumor cells that have become mesenchymal to revert to a more epithelial-like state. The approach ties back to the findings of NCI-supported work by Dr. Weinberg and others, primarily in breast cancer. Cells they have identified as cancer stem cells—cancer cells that on their own can produce other tumor cells that then further differentiate and form tumors—often express mesenchymal-like markers.

In the tumor types in which they’ve been identified, cancer stem cells have demonstrated resistance to current therapies and are associated with disease recurrence. Thus, forcing these cells to return to an epithelial-like state could potentially make them more responsive to existing therapies.

In January, researchers from the Georgia Institute of Technology reported some success along these lines. They found that introducing a specific microRNA into a highly metastatic ovarian cancer cell line changed the appearance of these mesenchymal-like cancer cells, making them more rounded and epithelial-like, a transformation that was accompanied by decreased levels of mesenchymal markers and an increase in E-cadherin levels.

There is still a tremendous amount of research to do around EMT, Dr. Condeelis acknowledged. “The next step is to better understand the context of EMT in normal embryonic development and why these processes are repeated in tumors,” he said. “We’re still missing much of the story.”

Carmen Phillips

Featured Clinical Trial

Optimizing Adjuvant Therapy for Resected Pancreatic Cancer

Name of the Trial
Phase III Randomized Study of Adjuvant Gemcitabine Hydrochloride with Versus without Erlotinib Hydrochloride Followed by the Same Chemotherapy Regimen with Versus without Chemoradiotherapy with Either Capecitabine or Fluorouracil in Patients with Resected Head of Pancreas Adenocarcinoma (RTOG-0848). See the protocol summary.

Dr. Ross Abrams Dr. Ross Abrams

Principal Investigator
Dr. Ross Abrams, Radiation Therapy Oncology Group

Why This Trial Is Important
Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States. It develops in the lining of ducts in the pancreas that deliver digestive juices to the small intestine through the main pancreatic duct. The majority of pancreatic adenocarcinomas occur in the head of the pancreas, the part of the organ that is closest to the small intestine.

The only potentially curative treatment for pancreatic adenocarcinoma is a complex surgical procedure called the Whipple procedure. However, most patients are not eligible for this treatment because the cancer has spread beyond the pancreas by the time it is diagnosed. Furthermore, about 80 percent of those who have the Whipple procedure relapse and die within 5 years due to the presence of microscopic deposits of tumor cells that remain behind after surgery. Consequently, doctors often use adjuvant therapies to try to destroy the remaining cancer cells.

Chemoradiotherapy that includes a radiosensitizing agent, such as 5-fluorouracil (5-FU), is often used as adjuvant treatment for surgically resected pancreatic cancer. More recently, adjuvant chemotherapy with the drug gemcitabine has been shown to delay recurrence and modestly improve survival. Doctors are now investigating whether combining these adjuvant therapies can further increase survival after surgery. Additionally, they want to know if adding a second drug to gemcitabine will improve survival compared with gemcitabine alone. In patients with advanced, inoperable pancreatic cancer, the drug erlotinib has shown the ability to prolong survival when combined with gemcitabine. Therefore, doctors are hopeful it will also help patients who have had surgery.

In this clinical trial, patients with resected adenocarcinoma of the head of the pancreas will be randomly assigned to receive either gemcitabine for 5 treatment cycles or gemcitabine and erlotinib for 5 cycles. Patients who do not experience disease progression (recurrence or growth of residual tumor tissue) will then be randomly assigned to undergo an additional cycle of the same chemotherapy regimen with or without subsequent chemoradiation using either intravenous 5-FU or a similar oral drug called capecitabine. Doctors will follow the patients’ survival, compare the toxicity of these treatments, and try to determine whether certain biological characteristics of the patients are associated with outcomes.

“This trial is basically asking two questions,” said Dr. Abrams. “The first question is, do patients treated with gemcitabine and erlotinib do better than those treated with gemcitabine alone? The second question is, for those patients who finish chemotherapy without evidence of recurrence or progression, does the addition of radiation to the area where the tumor was removed, along with 5-FU or capecitabine, accomplish something above and beyond the chemotherapy?”

For More Information

See the lists of entry criteria and trial contact information or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/ft-all-featured-trials.

