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August 9, 2011 • Volume 8 / Number 16

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NEWS

Genome Region Tied to Risk of Second Cancers after Radiation Therapy

Illustration of a child, a physician, and a DNA strandA new study may provide an important clue about the long-term risk of second primary cancers in children with Hodgkin lymphoma who receive radiation therapy as part of their treatment. 

In the study, researchers identified two genetic variants, called single nucleotide polymorphisms (SNPs), in a region of chromosome 6 that were strongly associated with an increased risk of a second cancer in this group of cancer survivors. Read more > >

A MESSAGE TO READERS

NCI Cancer Bulletin Publication Break

The NCI Cancer Bulletin will not be published on August 23. Our next issue will be released on September 6, when we resume our usual biweekly publication schedule. If you are not yet a subscriber, please submit your e-mail address in the toolbox at the top right-hand corner to begin your free subscription.

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IN DEPTH

UPDATES

  • Cancer.gov Update

    • Updated HINTS Website Unveiled
  • Notes

    • Varmus Reflects on First Year as NCI Director
    • DCEG's Chatterjee Wins Statistical Awards
    • NCI Researchers Win NIH Director's Awards
    • CCR's Gonzalez and Colleagues Honored for Diagnostic Test
    • Comments Sought on Changes to Human Subject Protections

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.

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

Featured Article

Genome Region Tied to Risk of Second Cancers after Radiation Therapy

Illustration of a child, a physician, and a DNA strandTwo genetic variants are strongly associated with an increased risk of a second cancer in survivors of childhood Hodgkin lymphoma treated with radiation.

A new study may provide an important clue about the long-term risk of second primary cancers in children with Hodgkin lymphoma who receive radiation therapy as part of their treatment. In the study, researchers identified two genetic variants, called single nucleotide polymorphisms (SNPs), in a region of chromosome 6 that were strongly associated with an increased risk of a second cancer in this group of cancer survivors.

Published July 24 in Nature Medicine, the study is among the first genome-wide association studies focused on second cancer risk, and one of the few such studies to date that limited the study population to a group that received a specific therapeutic intervention.

Approximately 90 percent of children and adolescents diagnosed with Hodgkin lymphoma are cured. But that cure can come at a price: Nearly 20 percent of survivors will develop a second cancer, which is the second leading cause of death in this population.

Researchers have struggled to identify which patients have an increased risk for a second cancer and should receive different treatments or should undergo more intensive surveillance for a second cancer as they grow older, explained the study's senior investigator, Dr. Kenan Onel of the University of Chicago.

That is part of what makes these findings so "tantalizing," Dr. Onel said. "In the setting of this exposure, [these variants] seem to have a large effect." Survivors with the risk-conferring SNPs were more likely to develop a second cancer than survivors without those SNPs.

But this was a relatively small study, he stressed, so larger studies will be required to confirm the findings. "Much more work is needed before we can say that this is something that doctors or patients can base treatment decisions on."

To find the chromosome region involved, Dr. Onel and his colleagues scanned the DNA of 178 survivors of childhood Hodgkin lymphoma treated with radiation, 96 of whom had developed second cancers. Three genetic variations (or SNPs) were associated with a higher risk of a second cancer.

It is our hope that in the future we may be able to tailor health care for survivors more effectively to reduce the burden of second cancers.

—Dr. Lindsay Morton
When the researchers replicated their results in a second set of similarly treated survivors, of whom 62 developed a second cancer and 71 did not, two SNPs in a chromosome region known as 6q21 showed a statistically significant association with increased second-cancer risk.

Exactly how these genetic variants might increase cancer risk is unclear. But the region of chromosome 6 on which the variants reside is near a gene called PRDM1. Other studies (here and here) have recently identified PRDM1 as a possible tumor suppressor gene in a subtype of diffuse large B-cell lymphoma

In additional experiments in cell lines, Dr. Onel and his colleagues showed that the presence of the risk variants, or alleles, was associated with lower levels of PRDM1 protein and that PRDM1 protein levels rose in response to radiation only in cells that had alleles "protective" against second cancers.

The researchers did not rule out the possibility that other genes may be involved, however.

To help clarify the roles of the two risk alleles when combined with radiation therapy in predisposing patients to second cancers, a similar analysis needs to be done that includes survivors who were not exposed to radiation, explained Dr. Lindsay Morton of the Radiation Epidemiology Branch in NCI's Division of Cancer Epidemiology and Genetics (DCEG).

This study paves the way "for further investigations of the complex interplay between genetic susceptibility and environmental exposures involved in the development of second cancers," wrote Drs. Morton and Stephen Chanock, chief of DCEG's  Laboratory of Translational Genomics, in an accompanying commentary. Future investigations need to assess the role of radiation dose and other treatments, such as certain types of chemotherapy, they wrote. 

Another important future project, Dr. Onel said, will be to see if the findings apply to survivors of other childhood cancers.

There are nearly 12 million cancer survivors in the United States, and this number will continue to grow as treatments and diagnostic tools improve. "This study is an important first step toward identifying patients who may be at increased risk for a second cancer later in life," said Dr. Morton. "It is our hope that in the future we may be able to tailor health care for survivors more effectively to reduce the burden of second cancers."

Carmen Phillips and Edward R. Winstead

Cancer Research Highlights

Mobile Phone Use Does Not Raise Cancer Risk in Children and Adolescents

The first-ever study of mobile phone use by children and adolescents carried out in four European countries found no increased risk of brain cancer, according to a report published online July 27 in the Journal of the National Cancer Institute (JNCI).

Investigators in Denmark, Sweden, Norway, and Switzerland conducted a multicenter case-control study involving children and adolescents 7 to 19 years of age who were diagnosed with a brain tumor between 2004 and 2008. The investigators, led by Dr. Denis Aydin of the Swiss Tropical and Public Health Institute in Basel, conducted interviews with 352 brain tumor case patients, 646 healthy control subjects, and their parents.

