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March 22, 2011 • Volume 8 / Number 6

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NEWS

Fertility Still Possible for Many Male Cancer Survivors, Study Finds


A child sitting on his father's shouldersMany male survivors of childhood cancer have long been thought to be sterile and, therefore, incapable of conceiving a child. But a new study suggests that conception and fatherhood may be possible for a substantial number of these men, through the use of a surgical procedure to retrieve healthy sperm combined with a form of in vitro fertilization. 

In the retrospective study, researchers from New York-Presbyterian Hospital/Weill Cornell Medical Center showed that nearly 2 decades after cancer treatment, healthy sperm could be retrieved from the testicles of more than one-third of male cancer survivors who had a condition in which no viable sperm was detectable in their semen. Read more > >


COMMENTARY

Devastation and Hope: An NCI Scientist's First-Hand Account of Japan's Resilience

by Dr. James L. Gulley

As the horrifying events and aftermath of the Japanese earthquake and tsunami continue to unfold on our television and computer screens, it’s difficult to imagine how any nation could recover from such calamities. But, based on what I personally witnessed, I have great hope for Japan’s future. Read more > >

Dr. James L. Gulley

  

A MESSAGE TO READERS

Coverage of AACR Annual Meeting

Tile of NCI at AACR 2011The American Association for Cancer Research 102nd Annual Meeting will take place April 2–6 in Orlando, FL. Click on the tile to learn more about NCI-sponsored sessions and activities at the NCI exhibit booth. Look for highlights from the meeting in the April 5 issue of the NCI Cancer Bulletin.

IN DEPTH

UPDATES

  • FDA Update

    • Menthol Cigarettes Adversely Affect Public Health, FDA Advisory Committee Finds
  • Notes

    • National Cancer Clinical Trials Cooperative Groups Announce Mergers
    • Research Symposium on Radiation and Cancer Honors Dr. Elaine Ron
    • Funding to Support Collaborations between U.S. and Chinese Scientists

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

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

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

Featured Article

Fertility Still Possible for Many Male Cancer Survivors, Study Finds

A child sitting on his father’s shoulders A retrospective study has shown that healthy sperm could be retrieved from male cancer survivors who had no viable sperm in their semen 2 decades after being treated for cancer.

Many male survivors of childhood cancer have long been thought to be sterile and, therefore, incapable of conceiving a child. But a new study suggests that conception and fatherhood may be possible for a substantial number of these men, through the use of a surgical procedure to retrieve healthy sperm combined with a form of in vitro fertilization (IVF).

In the retrospective study, researchers from New York-Presbyterian Hospital/Weill Cornell Medical Center showed that nearly 2 decades after cancer treatment, healthy sperm could be retrieved from the testicles of more than one-third of male cancer survivors who had a condition in which no viable sperm was detectable in their semen. Following sperm retrieval, IVF procedures led to a 50 percent pregnancy rate and a slightly lower overall rate of child birth.

The findings were published online March 14 in the Journal of Clinical Oncology.

Use of the sperm-retrieval procedure, called microdissection testicular sperm extraction, or microTESE, in cancer survivors has been limited, explained study leader Dr. Peter Schlegel, chair of the Department of Urology at NY-Presbyterian/Weill Cornell, who developed microTESE and performed all of the procedures in the study. “Having this sort of information about our experience, and more details about who tends to do well, will be very important for expanding the potential utilization of [microTESE],” he said.

A very low sperm count is a common, long-term side effect in men who received chemotherapy in childhood or adolescence. In this study, the NY-Presbyterian/Weill Cornell researchers analyzed 73 male cancer survivors with this condition, known as azoospermia, who had undergone microTESE procedures between 1995 and 2009. On average, the procedures were performed nearly 19 years after cancer treatment.

Healthy sperm was retrieved from 37 percent of the men and in approximately 43 percent of individual procedures, since some men underwent microTESE more than once. Using a process called intracytoplasmic sperm injection (ICSI), single sperm were then used to fertilize an egg, with an overall fertilization rate of 57 percent. Thirty-six embryo implantation procedures were performed, half of which resulted in a pregnancy. Overall, 20 children were ultimately delivered, including 5 sets of twins.

The availability of healthy sperm appeared to be associated with the type of chemotherapy received, Dr. Schlegel noted. Men treated with platinum-based chemotherapy agents had the highest retrieval rates. For example, men treated for testicular cancer, for which the platinum-based chemotherapy drug cisplatin is a standard treatment, had an 85 percent retrieval rate. Men treated with alkylating agents, which are commonly used to treat lymphomas and sarcomas, had the lowest retrieval rates.

“MicroTESE and ICSI revolutionized the treatment of men with azoospermia from testis failure, such as those who have had chemotherapy,” said Dr. Craig Niederberger, head of the Department of Urology at the University of Illinois at Chicago Medical Center. Before the availability of microTESE “you would just do a testis biopsy, and if you found no sperm, it was game over,” he said.

With microTESE, the surgeon uses optical magnification to examine the testis more closely and identify seminiferous tubules, hollow tube-like structures that transport semen, that are dilated and thus likely to contain sperm. Studies Dr. Schlegel has conducted indicate that, compared with other standard methods, microTESE not only increases the success rate of sperm capture, but also the quantity of sperm obtained and with less damage to the testicle.