Community Update

Radically Reducing Radiation Exposure during Routine Medical Imaging

Since the 1980s, the average annual per capita exposure to radiation from medical imaging in the United States has increased almost sixfold. Although debate continues over the health risks from this exposure, doctors and researchers want to limit exposure while maintaining the many benefits of modern medical imaging.

A colorized CT scan of the heart using only 0.7 mSv of radiation (Image courtesy of Drs. Marcus Chen and Andrew Arai of the National Heart, Lung, and Blood Institute) A colorized CT scan of the heart using only 0.7 mSv of radiation. The image is of high enough quality to be used for diagnostic purposes. (Image courtesy of Drs. Marcus Chen and Andrew Arai of the National Heart, Lung, and Blood Institute)

On February 24 and 25, the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute, NCI, and the Coalition for Imaging & Bioengineering Research sponsored a meeting to promote this effort: “The Summit on Management of Radiation Dose in Computerized Tomography: Toward the Sub-mSv Exam.” (A millisievert, abbreviated mSv, is a measurement that scientists use to estimate the overall health risk of exposure to a dose of ionizing radiation.)

Among medical imaging technologies that use radiation, the use of computed tomography (CT) has increased the most over the past few decades. The challenge, said Dr. James Thrall, president of the American College of Radiology, is to reduce the mean dose of 95 percent of CT scans from the current level of about 7 mSv to less than 1 mSv.

“Up to this point, our efforts have been focused on achieving dose savings in small, incremental amounts,” said Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health. “[This] summit is radically different; setting an ambitious goal to reduce radiation from CT imaging to less than 1 mSv; seeking to reduce dose by an order of magnitude…as opposed to by just a few percentage points.

“We fully expect that this goal will only be achieved through a revolutionary change in how we approach every aspect of CT imaging,” Dr. Shuren continued.

Two areas of diagnostic medicine already have shown the feasibility of the sub-mSv CT exam. Presenters at the meeting shared lessons learned from cardiac CT and pediatric CT. For example, radiologists performing cardiac CTs in some hospitals have decreased exposure time in the CT scanner, lowered the X-ray tube current required for a scan, and made better use of other companion diagnostic procedures that don’t require radiation, thereby reducing the average radiation dose below 1 mSv. (See the images in this article.)

In pediatrics, the international Image Gently campaign has successfully raised awareness that much smaller doses of radiation can accurately capture pictures of children’s smaller bodies. The theme of the “right-sized dose” ran throughout the summit. “Patients aren’t all standard [sized],” said Dr. Cynthia McCollough of the Mayo Clinic. Any program of CT dose reduction will need to take into account the different doses required to image patients of different sizes, from newborns to morbidly obese adults, she explained.

Radiologists and technologists have an opportunity to reduce radiation doses rapidly by confining scans to the areas doctors intend to image, according to Dr. Leslie Quint, of the University of Michigan Health System. In several studies of thoracic imaging reviewed by Dr. Quint and her colleagues, they found that 21 to 57 percent of the total radiation dose from CT scans was due to imaging extra tissue at the beginning or end of the scan. And in a review they performed of general CT scanning at their institution, they found a mean 10 percent excess dose from imaging unnecessary tissue.

Part of this over-imaging may be due to a lack of appropriate training for the people who operate the scanners, who may not understand the science behind the instructions entered into a CT scanner for individual patients, several participants suggested. Better training is vital, summit participants agreed, since the choices made in real time by technologists can impact the final radiation dose from any given scan.

A CT scan of a coronary artery using only 0.7 mSv of radiation (Image courtesy of Drs. Marcus Chen and Andrew Arai of the National Heart, Lung, and Blood Institute) A CT scan of a coronary artery taken to look for blockages in blood flow. Only 0.7 mSv of radiation was used to capture the scan. (Image courtesy of Drs. Marcus Chen and Andrew Arai of the National Heart, Lung, and Blood Institute)

Participants also discussed the need for new, high-tech dose-reduction strategies for both CT hardware and software. Many innovations could be made in hardware components of modern CT scanners, including the x-ray sources and the devices that shape the radiation beams, to reduce dose, asserted Dr. Willi Kalender from the Institute of Medical Physics at the Friedrich-Alexander University, Erlangen-Nuremberg, Germany.