The children who regularly used mobile phones were not statistically significantly more likely to have been diagnosed with brain tumors than nonusers, the researchers reported. In addition, those who used mobile phones for at least 5 years did not have a statistically significantly higher risk of developing brain tumors. Moreover, the investigators found no increased risk of brain tumors in the parts of the brain that typically receive the highest levels of mobile-phone radiation exposure.

For some of the children, the investigators were also able to obtain data from mobile phone service providers. In these children, brain tumor risk rose with the amount of time since the family began its mobile phone subscription but not with the amount of mobile phone use as recorded by the service providers, the researchers added.

Previous epidemiologic studies among adult users have found no overall increased risk of brain cancer from mobile phone use. This study addressed concerns that the developing brains and nervous systems of children and adolescents might be more vulnerable to the potential adverse health effects of mobile phone use.

“Researchers continue to monitor trends in brain cancer and mobile phone use,” commented Dr. Martha Linet, chief of the Radiation Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics. “Other ongoing research includes a large study of rodents exposed to mobile phone frequencies that is being conducted by the National Toxicology Program; a prospective study recruiting 250,000 mobile phone users in five European countries; and a case-control study comparing 2,000 young people between the ages of 10 and 24 who were diagnosed with brain tumors and an equal number of control subjects from 13 countries.”

Further reading: “A Conversation with Dr. Martha Linet on Cell Phone Use and Cancer Risk

Computer System for Reading Mammograms Does Not Appear to Improve Cancer Detection

A widely used and expensive computer system created to help radiologists identify suspicious spots on mammograms may not help detect breast cancer, new research suggests. The study, led by Dr. Joshua J. Fenton of the University of California, Davis, appeared online July 27 in the Journal of the National Cancer Institute (JNCI).

In the first large clinical study to assess the performance of computer-aided detection (CAD) in the United States, the technology did not improve the detection of invasive breast cancer. The finding was based on data from approximately 684,000 women and more than 1.6 million mammograms administered at Breast Cancer Surveillance Consortium facilities between 1998 and 2006.

CAD systems are now used to help interpret most screening mammograms in the United States, with annual direct Medicare costs in excess of $30 million, the study authors noted. The Food and Drug Administration approved the technology in 1998 based on limited data, and Medicare began to pay for CAD soon after.

In 2007, the investigators published preliminary results from this population-based observational study. At that time, they found that the use of CAD led to a substantially higher false-positive rate compared with the false-positive rate of radiologists who read mammograms without CAD.

The updated analysis included nearly twice the amount of data that were assessed in the 2007 preliminary study, but the conclusion was essentially the same. As the editors of JNCI summarized, the health benefits of using CAD to interpret screening mammograms “remain unclear, and the data indicate that the associated costs may outweigh the potential benefits.”

CAD technology is popular, in part, because the devices are built into digital mammography systems, which are increasingly common in the United States. Another reason is the financial incentive from Medicare reimbursement, noted Dr. Donald Berry of the University of Texas M. D. Anderson Cancer Center in an accompanying editorial.

Researchers and device companies should work to improve the system, Dr. Berry continued. “But this should happen in an experimental setting and not while exposing millions of women to a technology that may be more harmful than it is beneficial. In the meantime, economic incentives may stoke its continued proliferation.”

Further reading: "Mammogram Study Evaluates Computer-Aided Detection"

Higher Breast Density Linked to Increased Cancer Risk and Aggressive Tumors

A study of postmenopausal women has confirmed that higher breast density is associated with a greater risk of breast cancer and revealed that the tumors that do develop are more likely to be aggressive. The findings were published online July 27 in the Journal of the National Cancer Institute.

Dense breast tissue, which has less fat and more glandular and connective tissue, is a known risk factor for breast cancer, and mammograms of dense breast tissue are often more difficult to read and interpret. But whether there are cancer subtypes specific to women with denser breast tissue is unclear.

Researchers from Harvard Medical School analyzed Nurses’ Health Study data from 1,042 women diagnosed with breast cancer between 1989 and 2004 and 1,794 matched healthy control subjects. The women with breast cancer had a higher average breast density than the women in the control group. Those with the highest breast density were more than three times more likely to develop cancer than those with the lowest breast density.

Breast density was associated most strongly with in situ, or noninvasive, tumors. Higher breast density was also associated with larger, higher-grade, and estrogen receptor (ER)-negative tumors, which tend to be more aggressive. The authors pointed out several study limitations. Most important, the findings may apply only to postmenopausal women.

In an accompanying editorial, Dr. Karla Kerlikowske of the University of California, San Francisco, and Dr. Amanda Phipps of the Fred Hutchinson Cancer Research Center suggested that a “masking effect,” in which dense tissue prevents the detection of smaller tumors by mammography, could be responsible for the observed association between dense breast tissue and larger, more aggressive tumors.

They also proposed that tumors may arise more often in dense breast tissue because of interactions with the larger number of epithelial and stromal cells present.

The results “suggest that breast density is an important risk factor for a range of biologically diverse subtypes of breast cancer, including tumors exhibiting characteristics indicative of poorer prognosis,” wrote the editorialists. “Given that the magnitude of the association with breast density is strong across all breast cancer subtypes and particularly for ER-negative disease, breast density should be included in risk prediction models across tumor subtypes,” they concluded.

Further reading: “Breast Density in Mammography and Cancer Risk

Genetic Study Provides Clues to Non-Hodgkin Lymphoma

Gene mutations that disrupt the normal packaging of DNA in chromatin, the complex of DNA and proteins in chromosomes, are common in some forms of non-Hodgkin lymphoma (NHL) and may play a role in the diseases, new research suggests. The study adds to growing evidence that the proper regulation of DNA packaging—through a process known as chromatin remodeling—may be disrupted in cancer.

Understanding these changes could lead to strategies for treating the disease, Dr. Marco Marra of the BC Cancer Agency in Vancouver and his colleagues reported online in Nature on July 27.