The study’s findings “should not be interpreted by medical oncologists as ‘We don’t need to offer sperm cryopreservation prior to beginning chemotherapy,’” Dr. Niederberger stressed. “Already there is a lot of pressure to not do it because they want to get cancer therapy started as soon as possible.” But cryopreservation is still the best way to give adolescents and young men with cancer the potential to have their own children in the future, he said.

At the time they were treated for their cancer, most of the patients in the current study were old enough for sperm collection, noted Dr. Robert Brannigan, an associate professor of urology at the Northwestern University Feinberg School of Medicine. Fertility preservation is often still absent from many discussions between patients and their oncologists, he continued, including pediatric oncologists who typically treat adolescent patients.

A recent nationwide survey of pediatric oncologists, for example, found that many pediatric oncologists don’t routinely refer adolescent patients to fertility specialists.

For many oncologists “there can be discomfort in speaking specifically about reproductive health issues, particularly with adolescent patients,” Dr. Brannigan continued. Timing, cost, and insurance coverage can also be barriers to fertility preservation, he added.

“Even in the best hands and with this excellent technique, only a minority of patients with azoospermia after chemotherapy have sperm found and extracted,” Dr. Brannigan said.

“These are very difficult cases, and Dr. Schlegel’s success rates are outstanding,” he continued. “But this study underscores that many of these patients may not have needed to undergo this procedure in the first place if they had had [fertility preservation] counseling before starting treatment for their cancer.”

Carmen Phillips

For more on this subject, read: Preserving Fertility While Battling Cancer

Cancer Research Highlights

U.S. Cancer Survivors Increase to Nearly 12 Million

The number of U.S. cancer survivors increased from 9.8 million in 2001 to 11.7 million in 2007, according to an analysis of new cancer cases and follow-up data from NCI’s Surveillance, Epidemiology, and End Results (SEER) program. The findings appeared in the March 11 Morbidity and Mortality Weekly Report.

According to the report, breast, prostate, and colorectal cancers were the most common types of cancer among survivors, accounting for 51 percent of diagnoses. Among all cancer survivors, 54.3 percent were female, 45.7 percent were male, nearly 7 million were 65 years of age or older, and 4.7 million received their diagnosis 10 or more years earlier.

The number of survivors has risen markedly since 1971, when an estimated 3 million people were living with cancer. The increase seen over the past 4 decades is attributable to a variety of factors, including an aging U.S. population, earlier detection, and more sophisticated treatments that allow individuals to live longer following initial diagnosis.

Because of the considerable growth in the number of cancer survivors, health care and public health professionals should become familiar with their unique medical and psychosocial issues, stressed Dr. Arica White of the CDC’s Division of Cancer Prevention and Control in a news release announcing the findings.

“For many cancer survivors and those around them, the effect of cancer does not end with the last treatment,” said Dr. Julia H. Rowland, director of NCI’s Office of Cancer Survivorship. “Research has allowed us to better understand some of the long-term health risks and quality of life concerns among this population.”

The analysis by NCI and CDC scientists underscores the need for continued research and coordinated efforts to develop and implement best practices for ensuring optimal post-treatment care and support for all cancer survivors, she explained.

ThyroidCancer Risk Persists in People Exposed to I-131 Radiation as Children

People who were exposed to radioactive iodine (I-131) as children or adolescents after the 1986 Chernobyl nuclear disaster have a long-term increased risk of developing radiation-related thyroid cancer. In a study of more than 12,000 people in three Ukrainian states near the Chernobyl site, researchers found that the risk of radiation-related thyroid cancer doubled for every gray (Gy) of exposure to the thyroid. (A gray is an international measurement used for radiation dose.) This risk did not decrease over 9 years of follow-up during the study.

The findings were published March 14 in Environmental Health Perspectives.

Researchers led by Dr. Alina Brenner of NCI’s Division of Cancer Epidemiology and Genetics, in collaboration with Ukrainian scientists, prospectively studied 12,514 people who were younger than 18 years of age at the time of the accident and were exposed to a wide range of I-131 doses. All participants had direct measurements of thyroid radioactivity taken within 2 months of the accident. Additional data on I-131 exposure included information on diet (the greatest source of exposure was from consumption of contaminated milk) and lifestyle around the time of the accident.

Between the start of the study in 1998 and 2007, all participants underwent screening examinations every 2 years, regardless of their dose. Individuals diagnosed with thyroid cancer during the first examination were excluded from this analysis.

Sixty-five cases of thyroid cancer were discovered during follow-up. Radiation-related risk of thyroid cancer increased with increasing I-131 dose and was greatest for those individuals who were younger at the time of exposure. Risk appeared similar for men and women.

“Our results suggest that thyroid cancers attributable to I-131 exposure continue to occur two decades after exposure,” concluded the authors. In addition, they wrote, the risk per Gy of exposure does not appear to diminish with time, at least not in the amount of time that this cohort has been followed. Since radiation-related cancer risks are known to persist for many decades, the participants will need to be followed for a longer period of time to determine if an eventual decline in risk occurs.

IncidenceRate of Second Cancer in the Opposite Breast Has Declined in U.S.