The development of computer-based decision support systems for all points of the scanning process would also help reduce doses, for example by preventing doctors from ordering duplicate scans and ensuring optimum protocol selection on the machines. In addition, sophisticated simulators could let radiologists experiment with noise and contrast to assess new potential protocol variations before trying them on patients. And innovations in methods used to assemble images from the data collected by the scan (image reconstruction) could reduce doses even further while maintaining imaging quality.

The field would also greatly benefit from evidence-based clinical guidelines on CT use, which so far have been lacking, said Dr. Hedvig Hricak of Memorial Sloan-Kettering Cancer Center.

The second day of the conference concluded with the generation of priorities for agencies, including NIH, that could supply future grant funding in this area of research. Recommendations from three working groups convened during the conference are being prepared for publication. These recommendations will focus on “how to leverage this wealth of information, how to harvest these ideas, and how to translate them to practical benefits and improvements for the health care enterprise and for the nation,” concluded NIBIB Director Dr. Roderic Pettigrew.

Sharon Reynolds

An archived video of the meeting is available online.

Legislative Update

Early Actions by the 112th Congress

A prolonged struggle to set government spending levels has highlighted ideological and pragmatic differences within the 112th Congress. The new Congress inherited a budget impasse from the last Congress, which was unable to pass legislation to allocate funds for government operations for the full 2011 fiscal year (FY). Instead, before adjourning, the 111th Congress enacted a series of continuing resolutions to maintain most government agencies, including NIH, at FY 2010 appropriations levels. The last of these stopgap funding measures, Public Law 111-322, which was passed on December 21, provided funds through March 4 and ceded appropriations responsibility for the remainder of FY 2011 to the 112th Congress.

The new Congress, with a narrowed Democratic majority in the Senate and a new Republican majority in the House, is divided on budget management strategies and the role of government in American life. In line with Republican priorities, the House introduced a long-term continuing resolution (HR 1) to fund the government through the remaining 7 months of the fiscal year. Floor debate began on February 15 with an unusual open rule that allowed members to offer amendments within specified limits. After sorting through hundreds of amendments, voting on 153, and adopting 67, the House voted mostly along party lines to pass HR 1 in the early hours of February 19. The bill contains more than $60 billion in cuts from FY 2010 spending levels, including a $1.6 billion reduction for NIH, and includes several provisions that block funding associated with the implementation of health care reform.

Senate Democrats have joined their colleagues in the House in opposing the deep spending cuts described in HR 1, and President Obama has also expressed opposition to the bill. On March 4 Senate appropriators proposed an alternative version of the bill that features approximately $6.5 billion in cuts. The Senate version would freeze funding for many government agencies, including NIH, at 2010 levels.

Both the House and Senate versions of the year-long continuing resolution could significantly constrain NIH’s ability to support new research. The proposed reductions in the House version span all NIH Institutes and Centers, and are based on projected total funding and projected funding for non-competing research project grants. At the same time, the bill would require NIH to fund a minimum of 9,000 new competing research project grants and would place a $400,000 cap on the average annual cost for competing research project grants. 

The Senate version maintains funding at FY 2010 levels and does not impose requirements about numbers of grants or funding levels. However, the rising costs of biomedical research and commitments to research projects already underway could reduce the level of support available for new grantees in FY 2011, although less dramatically than the House version would.

Senate Majority Leader Harry Reid (D-NV) announced his intention to hold test votes on both versions of the continuing resolution this week. Neither version is expected to pass; the maneuver is designed to demonstrate the necessity for bipartisan compromise.

Lawmakers now have less than 2 weeks to find some common ground and reach an agreement about FY 2011 appropriations. The Congress imposed a new deadline by quickly passing a 2-week continuing resolution just as the last one was set to expire. This latest stopgap measure (H J Res 44; PL 112–4), which was signed by President Obama on March 2, contained $4 billion in spending cuts palatable to both parties. Many government agencies, including NIH, will continue operating at FY 2010 levels until this continuing resolution expires on March 18 or until an agreement for either a long-term solution or another stopgap reprieve can be reached.