To learn more about the biology of NHL, the researchers sequenced the genomes of 13 patients with diffuse large B-cell lymphoma and one with follicular lymphoma—the two most common forms of NHL. After surveying the genetic changes in another 113 NHL cases, the researchers identified 26 genes with recurrent mutations that could be involved in cancer.

Five of the most commonly mutated genes encode proteins that are involved in the chemical modification of histones, which are chromatin proteins responsible for packaging DNA. When histones are modified, the DNA in chromatin is packaged less tightly and gene expression is facilitated; when histone modifications are removed, the DNA becomes more tightly packaged and gene expression is suppressed. Thus, proteins involved in histone modification can alter the activity of genes across the genome.

Mutations in one of the five genes, MLL2, were identified in 89 percent of the patients with follicular lymphoma, which would make it one of the most commonly mutated genes in NHL. Noting that the gene is mutated in other cancers as well, the study’s authors suggested that the MLL2 protein may normally help suppress tumor formation.

The second mutated gene the authors highlighted, MEF2B, had not previously been linked to cancer, but the pattern of mutations in this gene resembled patterns found in other known cancer-related genes. Based on their findings, the researchers concluded that the mutation of genes involved in histone modification is likely to be a central event in the development of some forms of NHL.

These findings confirm and extend recent reports of mutations in histone-related genes in NHL (here and here). Similar genetic alterations have also been found in a form of kidney cancer and the childhood cancer medulloblastoma. Drugs with the potential to reverse epigenetic changes in cells, such as histone modifications, are available, but some researchers caution that the relationship between the recently identified mutations and cancer is unclear.

“This study opens quite a few new avenues for researchers by introducing a list of genes that no one had thought would be involved in these diseases,” said the first author, Ryan Morin of the BC Cancer Agency. And because certain mutations were found in only some subtypes of NHL, the alterations, if confirmed, could help doctors diagnose the disease and select the most appropriate therapies, he added. 

Studies Reveal the Genetic Complexity of Head and Neck Squamous Cell Cancers

Two independent, multi-institution research teams have identified a large number of previously unknown genetic defects associated with head and neck squamous cell carcinoma (HNSCC), the most common form of head and neck cancer. The researchers sequenced the entire protein-coding regions, or exomes, of the DNA in dozens of patient tissue samples, and the findings were published online July 28 in two papers in Science (here and here).
 
The studies were led by researchers from the Broad Institute of MIT and Harvard, the University of Pittsburgh Cancer Institute, the Johns Hopkins Kimmel Cancer Center, and the University of Texas M. D. Anderson Cancer Center.

Tobacco use, excessive alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for HNSCC, which includes cancers arising in the mouth and throat. The 5-year survival rate for many types of HNSCC has improved little over the past 40 years.

To search for gene defects, or mutations, that may play a role in HNSCC, the researchers compared whole-exome sequences of tumor tissue with those of matched normal tissue from the same patients. Both research teams confirmed genetic abnormalities that were previously implicated in HNSCC, including mutations in the TP53 tumor suppressor gene, which were by far the most common.

The two teams also identified a large number of unexpected gene mutations in HNSCC, most notably in the NOTCH1 gene and other genes involved in squamous cell differentiation—the process by which less mature, rapidly dividing cells develop into more specialized squamous cells that divide more slowly.

“The degree of differentiation—that is, tumor cell grade—has never consistently been shown to be a clinical prognostic factor” in HNSCC, said Dr. Jennifer Grandis of the University of Pittsburgh, a senior author of one of the studies. “So it was surprising to find mutations in a series of genes that…appear to contribute to differentiation.”

Both studies found far fewer mutated genes in HPV-positive tumors than in HPV-negative tumors, supporting the idea that HPV-positive HNSCC, which has a better prognosis, is a distinct disease and thus merits different treatment.

The results of multidisciplinary collaborations such as these “will allow us for the first time to understand the complex biology of head and neck cancer,” Dr. Grandis said. “It’s clearly not one disease. It’s many diseases, despite appearing identical under the microscope.

“It’s right to be cautiously pessimistic,” Dr. Grandis said. But she believes that delving into the biological complexity of cancers such as HNSCC will ultimately reveal new therapeutic targets.

“We’re still in just the baby steps of these genetic findings,” she continued. The most important next step, she explained, is to identify the subset of mutations that drive tumor formation and figure out how to target them. “These are the patients’ tumors—they are speaking to us. Whether we understand what they say is a different question.”

Also in the Journals: Key Genetic Mutations Found in One Type of Brain Cancer

Researchers have identified mutations in two genes that may play a critical role in the development of oligodendroglioma, the second-most-common type of brain cancer in adults.

In the study, published online August 4 in Science, Dr. Chettan Bettegowda and his colleagues at the Johns Hopkins University Kimmel Cancer Center sequenced the exomes, or protein-coding portions of DNA, in seven oligodendroglioma tumors and found that two genes, CIC and FUBP1, were frequently mutated. The researchers then performed exome sequencing on 27 additional oligodendroglioma samples and again found that both genes were frequently mutated. The genes had a mutational pattern that is consistent with those commonly seen in tumor suppressor genes, the researchers reported.

“Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor,” said study co-author Dr. Nickolas Papadopoulos in a news release.

According to Dr. Bettegowda, further research is needed to determine whether the genes’ mutational status can be used to guide prognosis and whether the genes can be targets for therapy.

Spotlight

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

Tracking the Rise of Robotic Surgery for Prostate Cancer

Drs. Peter Pinto and Gennady Bratslavsky of NCI's Urologic Oncology Branch prep a prostatectomy patient for surgery with the da Vinci Surgical System. (Photo by Bill Branson, NIH) Drs. Peter Pinto and Gennady Bratslavsky of NCI's Urologic Oncology Branch prep a prostatectomy patient for surgery with the da Vinci Surgical System. (Photo by Bill Branson, NIH)

In the 11 years since the Food and Drug Administration (FDA) approved the first robotic surgical system for conducting abdominal and pelvic surgeries, its use has skyrocketed. The da Vinci Surgical System is now used to perform as many as 4 out of 5 radical prostatectomies in the United States. The robotic system is also increasingly being used to treat other cancers, including gynecologic and head and neck cancers. According to da Vinci's manufacturer, Intuitive Surgical, Inc., more than 1,000 of the robotic systems are in hospitals across the country.