Among women who survive breast cancer, the most frequent new cancer occurs in the opposite, or contralateral, breast. Since 1985, a new study reports, the incidence rate of contralateral breast cancer has declined steadily—at a pace of more than 3 percent per year. Although the causes of this trend are not known, the decline occurred as drugs such as tamoxifen were coming into widespread use to help prevent a recurrence of the disease, researchers reported online in the Journal of Clinical Oncology on March 14.

To assess the incidence rate of contralateral breast cancer over time, Dr. Amy Berrington de González of NCI’s Division of Cancer Epidemiology and Genetics (DCEG) and her colleagues analyzed statistics from the SEER database for the years 1975 to 2006.

The downward trend they observed was driven by declining rates of contralateral breast cancer among women whose first breast cancer tested positive for the estrogen receptor (ER). No clear decrease was seen among women with ER-negative tumors. Although the details of hormone treatments were not available in SEER, the annual declines of more than 3 percent after ER-positive first cancers “suggest an important role for the widespread usage of adjuvant therapies, especially hormone treatments,” the study authors noted.

“We know from randomized trials that drugs like tamoxifen significantly reduce the risk of a contralateral breast cancer, by about 40 percent,” said Dr. Berrington de González. The combination of the trial results, the timing of the decline, and the restriction to cancers following ER-positive first breast cancers all point to adjuvant hormonal therapy as a key factor in the decline, she added. 

Tamoxifen was widely adopted in the United States after the results of the Nolvadex Adjuvant Trial were published in 1983. In addition to adjuvant hormone therapies, other factors such as the increased use of chemotherapy may also have contributed to the decline, the study noted. “Newer hormonal therapies like aromatase inhibitors may be even more effective than tamoxifen at reducing contralateral breast cancer rates, and so we would hope to see further reductions in the future,” said Dr. Berrington de González.

Although the decline represents “a notable success,” the study authors cautioned that overall rates of contralateral breast cancer remain high, especially among women whose first breast cancer is ER-negative. “We still need new strategies for reducing risks after an ER-negative cancer, because rates can be as high as 1 percent per year for these women,” said Dr. Berrington de González.

EribulinImproves Survival of Women with Metastatic Breast Cancer

Treatment with eribulin (Halaven) improved overall survival in women with metastatic breast cancer whose disease progressed despite multiple rounds of prior chemotherapy, according to the results of a phase III clinical trial called EMBRACE. Based on these findings, the FDA approved eribulin last November for women with metastatic disease who have already undergone at least two previous chemotherapy regimens.

The study results were published online March 2 in The Lancet.

The improvement in overall survival makes the findings “clinically meaningful,” wrote the study’s lead author, Dr. Javier Cortes of the Vall d'Hebron Institute of Oncology in Barcelona, Spain, and his colleagues. “To our knowledge, EMBRACE is the first major single-agent study of a cytotoxic or biological agent to show significantly increased survival in patients with such heavily pretreated metastatic breast cancer.”

Eribulin is a laboratory-made form of halichondrin B, a substance derived from a sea sponge. Similar to some other chemotherapy drugs, it targets the protein tubulin in cells, although it binds to tubulin in a different way, interfering with cancer cell division and growth.

In the trial—funded by Eisai Co., Ltd., which manufactures eribulin—762 patients were randomly assigned to receive either eribulin or the treating physicians’ choice of therapy. Prior to enrolling, trial participants had received, on average, four previous chemotherapy regimens. Because there is no standard of care for women with progressive metastatic breast cancer, the treatments eribulin was compared with “[reflect] real-life choices made by oncologists and their patients,” the researchers wrote.

Women who received eribulin, on average, lived 2.5 months longer than those treated with their physician’s choice (13.1 months versus 10.6 months). Progression-free survival was similar between the groups. Overall, serious side effects were roughly equal in women in both trial arms, although women treated with eribulin had more serious cases of neutropenia, leukopenia, and peripheral neuropathy.

“EMBRACE provides much needed, high-level evidence for chemotherapy use in patients with heavily pretreated breast cancer,” wrote Drs. Nancy Lin and Harold Burstein, of Dana-Farber Cancer Institute, in an accompanying editorial. But a number of important questions remain about the use of eribulin in this group of patients, they noted, including whether there is a subgroup that is more likely to respond to the drug.

“The clinical gains from EMBRACE are sufficiently narrow,” the study authors continued, “that a better understanding of the relation between treatment, symptom control, and quality of life in study participants remains crucial.”

ExperimentalStrategy May Overcome Resistance to Breast Cancer Drug

Researchers have identified a protein that may play a critical role in preventing some tumors from responding to the breast cancer drug trastuzumab (Herceptin). The researchers also showed, in preclinical experiments, that it may be possible to overcome this resistance by combining trastuzumab with a drug to inhibit the protein, c-SRC. The findings appeared online in Nature Medicine on March 13.

Multiple mechanisms of resistance associated with trastuzumab have been identified, but there are no effective methods for overcoming this resistance. To address this problem, Dr. Dihua Yu, an NCI-supported investigator from the University of Texas M. D. Anderson Cancer Center, and her colleagues studied signaling pathways that are activated in resistant cancer cells. They found that cellular signals from multiple resistance pathways converged at c-SRC, which is known to play a role in some cancers.

