National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 19, 2010 • Volume 7 / Number 20

Page Options

  • Print This Document
  • Email This Document

BREAKING NEWS

Results from the Women’s Health Initiative released today show that combined hormone therapy is linked to a modest increase in breast cancer deaths. Read the story.

NEWS

Engraving of a bust of HippocratesCancer Screening Continues Even after Patients Are Diagnosed with Terminal Cancer

A number of patients with advanced, incurable cancer continue to undergo routine cancer screening tests that are unlikely to provide any medical benefit, reported researchers led by Dr. Camelia Sima from Memorial Sloan-Kettering Cancer Center in the October 13 issue of the Journal of the American Medical Association (JAMA).  Read more > >

COMMENTARY

Guest Commentary: Bringing Science to the Market

Michael WeingartenTo many people, NCI is thought of principally as a source of funding for cancer research. But the Institute is also an important driver of small business and technology development. Through its Small Business Innovation Research (SBIR) program, NCI plays a critical role in helping small businesses develop and commercialize innovative technologies that can improve how we prevent, diagnose, and treat cancer. Read more > >

  

IN DEPTH

UPDATES

  • FDA Update

    • Regulatory Science Initiative Will Prepare FDA for New Technologies
    • Warning about Carboplatin Dosing for Physicians and Principal Investigators
  • HHS Update

    • Advisory Committee Will Work to Heighten Breast Cancer Awareness
  • Notes

    • NCI’s Ira Pastan and Carl Wu Elected to Institute of Medicine
    • Meet NCI Experts at APHA

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

Cancer Screening Continues Even after Patients Are Diagnosed with Terminal Cancer

Engraving of a bust of Hippocrates The modern Hippocratic oath warns doctors against overtreatment, which can be broadly defined as medical care that provides no benefit to a patient, either in terms of increased life span or increased quality of life. The benefits of any medical procedure, including cancer screening, must be considered for each individual patient's circumstances. (Hippocrates, engraving by Peter Paul Rubens, 1638. Courtesy of the National Library of Medicine.)

A number of patients with advanced, incurable cancer continue to undergo routine cancer screening tests that are unlikely to provide any medical benefit, reported researchers led by Dr. Camelia Sima from Memorial Sloan-Kettering Cancer Center in the October 13 issue of the Journal of the American Medical Association (JAMA). 

The goal of the study was “to identify a potential opportunity to simultaneously improve care and eliminate wasteful spending in the Medicare program.” Dr. Sima and her colleagues anticipated that a small proportion of patients diagnosed with advanced cancer continue to be screened for cancers other than their primary tumor, despite the fact that they have essentially no chance of benefiting from these procedures. Instead, the researchers found that a “sizeable” proportion of patients with advanced cancer continue to undergo these types of cancer screening tests.

Among 87,736 Medicare recipients age 65 or older who had advanced lung, colorectal, breast, gastroesophageal, or pancreatic cancer listed in NCI’s Surveillance, Epidemiology, and End Results (SEER) tumor registries, almost 9 percent of women received a screening mammogram and 6 percent received a Pap test after diagnosis, 15 percent of men underwent prostate-specific antigen (PSA) screening, and 1.7 percent of all patients underwent endoscopic colorectal cancer screening. These tests were not related to diagnosis or follow-up of the patients’ primary cancer types.

“It takes several years before a clear survival benefit from cancer screening becomes apparent,” explained Dr. Stephen Taplin, chief of NCI’s Applied Cancer Screening Research Branch. “With breast cancer, for example, it takes at least 3 to 5 years after a screening test before fewer women in a screened group die than an unscreened group. That means that a woman needs to have a minimum life expectancy of at least 3 to 5 years to have breast cancer screening affect the length of her life in a meaningful way.” Median survival for the patients in the JAMA study ranged between 4.3 months and 16.2 months, depending on the cancer type, and that is “nowhere near the time needed to benefit from screening for any cancer,” he said.

To understand how the screening rates seen in patients with advanced cancer compared with the screening rates of their peers without cancer, the researchers also looked at the incidence of cancer screening among 87,307 Medicare enrollees without a cancer diagnosis from a random SEER sample who were matched to the cancer patients by age, sex, race, and geographic location. Each control subject had been followed for the same amount of time as the corresponding cancer patient.

In the control group, 22 percent of women underwent mammography during the period studied, 12.5 percent of women received a Pap test, 27.2 percent of men underwent PSA testing, and 4.7 percent of all control subjects underwent endoscopic colorectal cancer screening. The rates of screening among the patients with cancer ranged from 35 percent to 55 percent of the rates observed in the cancer-free control subjects.