Several recent studies suggest that the ascendance of robotic prostatectomy has had numerous consequences, including a mass migration of prostate cancer patients to hospitals with robotic systems and an overall increase in the number of prostatectomies performed each year. The latter trend has raised some concern because it coincides with a period during which prostate cancer incidence has declined slightly.

How robotic prostatectomy proliferated so quickly, and what it means for patients and the health care system, is still a matter of study and debate. But the shift appears to have altered the surgical treatment of prostate cancer permanently, observed urologic surgeon Dr. Hugh Lavery of the Mount Sinai Medical Center in New York.

"I think that traditional open and laparoscopic prostatectomies have faded," Dr. Lavery said. The available data indicate that patients and surgeons "are pushing for the robots," he added, "and they're getting them."

A Compelling Technology, an Intrigued Audience

Type "robotic surgery prostate cancer" into an Internet search engine, and the results will typically include glowing testimonials from patients who were treated with robotic surgery and videos of da Vinci's surgical instruments roaming about the peritoneal cavity suturing, cutting through tissue, removing fat. In these videos, the surgeon is on the other side of the room, head buried in a console, and hands at the robot's controls, maneuvering the instruments with the aid of a camera that offers a crisp, 3-dimensional image of the surgical field. (Read more about how the robotic system works.)

Dr. Peter Pinto sits at the da Vinci robot console to perform minimally invasive prostate surgery. (Photo by Bill Branson, NIH) Dr. Peter Pinto sits at the da Vinci robot console to perform minimally invasive prostate surgery. (Photo by Bill Branson, NIH) [Enlarge]

The Internet videos are just one component of the extensive marketing campaign behind da Vinci by individual hospitals and the system's manufacturer. A study of 400 hospital websites, published online in May, found that 37 percent of the sites featured robotic surgery on the homepage, 61 percent used stock text provided by the robot's manufacturer, and nearly one in three sites had claims that robotic procedures led to improved cancer control.

"The tendency is to associate better technology with better care," explained the study's lead investigator, Dr. Marty Makary of the Johns Hopkins University School of Medicine.

Dr. Makary said he performs most operations, including complex pancreas surgery, laparoscopically because he believes the robot does not offer sufficient tactile feedback and takes more operative time. Traditional laparoscopy, however, is now rarely used for prostatectomies because the procedure is considered technically demanding, according to several researchers. One estimate put the number of laparoscopic prostatectomies each year in the United States at less than 1 percent of the total.

Patients often arrive for an office visit knowing that they want a prostatectomy performed with the robot, said Dr. William Lowrance, a urologic oncologist at the Huntsman Cancer Institute at the University of Utah. "It may be based on something they saw on the Internet or because of a friend or relative who had a good experience" with robotic surgery, he explained. Approximately 70 percent of the prostatectomies he performs are done with da Vinci.

Patient-to-patient referrals and the fact that the robotic procedure is minimally invasive have been two key drivers of the robot's popularity, said Dr. Ash Tewari, director of the Prostate Cancer Institute at New York-Presbyterian Hospital/Weill Cornell Medical Center, who performs nearly 600 robotic prostatectomies a year.

Several studies have documented that there can be a fairly steep learning curve before surgeons achieve proficiency with the robot. But according to Dr. Warner K. Huh, a gynecologic oncologist and surgeon at the University of Alabama Birmingham Comprehensive Cancer Center, the robot makes it easier to perform many minimally invasive procedures.

"For many surgeons, they feel they can do a minimally invasive procedure more effectively and safely robotically, and I think that's a big reason that it's taken off," Dr. Huh said.

The growth of robotic surgery is more than just a marketing phenomenon, agreed Dr. Tewari. "It has been supported with a lot of good science," he continued. "We want to make this field better and beyond the hype of robotics."

What the Science Says So Far

Based on studies to date, there seems to be agreement that robotic surgery is comparable to traditional laparoscopic surgery in terms of blood loss and is superior to open surgery in terms of blood loss and length of hospital stay. Recovery time may also be shorter following robotic surgery than open surgery.

But for the big three outcomes—cancer control, urinary control, and sexual function—there is still no clear answer as to whether one approach is superior to another, Dr. Lowrance noted.

A large, randomized clinical trial comparing any of the approaches seems out of the realm of possibility at this point. At Weill Cornell, Dr. Tewari has approval to conduct a trial comparing robotic prostatectomy with open surgery. But the trial never got off the ground because there are not enough patients willing to be randomly assigned to surgery without the robot, he said.

A randomized trial may not even be that informative. "Many open surgeons have excellent outcomes, which may be hard to improve upon," said Dr. Lavery. "I think that if you have an expert surgeon doing either procedure, you're likely to have an excellent outcome."

The Peak of the "Robotic Era"?

The remarkably swift proliferation of the da Vinci system in surgery suites across the United States appears to have had population-wide effects. In a study Dr. Lavery presented at the American Urological Association annual meeting in March, he showed that, from 1997 to 2004, the number of prostatectomies performed in the United States was fairly stable, around 60,000 per year.

From 2005 to 2008, however—what Dr. Lavery and his colleagues called the first true years of the "robotic era"—the number of prostatectomies and robotic procedures spiked. The number of prostatectomies rose to roughly 88,000 in 2008, and the number of robotic procedures jumped from approximately 9,000 in 2004 to 58,000 in 2008.

 The number of prostatectomies rose to roughly 88,000 in 2008, and the number of robotic procedures jumped from approximately 9,000 in 2004 to 58,000 in 2008.