When activated, c-SRC may be a critical component of multiple resistance pathways. Rather than targeting several different signaling pathways individually in resistant cells, it may be possible to inhibit a central component common to all these pathways to overcome resistance, the researchers suggested.

To test this idea, resistant cells were exposed to a combination of trastuzumab plus a c-SRC inhibitor called saracatinib. In the cells and animal models, this combination of drugs made resistant cells more sensitive to trastuzumab, and tumors shrank. Using data from women treated with trastuzumab, the researchers were also able to confirm the association between c-SRC activation and trastuzumab resistance in patients.

“By targeting c-SRC, we reversed its activation in several model systems,” said Dr. Yu. “We consider this to be a powerful strategy for overcoming resistance.” The next steps would be to evaluate clinically applicable c-SRC inhibitors, including dasatinib, and develop a clinical trial to test the approach in patients, she noted.

Also in the Journals: New Clue to Triple-Negative Breast Cancer

A protein that normally helps suppress cell proliferation and tumor formation is mutated or missing in some cases of triple-negative breast cancer, and these alterations may play a role in the development of this disease. The discovery, reported in the March 4 Cell, provides new insights into this aggressive form of breast cancer, which is both poorly understood and difficult to treat.

In normal cells, the protein PTPN12 appears to block growth-promoting signals from proteins called tyrosine kinases. But, in triple-negative breast cancer, PTPN12 activity may be lost. Without this protein acting as a tumor suppressor, cells may produce a range of abnormal growth signals, the researchers found.

The results suggest that it may be possible to treat some triple-negative breast cancers with combinations of available drugs called tyrosine kinase inhibitors.

Guest Commentary by Dr. James L. Gulley

Devastation and Hope: An NCI Scientist’s First-Hand Account of Japan’s Resilience

Dr. James L. Gulley Dr. James L. Gulley

As the horrifying events and aftermath of the Japanese earthquake and tsunami continue to unfold on our television and computer screens, it’s difficult to imagine how any nation could recover from such calamities. But, based on what I personally witnessed, I have great hope for Japan’s future.

As some may know, NCI has had a long and vibrant relationship with the Japanese cancer research community. At any given time, dozens of scientists and researchers from both countries trade places to collaborate on research projects, participate in training, or deliver lectures. My latest—and most memorable—lecture in Japan happened to fall on Friday, March 11.

I had been invited to take part in an international meeting in Japan that included a short presentation and discussion with some of the conference participants. The venue for this talk was the 11th floor of an office building in Kawasaki City, 30 minutes south of Tokyo by Metro train.

I was only about 10 minutes into the lecture when, at 2:46 p.m. local time, the earthquake hit. Having lived in southern California for 8 years, I was somewhat accustomed to earthquakes, but this was an experience that really had no precedent for me.

It started as a relatively mild tremor that became a slow steady crescendo, culminating in a cross between a rollercoaster with sharp turns and a very turbulent flight. The clear sway of the building felt like a tree being whipped by the winds of a hurricane. I was standing, but my more experienced hosts calmly directed me to sit down. After the shaking continued for about 20–30 seconds, they encouraged me to get under the conference room table.

One of my first thoughts was that, if I were to be in the vicinity of an earthquake, what better place than in a building designed by Japanese engineers and built to Japanese code. We nervously joked about developing motion sickness but earnestly hoped the quake would stop soon. My thoughts raced and questions swirled in my mind as I looked into the eyes of my colleagues. Where is the epicenter? How serious is this?

One thing was clear: This wasn’t a routine earthquake.

As soon as the tremors stopped, we made our way in a single-file march down the 11 flights of stairs and out to a large courtyard. I couldn’t help but be impressed by the complete order and clear preparedness of those around me.

Once gathered below, we didn’t have to wait long for information. Although the electricity had been knocked out and cell phone service allowed only emergency calls to get through (an automatic measure to avoid overloading the system), text messaging was working, and the ubiquitous smart phones were getting information about the epicenter and magnitude of the quake from news sources.

Word arrived quickly that the danger was far from over and that a 6-meter tsunami was likely.

As someone with an interest in natural disasters, this bit of news concerned me much more than the earthquake itself because I knew buildings could be built to withstand even a mighty quake, but a 6-meter tsunami could be much more ruthless and devastating. Of course, it was numbing to hear moments later that the tsunami estimate had been increased to 10 meters.

Despite this warning, the “all clear” was given, and my colleagues and I filed back up to our 11th floor conference room and finished the lecture. Since the electricity was out, I presented on one laptop to the front of the room while those in the back of the room followed along on a separate laptop.

Our discussions were lively and somewhat nervous, given what we had just experienced. The exchanges were punctuated by dozens of aftershocks and announcements on the PA system that the power was out (as if we didn’t know).

We ended our discussions at 6 p.m., still unaware of the full degree of devastation unfolding in the north. Clearly our plans to go out for dinner were going to be put on hold. Unfortunately, the quake had ended all train service. The normally efficient mass transit system ground to a halt while engineers inspected the rails. The sidewalks and streets were clogged with a torrent of people heading out to the suburbs.

My hotel was a 3-hour walk away and no taxis could be found. So my colleagues and I resolutely started our cold (40 degrees Fahrenheit) blustery (gusts up to 30 MPH) journey. I wished I had brought my hat. Our conversations soon drifted to relatives and friends who lived north of Tokyo. These conversations turned to small cheers when several were reached by texting.