Stacye Bruckbauer

Notes

President Appoints New Members to the National Cancer Advisory Board

On February 24, President Barack Obama announced the appointment of five new members to the National Cancer Advisory Board (NCAB). The new appointees are: 

  • Dr. Marcia Cruz-Correa, associate professor of medicine and biochemistry at the University of Puerto Rico, visiting associate professor of medicine at the Johns Hopkins University, and adjunct associate professor of surgical oncology at the University of Texas M. D. Anderson Cancer Center

  • Dr. Kevin J. Cullen, director of the Marlene and Stewart Greenebaum Cancer Center at the University of Maryland, which became an NCI-designated Cancer Center in 2008 under his leadership

  • Dr. Jonathan M. Samet, professor and Flora L. Thornton Chair of the Department of Preventive Medicine at the Keck School of Medicine of the University of Southern California (USC) and director of the USC Institute for Global Health

  • Dr. Bill Sellers, vice president and global head of oncology for the Novartis Institutes of BioMedical Research, where he oversees small molecule- and antibody-based drug discovery efforts in oncology

  • Dr. Olufunmilayo Falusi Olopade, Walter L. Palmer Distinguished Service Professor of medicine and human genetics, associate dean for global health, and director of the Center for Clinical Cancer Genetics at the University of Chicago

The NCAB is an advisory board, mandated as part of the Public Health Service Act, that advises the secretary of the U.S. Department of Health and Human Services and the NCI director on the Institute’s activities, including reviewing and recommending cooperative agreements following technical and scientific peer review.

In his announcement, President Obama stated, “These dedicated individuals bring a wealth of experience and talent to their new roles, and I am proud to have them serve in this Administration. I look forward to working with them in the months and years to come.”

Greenwald Named NCI Associate Director for Prevention

Dr. Peter Greenwald Dr. Peter Greenwald

NCI Director Dr. Harold Varmus selected Dr. Peter Greenwald to serve as NCI’s associate director for prevention beginning February 27. Dr. Greenwald will advise the director and other NCI leaders, guide NCI-wide cancer prevention research programs, set research policy and strategic goals, further cancer prevention research training programs, expand NCI collaborations, and serve as an NCI spokesperson and representative on prevention for the NCI director.

Dr. Greenwald joined NCI in 1981 as director of NCI’s Division of Cancer Prevention and Control, where he notably provided leadership against the use of tobacco, and played a role in creating the 5 A Day nutrition education program and the Community Clinical Oncology Program. After a restructuring of the Institute in 1997, he continued as director of the Division of Cancer Prevention (DCP). Under his leadership, NCI conducted research in nutritional science, basic and preclinical prevention studies through first-in-human to phase III clinical trials, biomarker discovery and validation, biometry, and systems approaches to cancer prevention.

Dr. Greenwald received his medical degree from the State University of New York College of Medicine in Syracuse and his master’s degree and doctorate in public health from the Harvard School of Public Health. He is board certified in both internal medicine and preventive medicine. Dr. Greenwald rose to the rank of a two-star rear admiral and assistant surgeon general in the U.S. Public Health Service Commissioned Corps. He retired from the corps to take his new position at NCI.

Dr. Lori Minasian will serve as the acting director of DCP until a permanent division director has been selected.

NCI Launches Interactive Cancer Control Community of Practice

screenshot of Research to Reality Web site

NCI has launched a free online community of practice linking cancer control practitioners and researchers. The Web site, Research to Reality (R2R): Collaborating for Cancer Control, is designed to extend the work of Cancer Control P.L.A.N.E.T. and facilitate partnerships by engaging individuals and connecting organizations involved in cancer control. Those who are interested can visit the Web site to gather evidence-based information and discuss emerging issues related to the research and practice of cancer control dissemination and implementation.

Research to Reality has several interactive features, including discussion forums, community profiles, an events calendar, and monthly cyber-seminars that provide information about identifying and adapting evidence-based cancer control programs.

The next cyber-seminar, on March 21 from 11:15 a.m. to 12:45 p.m., is a special videocast of the Dissemination and Implementation (D&I) Science Conference panel on international perspectives of D&I. Future plans include a mentorship program that will help a select cohort of public health practitioners build their capacity to identify and implement evidence-based cancer control and prevention interventions, with much of the information to be shared through the online community.