Two other recent analyses that looked at smaller geographic regions—New York, New Jersey, and Pennsylvania in one study and Wisconsin in the other—yielded similar results. But they also showed something else: Hospitals that acquired robots saw a significant increase in the number of radical prostatectomies they performed. At the same time, the number of procedures at hospitals that did not acquire a robot fell.

"The overall result has been a sudden, population-wide, technology-driven centralization of procedures that is without precedent," wrote Dr. Karyn Stitzenberg of the University of North Carolina Division of Surgical Oncology and her colleagues, who conducted the study in New York, New Jersey, and Pennsylvania.

Whether the rise in the number of procedures has meant that patients who might have been strong candidates for a different treatment, including active surveillance, instead opted for surgery is "speculative," Dr. Lowrance said.

"My own feeling is that radical prostatectomy rates in general have probably peaked and are on their way down," he said, in part because of the increased emphasis on active surveillance in men with localized, low-risk prostate cancer.

Cost Implications Unclear

Another uncertain aspect centers on whether there has been any economic fallout from the increased use of this fairly expensive technology. Hospitals are not paid more for procedures using the robot, despite the fact that its use carries significant extra costs.

The robot itself runs anywhere from $1.2 million to $1.7 million (and many hospitals have several), a required annual maintenance contract is approximately $150,000, and about $2,000 in disposable equipment is required each time the robot is used. Studies have suggested that using the robot may add as much as $4,800 to the cost of each surgery.

Shorter hospital stays and less need for blood transfusions may offset some of these costs, however. In fact, data from a study that Dr. Lowrance and his colleagues have in press indicate that, after adjusting for various factors and excluding the fixed cost of the robot, the cost of robotic prostatectomy and the medical care needed for the ensuing year is comparable to the cost of open surgery and the ensuing year of care in a group of Medicare patients.

Although no other surgical robots have been approved by the FDA, at least two companies are developing similar robotic systems that could, eventually, compete with da Vinci, Dr. Lavery noted, which could reduce costs further.

The dramatic centralization of robotic prostatectomy procedures could be a double-edged sword, Dr. Stitzenberg and her colleagues concluded. A multitude of studies have demonstrated that higher volume is linked to better outcomes, suggesting that having fewer centers performing prostatectomies could improve the overall quality of care. But centralization also raises the specter that access to care could be impaired, particularly in rural areas where market forces could limit the availability of surgeons who can perform the procedure.

The rapid growth of robotic prostatectomy is a proxy for the larger debate about the role of technology in medicine, Dr. Lowrance believes. For example, intensity-modulated radiation therapy and proton-beam therapy—which cost tens of thousands of dollars more than robotic surgery—are also gaining popularity as treatments for localized prostate cancer, even though neither has been shown to produce better outcomes than standard radiation therapy.

"The big question is: How do we balance the uptake of new technology and its cost with the additional [clinical] value it may provide?" he continued. "It's hard to do those types of studies, but we have to continue to ask whether [a new technology] is always worthwhile."

Carmen Phillips

Not Just for the Prostate: Robotic Surgery Makes Inroads in Gynecologic Cancers

The meteoric growth of robotic surgery to treat prostate cancer over the past decade has been mirrored by a similar growth in the treatment of gynecologic cancers, such as cervical and endometrial cancer. (Robotic surgery for gynecologic cancers typically involve a hysterectomy, which may be accompanied by lymph node dissection.)

Minimally invasive surgery with traditional laparoscopy has been a common treatment for gynecologic cancers for two decades, said Dr. Warner Huh of the University of Alabama Birmingham Comprehensive Cancer Center. But many surgeons have switched to the robotic procedure. In particular, the robotic procedure has given surgeons an important new option for treating obese women, Dr. Huh said. Traditional laparoscopy often cannot be performed on obese women, so before robotic surgery these patients typically had to have open surgery.

"An open surgery in these patients is extremely difficult to do," he said. "Some of these women had horrific complications related to their incision."

Obesity rates in Alabama are among the highest in the nation, so robotic surgery has provided an important new clinical option for many women in the state. The average hospital stay following open surgery in obese patients was 4 to 5 days, he said. Now, with the robotic procedure, the average stay is often 24 hours or less. Complication rates have dropped from anywhere between 5 to 10 percent with open surgery to 1 to 2 percent with robotic surgery.

"It's completely changed how we manage these diseases in morbidly obese women," Dr. Huh said.

A Closer Look

New Guidance for Personalized Breast Cancer Screening

The most recent update of the U.S. Preventive Services Task Force (USPSTF) recommendations on breast cancer screening caused widespread confusion among many women and their physicians when it was released in November 2009.

A mammogram of a fatty breast and a dense breast A mammogram of a fatty breast (left) and a dense breast (right). Large areas of dense tissue appear white on a mammogram, which can mask tumors and make them more difficult to detect. [Enlarge]

The most important change made to the recommendations was small but significant—instead of recommending routine mammography for all women beginning at age 40, the task force suggested that the decision to be screened before the age of 50 "should be an individual one and take into account patient context."

"The recommendations were widely interpreted as meaning that no woman under the age of 50 should ever have a screening mammogram, and that was not the intention of the task force, nor would that be very good policy," said Dr. Diana Petitti, professor of Biomedical Informatics at Arizona State University, who was the vice chair of the task force at the time of the 2009 release. "Unfortunately, people couldn't get past the phrase 'recommends against routine screening mammography' for that age group," she continued.

"We were attempting to point physicians and women in the direction of individualized decision making, taking into account a woman's specific constellation of risk factors," explained Dr. Petitti. One persistent obstacle to that approach has been the dearth of guidance available to help individual women predict their risk of breast cancer.

The Influence of Individual Risk Factors

In a study published last month in the Annals of Internal Medicine, a group of researchers led by Dr. John Schousboe of the Park Nicollet Health Services in Minnesota examined the health benefits and cost effectiveness of screening mammography for different groups of women based on a set of known risk factors. They found that breast density was a powerful indicator of who might benefit from earlier screening.