Eventually, we were able to make it across the river into Tokyo and located a bus that would take us a bit closer to the town center. An hour or so later, we arrived at the home of Den, a prominent doctor in Tokyo and one of the meeting participants. Although he could have driven me to my hotel, Den and his wife Adair took into account the day’s events and instead invited me for a home-cooked, vegetarian Japanese dinner.

Fortunately, by this time, cell phone service had been restored, and I was able to let my family know I was safe.

When we checked a GPS, we saw that all the roads into town were completely blocked. The seriousness of what had occurred began to settle in, although we still didn’t fully comprehend the degree of the devastation. By this time, it was after 10 p.m. My hosts graciously invited me to stay with them, and I was able to sleep (despite intermittent sharp aftershocks) in their study.

Of course, it wasn’t a surprise that my flight out the next day had been cancelled, but thankfully I was able to return home on Sunday, March 13. By that time, news about the lives lost, the extent of the destruction, and the uncertainty about the future began to emerge.

Looking back, I know that my experience pales when compared with what many Japanese citizens are going through. But I can’t say enough about the resilience I witnessed, as well as the gracious concern and hospitality of my scientific colleagues. Even when they had relatives they couldn’t contact, their first thought was to ensure the safety and well-being of those around them.

I am certain that this fortitude, along with the help and support of countries around the world, will sustain the nation of Japan and its residents in the difficult months and years to come.

Dr. James L. Gulley 
Director, Clinical Trials Group, Laboratory of Tumor Immunology and Biology
Principal Investigator, Medical Oncology Branch 
NCI’s Center for Cancer Research

Special Report

Colorectal Cancer Test Targets Cancer Stem Cells in Blood

Researchers in Japan have developed an experimental blood test that may help identify patients with colorectal cancer who have an aggressive form of the disease and could benefit from additional therapy after surgery.

The test screens the blood for tumor cells that have three molecular markers, including a marker for the protein CD133. This marker is found on some cells that have the properties of stem cells, such as the ability to self renew. Without CD133, the test results were not informative, suggesting to the researchers the importance of this cancer stem cell marker.

Patients whose cells had detectable messenger RNA (mRNA) for the three markers had worse disease-free survival and overall survival than patients whose blood tested negative for these markers. Further work is needed before the test could be used in the clinic, noted the researchers, led by Dr. Hisae Iinuma of the Teikyo University School of Medicine in Tokyo.

The findings appeared online in the Journal of Clinical Oncology on March 21.

“This is really the first study to show that detecting circulating cancer stem cells in blood has a direct clinical correlation,” said Dr. Max Wicha, director of the University of Michigan Comprehensive Cancer Center, who co-authored an editorial about the results.

According to the cancer stem cell hypothesis, tumors include a small fraction of cells that have the ability to self-renew and to give rise to the diverse types of cells within a tumor. Known as tumor-initiating cells or cancer stem cells, these hardy cells may drive the spread of the disease and also resist conventional treatments.

“The message of this study is that cancer stem cells may be important not only because they drive the tumor,” said Dr. Wicha, “but also because we may actually have a way to measure them in blood. And this could help us to assess the efficacy of drugs in our clinical trials.”

The more immediate applications could be to help doctors identify patients at risk of a recurrence of colorectal cancer. Additional (adjuvant) treatments are available following surgery. But new tools are needed to identify patients who may benefit from these treatments, as well as patients with a lower likelihood of relapse who could be spared the toxic effects and costs of the therapy.

For the current study, the researchers created a polymerase chain reaction (PCR)-based test to detect mRNAs for CD133 and two other markers—cytokeratin and carcinoembryonic antigens—in tumor cells circulating in the blood of patients with colorectal cancer.

The test was initially evaluated using archived specimens from 420 patients and, then, in another 315 patients who enrolled in a prospective validation study.

In the editorial, Dr. Wicha and his colleague Dr. Daniel F. Hayes cited the “the rigorous technical and clinical efforts the authors have applied to this prospectively performed study of circulating tumor cells (CTCs).”

A technology for capturing and counting CTCs, called CellSearch, has been cleared by the FDA for use as a prognostic tool in patients with metastatic breast, prostate, and colorectal cancers. CTC counts above certain thresholds (three or more per sample in colorectal cancer) are associated with a poor prognosis and may be an indication that the disease is progressing.

The CellSearch technology detects CTCs using antibodies against the proteins EpCAM (epithelial cell adhesion molecule) and cytokeratin. But these epithelial markers may not be expressed on many cancer stem cells and other tumor cells that undergo a transformation that allows them to escape into the bloodstream and navigate to other parts of the body.

This suggests that the general CTC markers “[might not be] able to detect the most aggressive cells in the circulation,” the study authors wrote. A limitation of the test evaluated in the current study is that it cannot capture single cells, they noted. Still, the technology has the potential to detect some tumor-initiating cells that may be EpCAM-negative.

“The problem with [the CellSearch] test is that it may miss a lot of the cancer stem cells that may be so important in the disease,” said Dr. Wicha. His group is trying to develop tests that could detect multiple markers associated with stem cells on a single cell. Future clinical trials at the University of Michigan will include a component to assess circulating cancer stem cells, Dr. Wicha said.