In all groups, both higher socioeconomic status and being married were significantly associated with a higher probability of being screened. The strongest predictor of screening in the cancer patients was having undergone screening previously, before a cancer diagnosis.

“The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits,” wrote the authors. “Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer…[a] culture of screening on ‘autopilot.'”

Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer…[a] culture of screening on ‘autopilot.’

—Dr. Camelia Sima et al.

This situation is aggravated by the slow proliferation of electronic health records and other “intelligent” technology that would help flag potentially unnecessary care for reconsideration, they continued.

Another contributing factor may be the difficulty, for both patients and physicians, of discussing a poor prognosis and end-of-life issues. “There is substantial evidence that even when physicians recognize that life expectancy is limited, they do not consistently communicate prognosis, and patients may use denial as a coping strategy to face impending loss,” the authors wrote.

But the communication flaws exposed in this paper go beyond end-of-life discussions, explained Dr. Julia Rowland, director of NCI’s Office of Cancer Survivorship. “It highlights the lack of communication between doctors and patients about the risks and benefits of these kinds of procedures. For each individual, you want to tailor your recommendation to the benefit that can be expected,” she explained.

“An important part of the risk-benefit equation is: will a patient have a better or longer life as a result of doing these tests?” said Dr. Rowland. “And the answer in these scenarios, barring rare cases, would be no. In the context of any screening, you have to take into consideration the health and well-being of the individual for whom you’re going to be making the screening referral.”

Some women with metastatic breast cancer can live for more than 5 years after treatment, and these women may benefit from continued screening for other types of cancer, but this is an individual discussion that needs to occur between doctor and patient, said Dr. Rowland.

“We’ve been very successful nationally in promoting routine screening, to both physicians and patients,” she concluded. “However, what we have not been as good at promoting is patient-doctor dialog.”

—Sharon Reynolds

Cancer Research Highlights

Abiraterone Improves Survival in Metastatic Prostate Cancer

A multinational phase III trial found that the drug abiraterone acetate prolonged the median survival of patients with metastatic, castration-resistant prostate cancer by 4 months compared with patients who received a placebo. The preliminary results from the study were presented October 11 at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, Italy.

Standard prostate cancer treatments reduce blood levels of testosterone, the hormone that fuels the cancer’s growth. However, most prostate cancers eventually become resistant to these treatments. Such cancers are called castration-resistant prostate cancers. Abiraterone acetate is designed to treat these tumors by inhibiting the production of androgen in the testes, adrenal glands, and prostate cancer tumors themselves.

The clinical trial included 1,195 patients from 13 countries whose metastatic prostate cancer had previously been treated with one of two chemotherapy regimens that included docetaxel. Among the 797 patients randomly assigned to receive abiraterone acetate plus the corticosteroid prednisone, median overall survival was 14.8 months. Among the 398 who received prednisone plus placebo, median survival was 10.9 months.

Differences between the placebo and treatment groups also emerged for all of the trial’s secondary endpoints, including the time that it took for prostate-specific antigen (PSA) levels to increase, progression-free survival according to medical imaging, and the number of patients who experienced reductions in PSA levels after treatment. The benefits of abiraterone were determined during a prespecified interim analysis of the study results, prompting the trial’s Independent Data Monitoring Committee to recommend unblinding the trial and offering abiraterone acetate to patients in the placebo arm.

“This is a major step forward in prostate cancer therapeutics,” said principal investigator Dr. Johann de Bono of the Institute of Cancer Research and the Royal Marsden Hospital in the United Kingdom. “Men with metastatic…castration-resistant prostate cancer have a poor prognosis, with only about one in three alive 5 years after diagnosis,” he explained. “For many men, abiraterone acetate can extend life.”

Similar Early-phase Trials Prohibit Different Drugs, Undermining Outcomes

Researchers speaking at the recent ESMO meeting reported “very high rates of unexplained inconsistencies” in the lists of drugs that patients are cautioned against or prohibited from taking while enrolled in phase I and phase II cancer clinical trials that were conducted in North America. Variability in such lists could make it harder to assess and compare study outcomes, they noted, and could compromise patient safety because of possible interactions between the experimental drug and other drugs the patients may be taking. The findings were presented on October 11 in Milan by Dr. Benoit You of Hospices Civils de Lyon in France and Dr. Eric Chen from Princess Margaret Hospital in Canada.

The researchers reviewed protocols for 100 phase I and phase II cancer trials conducted between 2004 and 2009, 77 of which included lists of cautioned or prohibited drugs. As just one example of the problem, they noted that 37 of these trials were studying similar experimental cancer drugs that are metabolized by the liver enzyme CYP3A4, and yet the lists of cautioned or prohibited drugs that should be avoided because they could interfere with this enzyme’s function ranged in size from one drug to up to 152 drugs.