"We tried to go beyond just reinforcing [the USPSTF guidelines] and give some guidance as to how one might go about assessing individual risk based on what we currently know," said Dr. Schousboe.

The researchers collected data on breast cancer incidence and mortality by age from the Surveillance, Epidemiology, and End Results (SEER) database, as well as data on breast cancers and false-positive results found during mammography from the Breast Cancer Surveillance Consortium—a project that NCI's Division of Cancer Control and Population Sciences (DCCPS) has been funding for over 15 years. The researchers also included data on change in quality of life after breast cancer diagnosis from a Swedish database.

Dr. Schousboe and his colleagues used this information to build models examining the health benefits and lifetime costs of mammography every year, every 2 years (biennially), or every 3 to 4 years for women ages 40 to 49, 50 to 59, 60 to 69, and 70 to 79. Within each age group, they refined their estimates based on breast density, history of breast biopsy, and family history of breast cancer—all known risk factors. Breast density was reported by radiologists in clinical practice using the Breast Imaging Reporting and Data System (BI-RADS), which classifies women's breast tissue into four categories, with 1 being the least dense and 4 being the most dense.

Knowing your risk is really important, and the reason breast density is so helpful is that other risk factors, such as family history, are present in only a relatively small minority of people. But half of the population has high breast density, including even more than half of women between the ages of 40 and 49.

—Dr. John Schousboe

For women ages 40 to 49 without dense breast tissue (BI-RADS category 1 or 2) and no other risk factors, biennial mammography was not cost effective. In contrast, biennial mammography was cost effective for women ages 40 to 49 with dense breasts (BI-RADS category 3 or 4), as well as for women with average breast density (BI-RADS category 2) in that age group with a family history of breast cancer and a previous breast biopsy.

Additional findings suggested that density continues to influence risk for older women. Biennial mammography was cost effective for women ages 50 to 59 and 60 to 69 in BI-RADS category 2, 3, or 4, but not for women with the least dense breasts and no other risk factors. This small subset of women could likely go 3 or 4 years between mammograms, Dr. Schousboe and his colleagues proposed.

Cost effectiveness can help women and physicians compare the health benefits of a screening procedure across risk groups, explained Dr. Rachel Ballard-Barbash, associate director of DCCPS's Applied Research Program. "In the area of prevention, we need to screen a large number of people to find the relatively few who are actually at risk," she said.

"So when you see a very high monetary value for a year of life gained, what that says is that the overall benefit is relatively low, and the adverse effects are relatively high. It becomes expensive because you have to screen so many people to benefit one," she summarized.

Can Personal Risk Be Communicated?

The authors of the Annals of Internal Medicine study contend their findings make the case for basing future screening decisions on a baseline mammogram performed at age 40. "Women may choose to have mammography at age 40 years, and those with average or low breast density and no other breast cancer risk factors may choose to repeat screening at age 50 years (including reassessment of breast density) and start periodic screening at that point," they wrote.

"Knowing your risk is really important, and the reason breast density is so helpful is that other risk factors, such as family history, are present in only a relatively small minority of people. But half of the population has high breast density, including even more than half of women between the ages of 40 and 49," said Dr. Schousboe.

"The finding that breast density can be used to determine optimal screening strategies is a provocative result, because it suggests the presence of a biological mechanism that could be exploited to develop biomarkers, monitor risk, and screen for breast cancer on the basis of risk," wrote Dr. Jeanne Mandelblatt of the Lombardi Comprehensive Cancer Center and several colleagues in an accompanying editorial.

Although the biological mechanisms behind breast density are not fully understood, and "while those are important research questions, I think we have enough information now to start using [risk-based personalization]," said Dr. Petitti. "But whether or not doctors can communicate this kind of information is an open question."

 The idea of refining screening recommendations based on individual risk has long been the standard in other areas of medicine.

"The time constraints primary care physicians are under make this communication difficult," commented Dr. Schousboe. Electronic health records that could provide automatic screening prompts based on risk information in a woman's medical history would help overextended physicians, he added.

What's Next for Personalized Cancer Screening

Several groups of researchers across the country are developing brief questionnaires to capture personal information and family histories that could be translated into a breast cancer risk score, according to Dr. Ballard-Barbash.

In addition, a new NCI program called Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) will study ways to individualize and improve screening for breast, colon, and cervical cancers based on recognized risk factors.

The idea of refining screening recommendations based on individual risk has long been the standard in other areas of medicine, explained Dr. Ballard-Barbash. For example, in cardiovascular disease, guidelines such as the Framingham Risk Score are used to identify the patients at high risk who would likely benefit from regular heart-disease screening. "We have not done this to any quantitative degree yet in breast cancer," she said.

The study by Dr. Schousboe and his colleagues and the studies that will likely emerge from PROSPR "are exactly the kind of research that we need—based on data taken from very large populations of women. [These studies are] really trying to understand what biological characteristics may influence risk and how we can identify the risk profiles that will determine which women would benefit or not benefit from specific types of screening," Dr. Ballard-Barbash concluded.

Sharon Reynolds

Read the related story in this issue: "Higher Breast Density Linked to Increased Cancer Risk and Aggressive Tumors"

Featured Clinical Trial

Comparing Targeted Lung Cancer Therapies Based on KRAS Mutation Status

Name of the Trial
Randomized Phase II Study of AZD6244 MEK-Inhibitor and/or Erlotinib in KRAS Wild Type or Mutant KRAS Advanced Non-Small Cell Lung Cancer (NCI-10-C-0218). See the protocol summary.

Dr. Giuseppe Giaccone Dr. Giuseppe Giaccone

Principal Investigator
Dr. Giuseppe Giaccone, NCI Center for Cancer Research

Why This Trial Is Important  
The anticancer drug erlotinib (Tarceva) is considered a standard therapy for patients with advanced non-small cell lung cancer (NSCLC) that has progressed after treatment with chemotherapy. Unfortunately, erlotinib has shown little benefit for NSCLC patients whose tumors have a mutated form of the gene KRAS; about 20 percent of NSCLC patients in the United States have tumors with KRAS mutations. Therefore, doctors are interested in finding other treatments that may help patients with KRAS-mutated NSCLC.