“The findings really point to our need to develop the technology to find the right cells with the right markers,” he added. “These are still early days.”

Edward R. Winstead

Further Reading: Putting Circulating Tumor Cells to the Test

A Closer Look

Technology
This is the sixth article in a series of stories related to new technology in cancer research. You can read more articles in the series here. 

Miniaturized Device Puts Nanotechnology to Work in Diagnosing Cancer

An experimental diagnostic device could be a valuable addition to a pathologist’s tool kit for diagnosing cancer, new research suggests. The miniaturized nuclear magnetic resonance, or micro-NMR, device can diagnose cancer within an hour, using patient samples of just a few thousand cells that are collected using a fine needle and a syringe.

Initial clinical studies by researchers at Massachusetts General Hospital (MGH) indicate that the micro-NMR system, which can quantify multiple protein markers in cells from a single patient sample, may be more accurate than standard diagnostic techniques.

An illustration of cancer cells (and red and white blood cells) passing through one of the coils of a miniaturized nuclear magnetic resonance device used to identify the cancer’s protein signature. (Image courtesy of H. Lee and R. Weissleder, Massachusetts General Hospital) A miniaturized nuclear magnetic resonance (NMR) device can detect cancer cells (dark brown) in a small sample of cells from a patient. The coils generate magnetic fields that excite magnetic nanoparticles attached to antibody-protein complexes, resulting in NMR signals that can be used to identify a cancer protein signature. (Image courtesy of H. Lee and R. Weissleder, Massachusetts General Hospital)

Conventional pathology, which is the current gold standard for diagnosing many cancers, is far from perfect. It takes several days to yield results, may require surgery to provide enough tissue, is technically challenging, and is subject to human interpretation. A biopsy for conventional pathology may be done either with open surgery, which yields samples containing billions of cells, or with a wide or fine needle. A pathologist processes and stains the tissue sample and examines it under a microscope. If enough tissue is available, the pathologist may use immunohistochemistry to visualize specific cancer markers in cross-sections of tissue.

The micro-NMR device uses principles similar to those of magnetic resonance imaging (MRI) to detect magnetic nanoparticles attached to antibodies, which flag protein biomarkers known to be associated with some cancers in patient samples. A physician can operate the portable device from the patient’s bedside with a smart-phone application that displays results on the phone’s screen.

Simplicity, Speed, and Sensitivity

The reactions for coupling the magnetic nanoparticle-antibody complexes to specific target proteins are performed at room temperature, and sample processing is simple and quick, the researchers said. In addition to eliminating waiting time, the rapid processing is an advantage because experiments showed that protein markers in patient samples degrade quickly.

Micro-NMR probably won’t replace conventional pathology and histology completely, but “it would be a good mechanism to triage patients before they undergo more invasive procedures,” said Dr. Cesar Castro, an oncologist and investigator at MGH. Dr. Castro co-led a recent clinical study that was the first to test the micro-NMR and nanoparticle technologies in patient samples.

The entire micro-NMR system costs about $200 and is roughly the size of a cube-shaped box of facial tissue. Developed by Drs. Hakho Lee and Ralph Weissleder at the Center for Systems Biology at MGH, the system is highly sensitive thanks to miniaturization of the device and the chemistry used to bind magnetic nanoparticles to their targets. The device can measure levels of individual tumor markers in a 1-microliter sample containing about 200 cells and—unlike technologies that rely on optical properties—works in nonpurified samples.

Advantages in the Clinic

If validated in larger clinical trials, the micro-NMR system could eventually be used not only to diagnose cancer but also to identify potential patient candidates for targeted therapies and to monitor the response to therapy, Dr. Castro said. When used for diagnosis, this approach could potentially reduce the time that patients are in limbo while waiting for results and provide more information to clinicians, while steering patients away from more invasive procedures and avoiding repeat biopsies, he noted.

“A key advantage of this technique is the ability to look at multiple markers at the same time,” said Dr. Piotr Grodzinski, director of NCI’s Office of Cancer Nanotechnology Research, which helped fund the work. This so-called multiplexing capability is important, he explained, “because cancer is heterogeneous and is not characterized by a single biomarker.”

Components of a diagnostic micro-NMR system, including a mini magnet; chip-sized, microliter-volume sensors; and a smart phone interface (Image courtesy of C. Min, D. Issadore, R. Weissleder and H. Lee) The diagnostic micro-NMR system includes a mini magnet (left); chip-sized, microliter-volume sensors (center); and a user-friendly smart phone interface (right). (Image courtesy of C. Min, D. Issadore, R. Weissleder and H. Lee)

The MGH researchers used micro-NMR to measure levels of nine established cancer-related markers in cells from fine-needle biopsies of deeper lesions, done with guidance from a CT scan or ultrasound. Using a four-protein signature, they were able to diagnose a range of epithelial cancers, including lung, breast, pancreatic, and gastrointestinal, with 96 percent accuracy.

In cell samples from 50 patients who had been referred for clinical biopsies, the four-marker panel correctly diagnosed 48 cases: 44 of 44 malignancies and 4 of 6 benign lesions. In contrast, the accuracy of conventional cytology and histology performed on specimens from the same patients was 74 percent and 84 percent, respectively. The diagnoses were confirmed independently using a combination of clinical, imaging, and pathology data.

The next step for Dr. Castro and his colleagues is to refine the system to identify specific cancers. “Our first endeavor will be customizing the assay with ovarian cancer-specific markers, and we’re enrolling patients treated at the MGH Gillette Center for Gynecologic Oncology for that study,” Dr. Castro said. The researchers hope eventually to apply the technology to blood and other fluids, such as ascites, in which tumor cells are scarce, and they are exploring other cancer applications as well.

Potential for Personalized Medicine

Many cancer researchers and companies recognize the need for diagnostic tools that could be used in tandem with targeted therapies, and in a range of clinical studies needed to develop such therapies.

“To fully achieve the potential of personalized cancer therapy will require noninvasive methods for analyzing genes and proteins in a patient’s tumor or serum, which can be used in real time to determine the best treatment or treatment combination,” said Dr. Roy Herbst, who recently assumed the role of chief of medical oncology at Yale Medical Center. “I think this [micro-NMR system] is clearly an example of a step in the right direction.”

“With this machine, we have the strong potential to start asking more refined and elegant questions in clinical research,” Dr. Castro said. Because the micro-NMR technology is sensitive and minimally invasive, he explained, it could be used in clinical trials that require repeated tumor sampling at various time points. For example, researchers could use micro-NMR to identify and validate new tumor markers for clinical use or to look at how markers change during the course of therapy.

“We consider this to be a platform technology because the markers are very interchangeable,” Dr. Castro explained. “So, as the science evolves, as we get more information from the clinic and from laboratories elsewhere, we can react to that.”

Elia Ben-Ari

Featured Clinical Trial

Novel Combination Chemotherapy for Localized Ewing Sarcoma

Name of the Trial
Phase III Randomized Study of Adding Vincristine Sulfate, Topotecan Hydrochloride, and Cyclophosphamide to Standard Chemotherapy in Patients with Non-Metastatic Extracranial Ewing Sarcoma (COG-AEWS1031). See the protocol summary.

Principal Investigator 
Dr. Mason Bond, Children’s Oncology Group (COG)

Dr. Mason Bond Dr. Mason Bond

Why This Trial Is Important  
Ewing sarcoma is a rare cancer of the bone or soft tissue that occurs primarily in adolescents and young adults. In fact, it is the second most common malignant bone tumor diagnosed in patients younger than 20 years of age. Most Ewing sarcomas have a characteristic chromosomal alteration that results in the expression of a fusion protein (EWS-FLI1) that inappropriately turns on cell-growth-promoting genes. Thus, these tumors tend to grow rapidly and often metastasize to the lung, bone, or bone marrow. The presence of metastases at diagnosis and being diagnosed at an older age are associated with a poorer prognosis.

Treatment for patients with Ewing sarcoma includes surgery, radiotherapy, or both, along with systemic chemotherapy. Until the introduction of combination chemotherapy, the 3- to 5-year survival rate for patients with Ewing sarcoma was less than 10 percent. However, results from several clinical trials have demonstrated improved survival for patients without metastases who were treated with a chemotherapy combination called VDC-IE, in which administration of the drugs vincristine, doxorubicin, and cyclophosphamide (VDC) is alternated with administration of the drugs ifosfamide and etoposide (IE), and by reducing the interval between cycles of VDC-IE.

In this clinical trial, which is being conducted in the United States, Canada, and Australia, researchers will test whether the addition of the drug combination vincristine, topotecan, and cyclophosphamide (VTC) to VDC-IE improves overall survival and event-free survival (survival without cancer progression or recurrence) in newly diagnosed patients with non-metastatic Ewing sarcoma of the bone or soft tissue (excluding the soft tissue of the skull). Eligible patients will be randomly assigned to receive six cycles of VDC-IE or VTC-IE-VDC followed by surgery, radiation therapy, or both and 11 more cycles of the initial chemotherapy.

Dr. Leo Mascarenhas Dr. Leo Mascarenhas

“Because topotecan and cyclophosphamide are active in patients when Ewing sarcoma recurs or relapses, our thinking is that the combination may contribute to improving survival or preventing relapse in newly diagnosed patients,” said Dr. Leo Mascarenhas, vice chair of the trial.

“This trial is unique in that it is the first COG trial available through NCI’s Cancer Trials Support Unit (CTSU) that will enroll both adolescents and young adults,” added Dr. Mascarenhas. “It provides broader access to patients who may not be treated at a pediatric center, which is the case for a significant number of patients with Ewing sarcoma.”

Secondary aims of the trial include assessing the importance of initial tumor volume, tumor histology, and response to treatment as measured by PET scans as prognostic factors for localized Ewing tumors. Additionally, the effect of the type of local therapy (surgery, radiotherapy, or both) on associated complications and survival will be evaluated. “There are a lot of issues we hope to address in this trial to help us understand this disease better to improve the outcome of patients,” said Dr. Mascarenhas.

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

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

FDA Update

Menthol Cigarettes Adversely Affect Public Health, FDA Advisory Committee Finds

The Food and Drug Administration’s Tobacco Products Scientific Advisory Committee (TPSAC) met on March 17–18 to discuss and finalize its report on the impact of menthol cigarette smoking on public health, including among children and minority populations. Under the Family Smoking Prevention and Tobacco Control Act, enacted in June 2009, the committee is required to submit the report by March 23 to the Secretary of Health and Human Services.