An experimental drug called AZD6244 (selumetinib) blocks the activity of a protein known as MEK, which is a critical component of a molecular pathway that is overactive in some patients with NSCLC. The protein product of the KRAS gene and another protein called EGFR, which is the molecular target of erlotinib, are both upstream components of the same molecular pathway. Early studies suggest AZD6244 may be active in patients with either mutated or normal (wild-type) KRAS genes.

In this trial, investigators will test the KRAS mutation status of tumors in patients with advanced NSCLC whose disease has progressed during or after chemotherapy, or who have refused chemotherapy. Those with wild-type KRAS tumors will be randomly assigned to receive either AZD6244 plus erlotinib or erlotinib alone, whereas those with mutated KRAS tumors will be randomly assigned to receive either AZD6244 plus erlotinib or AZD6244 alone.

Doctors want to know if AZD6244 will help patients live longer without further cancer progression. They will also monitor the patients to assess the safety and tolerability of AZD6244 alone and in combination with erlotinib and to determine whether any of the treatments improves overall survival in these patients.

"There really aren't any good treatment options for non-small cell lung cancer patients with mutations in KRAS," said Dr. Giaccone. "Because the experimental drug blocks a target downstream of EGFR, we think there may possibly be some synergy between AZD6244 and erlotinib.

"We have enrolled about 25 patients in the study so far and they have been tolerating the medications quite well, although there have been some side effects, such as diarrhea," Dr. Giaccone added.

Patients in the study will take AZD6244 twice a day and/or erlotinib once a day and will be required to keep a medication log of their side effects. They will also undergo blood tests and imaging tests and may undergo additional biopsies of their tumors. Treatment will continue in 28-day cycles until the patient's cancer progresses, the patient experiences unacceptable toxicity, the patient decides to leave the study, or the study is terminated.

For More Information
See the lists of entry criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

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

Community Update

Translational Science: From Molecular Information to Cancer Medicine

NCI Translational Science Meeting 2011 banner

More than 800 extramural and intramural researchers, patient advocates, industry representatives, and government officials convened on July 28 and 29 at the NCI Translational Science Meeting 2011 in Washington, DC. Hosted by NCI and co-chaired by Dr. Jennifer Grandis of the University of Pittsburgh and Dr. James Griffin of the Dana-Farber Cancer Institute, the meeting explored the convergence of molecular information and clinical care, with the goal of accelerating early translational cancer research to speed therapeutic benefit to patients.

The meeting featured renowned cancer scientists who presented research in a variety of areas. Each day started with a keynote address and a set of three different "Galvanizing Examples." During these Galvanizing Example sessions, scientists presented their translational research stories and shared their expertise and lessons learned in the successful translation of their project. The research presented underlined the promise of how molecular information has and will lead to more effective cancer detection and improved treatments for patients.

The main objectives of the meeting were to enhance opportunities for productive collaborations among all attendees and encourage cancer investigators to consider other potentially effective approaches to translational research. To that end, the meeting introduced speed poster presentations, during which selected abstract submitters had 3 to 4 minutes to share key information about their work and ideas for future collaborations. Attendees were encouraged to identify partnerships and exchange ideas with colleagues who share similar interests through tsm3Linked, a social networking site created for the meeting.

A variety of panel sessions highlighted the challenges and lessons learned in using molecular information in translational cancer research. These panel sessions were organized by experts in the field and designed to be interactive. Each session allowed time for discussion and questions from the audience. In addition, members of The Cancer Genome Atlas (TCGA) program held a workshop to inform attendees about key TCGA resources available to the scientific community. For the first time, TCGA released outputs from the Broad Institute's Firehose data analysis pipeline for review and discussion.

The meeting underscored NCI's commitment to link and foster collaborative research efforts among government, academia, and other stakeholders to bridge the divide between basic and clinical sciences to ensure that discoveries are translated into therapies for patients as quickly as possible.

The opening plenary sessions, Galvanizing Examples sessions, and Dr. Varmus' address to attendees  from day 1 and day 2 are available via videocast.

—Jennifer Kwok and Elizabeth Dean of NCI's Coordinating Center for Clinical Trials

Cancer.gov Update

Redesigned HINTS Website Unveiled

Screenshot of the Health Information National Trends Survey website

NCI's Division of Cancer Control and Population Sciences recently launched the newly redesigned Health Information National Trends Survey (HINTS) website.

HINTS is a nationally representative survey dedicated to learning how people find, use, and understand health information. The redesigned HINTS website has interactive features to ensure that the HINTS community can stay connected and informed.

The site allows users to:

  • Search HINTS by topic area and quickly access data, reports, and materials on all HINTS topics, from patient-provider communication to tobacco use
  • View HINTS questions to find data displayed in a user-friendly format with associated charts, HINTS Briefs, and publications
  • See a list of citations for all scientific articles published using a given HINTS item
  • Preview high-level findings from the data in the HINTS Data Spotlight
  • Analyze just-released data from HINTS Puerto Rico 
  • Preview the Health Information National Trends Survey Grid-Enabled Measures (HINTS-GEM) database to get a sneak peak at the measures being considered for HINTS IV

Notes

NCI Director Dr. Harold Varmus (Photo by Daniel Sone, NCI) NCI Director Dr. Harold Varmus (Photo by Daniel Sone, NCI)

Varmus Reflects on First Year as NCI Director

At a July 27 town hall meeting marking his first year as NCI director, Dr. Harold Varmus reflected on what he sees as the main accomplishments of his tenure so far and described five areas of "shared ambition" toward which he hopes to guide NCI in the near future.

A full videocast of the event is now online. 

Also available is a written summary of his remarks—which includes links to recent interviews with Dr. Varmus that appeared in Nature, Science, and The Cancer Letter.