The committee concluded:

  • There are no public health benefits of menthol compared with non-menthol cigarettes
  • Menthol cigarettes have an adverse impact on public health in the United States
  • Removal of menthol cigarettes from the marketplace would benefit public health in the United States 

The voting members of TPSAC (scientific experts and representatives from state governments, academia, and the public) who wrote the report stopped short of recommending specific action by the FDA. Experts within the FDA Center for Tobacco Products will review the TPSAC report, and the FDA intends to provide its first progress report on the review of the science in approximately 90 days.

“It is important to note that FDA’s receipt of the final report does not have a direct or immediate effect on the availability of menthol products in the marketplace,” wrote Dr. Lawrence R. Deyton, director of the FDA’s Center for Tobacco Products. “Although there is no required deadline or timeline for FDA to act on the issue of menthol in cigarettes, we recognize the strong interest in this issue among all stakeholders and will continue to communicate the steps the FDA is taking as it determines what future regulatory actions, if any, are warranted.”

Notes

National Cancer Clinical Trials Cooperative Groups Announce Mergers

In separate announcements, several NCI-supported national cancer clinical trials cooperative groups declared their plans to merge. On March 7, the Radiation Therapy Oncology Group (RTOG) and National Surgical Adjuvant Breast and Bowel Project (NSABP) announced their plans to consolidate operations. Two days later, a merger was announced by the American College of Surgeons Oncology Group (ACOSOG), Cancer and Leukemia Group B (CALGB), and North Central Cancer Treatment Group (NCCTG).

Most recently, on March 18, the Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) said they will merge clinical cancer research programs.

The cooperative groups, which conduct clinical trials primarily in adult patients, are merging in response to the Institute of Medicine’s April 2010 report calling for restructuring and consolidation of NCI’s Clinical Trials Cooperative Group Program and NCI’s subsequent announcement of its plan to consolidate the program to a maximum of four adult groups (down from nine current groups) and one pediatric group.

The cooperative groups involved in the mergers indicated that they have already begun discussing the transition to consolidate their current operations. In fact, ACOSOG, CALGB, and NCCTG integrated their statistical, data management, and information technology platforms in June 2010.

Research Symposium on Radiation and Cancer Honors Dr. Elaine Ron  

Dr. Elaine Ron Dr. Elaine Ron

On March 9, NCI’s Division of Cancer Epidemiology and Genetics (DCEG) held a symposium entitled Research Strategies in Radiation and Cancer to honor Dr. Elaine Ron, a senior investigator in DCEG and a widely respected expert in the field of radiation epidemiology. Dr. Ron died of cancer on November 20, 2010. (See the In Memoriam note featured in the November 30 NCI Cancer Bulletin.)

A group of Dr. Ron’s collaborators and peers reflected on her important contributions to radiation epidemiology studies and emphasized her successful research strategies. Included were the Life Span Study, which followed survivors of the Hiroshima and Nagasaki bombings, extensive collaborations with Ukrainian and Belarusian scientists tracking the aftermath of the Chernobyl nuclear disaster, a landmark pooled analysis examining radiation exposure and the risk of thyroid cancer, and an ongoing investigation evaluating cancer risk following childhood exposure to computed tomography scans.

Former and current DCEG research fellows spoke about the dedicated mentoring Dr. Ron provided throughout her career, which has greatly influenced a new generation of radiation epidemiologists.

Finally, DCEG investigators delivered presentations on “Evolving Research Strategies in Radiation,” which highlighted new directions in radiation epidemiology studies that are likely to accelerate progress in the field. Dr. Christopher Wild, director of the International Agency for Research on Cancer—where Dr. Ron served on the Scientific Council—spoke about “Two-Way Translational Research: From Basic Science to Both the Clinic and the Population,” with an emphasis on radiation-exposed populations. 

“Elaine was an enormously gifted epidemiologist whose groundbreaking research has contributed so much to a better understanding of the risks of cancer associated with a wide variety of exposures to ionizing radiation,” said Dr. Joseph F. Fraumeni, Jr., director of DCEG.

Funding to Support Collaborations between U.S. and Chinese Scientists   

NIH and the National Natural Science Foundation of China (NSFC) recently published corresponding funding announcements to encourage and support research cooperation between U.S. and Chinese scientists studying cancer, allergy, immunology, and infectious diseases, including HIV/AIDS and its comorbidities. NIH released an announcement for administrative supplements for U.S. investigators and NSFC published an announcement for new 1-year projects from Chinese collaborating investigators. This initiative is part of a U.S.-China Program for Biomedical Research Cooperation that was recently established by NIH and NSFC.

U.S. and Chinese collaborating investigators will work together to develop corresponding applications to NIH and NSFC. Applications will be reviewed in parallel by both agencies using similar selection factors, and funding decisions will be made by both agencies according to research priorities of both countries. NIH has pledged to support up to $3 million in FY 2011 under this program, whereas NSFC has indicated that approximately 300,000 renminbi (about $45,760) will be available per project to support Chinese collaborators.

A list of frequently asked questions, additional information, and application instructions are available online.