 

DCEG's Chatterjee Wins Statistical Awards

Dr. Nilanjan Chatterjee receives the COPSS Presidents' Award from Dr. Xihong Lin. Dr. Nilanjan Chatterjee (left) receives the COPSS Presidents' Award from Dr. Xihong Lin, president of COPSS.

Dr. Nilanjan Chatterjee, chief of the Biostatistics Branch in NCI's Division of Cancer Epidemiology and Genetics, received the Presidents' Award from the Committee of Presidents of Statistical Societies (COPSS). In the field of statistics, the award is considered the most prestigious honor for early career contributions. Dr. Chatterjee is the first recipient from outside academia in the award's 30-year history.

This year, Dr. Chatterjee also received the prestigious COPSS George W. Snedecor Award that is given biannually to a statistician who has made significant contributions to the theory of biometry and authored a notable publication within the last 3 years.

These awards are jointly sponsored by five statistical societies: the American Statistical Association, Institute of Mathematical Sciences, Eastern North American Region of the International Biometrics Society, Western North American Region of the International Biometrics Society, and Statistical Society of Canada.

NCI Researchers Win NIH Director's Awards

NCI researchers won two individual and four group NIH Director's Awards at a ceremony hosted by NIH Director Dr. Francis Collins in Bethesda, MD, on August 2.

Drs. Christine Berg and Sanford Dawsey Drs. Christine Berg and Sanford Dawsey

Dr. Christine Berg, chief of the Early Detection Research Group in NCI's Division of Cancer Prevention, received an award for her work as co-director of the National Lung Screening Trial (NLST). NLST was a randomized national trial involving 53,454 current and former heavy smokers ages 55 to 74. The final results of NLST showed that screening current or former heavy smokers with low-dose helical computed tomography (CT) reduced deaths from lung cancer by 20 percent compared with screening by chest x-ray.

Dr. Sanford Dawsey, a senior investigator in the Nutritional Epidemiology Branch in NCI's Division of Cancer Epidemiology and Genetics, received the Ruth L. Kirschstein Mentoring Award, an honor bestowed on those who have displayed significant leadership, skill, and ability while serving as a mentor. Dr. Dawsey's research focuses on the causes, prevention, and early detection of esophageal and gastric cancers. He was nominated for this award by two of the many research fellows he has supported and trained to lead studies in these areas. 

NCI researchers also won group awards for the following projects and collaborations: the NIH Patient Reported Outcomes Measurement Information System (PROMIS) Working Group; the National Collaborative on Childhood Obesity Research; the Deepwater Horizon Gulf Oil Spill; and the Gulf Long-Term Follow-Up Study.

CCR's Gonzalez and Colleagues Honored for Diagnostic Test

Dr. Frank Gonzalez, Mojdeh Bahar, and Dr. Betty Tong Dr. Frank Gonzalez, Mojdeh Bahar, and Dr. Betty Tong

Dr. Frank Gonzalez, chief of the Laboratory of Metabolism in NCI's Center for Cancer Research (CCR), and Dr. Pedro Fernandez-Salguero, a former CCR fellow who is now a professor in Spain, received the 2011 Federal Laboratory Consortium Award for Excellence in Technology Transfer for developing and transferring a life-saving diagnostic test to the marketplace. The award recognizes those who have done an outstanding job in transferring technology developed in a federal laboratory to partners in the private sector.

Drs. Gonzalez and Fernandez-Salguero determined the molecular basis of 5-fluorouracil (5-FU)-linked toxicity. They discovered a splicing mutation in the gene that encodes dihydropyrimidine dehydrogenase (DPD), an enzyme that is normally involved in degradation of the drug. Patients' sensitivity to 5-FU is directly associated with the presence of a mutated DPD gene and low DPD enzyme activity levels, resulting in the accumulation of 5-FU in the body. 

As a result of this work, patients can now be screened for the mutation before 5-FU is administered, which reduces the risk of life-threatening toxicity. The test has been nonexclusively licensed to several companies in Europe and the United States. 

Mojdeh Bahar and Dr. Betty Tong of NIH's Office of Technology Transfer were recognized for their contribution to the successful transfer of this diagnostic technology to a number of licensees. 

In the United States, approximately 275,000 cancer patients receive 5-FU annually. The transfer of this technology through nonexclusive licenses has allowed this diagnostic test to be widely disseminated.

"As a result of these multiple licenses," noted Dr. Gonzalez, "many patients around the world can avoid being treated with a drug that may prove to do them more harm than good."

Comments Sought on Changes to Human Subject Protections

The U.S. government is considering changes to the rules governing research involving human subjects and is seeking public input on proposed changes related to the ethics, safety, and oversight of human research. The proposed changes are designed to strengthen protections for human research subjects.

The current regulations governing human subject research, often called the Common Rule, were developed years ago when research was predominantly conducted at universities, colleges, and medical institutions, and each study generally took place at a single site. Expansion of human subject research into many new scientific disciplines and venues and an increase in multisite studies have highlighted ambiguities in the current rules and have led to questions about whether the regulatory framework is keeping up with the needs of researchers and research subjects.

Comment is sought on the following:

  • Revising the existing risk-based framework to more accurately calibrate the level of review to the level of risk
  • Using a single Institutional Review Board review for all domestic sites of multisite studies
  • Updating the forms and processes used for informed consent
  • Establishing mandatory data security and information protection standards for all studies involving identifiable or potentially identifiable data
  • Implementing a systematic approach to the collection and analysis of data on unanticipated problems and adverse events across all trials to harmonize the complicated array of definitions and reporting requirements, and to make the collection of data more efficient
  • Extending federal regulatory protections to apply to all research conducted at U.S. institutions receiving funding from the Common Rule agencies
  • Providing uniform guidance on federal regulations

The deadline for comments is September 26. To submit a comment, visit http://www.regulations.gov, enter HHS-OPHS-2011-0005 in the "Enter Keyword or ID" field, and click "Submit a Comment."