“We believe that inconsistency among lists of drugs may introduce a source of heterogeneity in patient eligibility, in management of study patient symptoms, and thereby in outcomes” of early-phase trials, said Dr. Benoit in a news release. “As a result, it might impact the comparability of different trials.”

Such confusion, the researchers said, is unlikely to have caused harm to patients, “but it may have significantly reduced the overall quality” of the trial results, and thus had an effect on new drug development. “The development of realistic consensual standardized lists of cautioned and prohibited drugs is warranted,” they said.

Surgical Procedure Reduces Disability and Pain Caused by Spine Fractures in Cancer Patients

A surgical technique known as balloon kyphoplasty (BKP) reduces pain and disability due to compression fractures of the spine in cancer patients, according to results of a randomized trial presented October 9 at the ESMO meeting in Milan, Italy. Compression fractures of the spine, which occur when bones in the spine become brittle, are a significant cause of pain and disability in many patients with multiple myeloma or with cancers that have metastasized to the spine.

A multinational research team led by Dr. Leonard Bastian of Klinikum Leverkusen, Germany, followed 134 adults with cancer, who had fewer than three painful vertebral compression fractures (VCFs), and randomly assigned them to receive either BKP (70 patients) or nonsurgical management (64 patients). Patients who had the surgery showed statistically significant reduced levels of disability after 1 month, as assessed by a questionnaire designed to measure disability, and also had significant improvement in back pain 1 week after surgery. Patients who received nonsurgical management showed no improvement in disability or back pain.

After 1 month, patients who had been randomly assigned to nonsurgical management were given the opportunity to receive BKP, and 38 chose to do so. The researchers followed all patients for 12 months and found that all those who underwent BKP reported continued improvements in back pain, activity level, and quality of life over the study period. The number of adverse events was similar between groups.

With BKP, a surgeon inserts a small balloon through a 1 cm incision into the fractured vertebra and inflates the balloon to temporarily restore the shape and height of the vertebra. The surgeon then deflates and removes the balloon and injects a quick-setting bone cement into the vertebral body—the large, roughly cylindrical part of the vertebra—to stabilize it.

BKP “may be the right treatment option for vertebral compression fractures if conventional pain medication has not been effective or has too many side effects,” said Dr. Bastian in an ESMO news release.

“As research into this technique continues, it will be important to conduct double-blind, placebo-controlled studies to identify the place of balloon kyphoplasty in cancer care,” Dr. Fausto Roila of Ospedale Santa Maria, Terni, Italy, commented in the press release.

Guest Commentary by Michael Weingarten

Bringing Science to the Market

Michael Weingarten Michael Weingarten

To many people, NCI is thought of principally as a source of funding for cancer research. But the Institute is also an important driver of small business and technology development. Through its Small Business Innovation Research (SBIR) program, NCI plays a critical role in helping small businesses develop and commercialize innovative technologies that can improve how we prevent, diagnose, and treat cancer. And through an array of new initiatives, NCI is playing a major role in facilitating the success of the small businesses it funds.

Current SBIR awardees are developing technologies that address a broad range of pressing needs, from novel therapeutics to highly sensitive and cost-effective diagnostic and imaging devices. Our newly released funding opportunities cover technologies in some of the most promising areas of cancer research, such as circulating tumor cell analysis and companion diagnostics. In order to secure SBIR funding, applicants can submit unsolicited grant proposals or respond to specific contract proposals for technology development that NCI has identified as a priority, a mechanism that is increasingly being used.

One of the most important changes to the SBIR program is the launch 2 years ago of the Phase II Bridge Awards. Following a model pioneered by the National Science Foundation, the Bridge Awards are intended to help small businesses survive what has come to be known as the “valley of death,” the critical time between early- and late-stage development of new cancer therapeutics, diagnostics, or devices. It is during this time when funding sources can dry up and technologies or interventions with tremendous potential can end up as casualties of an unpredictable and often unforgiving business environment.

Bridge Awards are designed to support the next stage of development for previously funded SBIR Phase II projects. To be competitive for a Bridge Award, which provides up to $3 million in funding, Phase II companies should secure matching funds from the private sector, such as a venture capital firm or a strategic partner (e.g., a large pharmaceutical or device company). In effect, a Bridge Award gives the small business some leverage to attract additional resources.

The results of the first round of Bridge Awards exceeded our most optimistic expectations: awards totaling $17 million went to six companies, and those companies secured approximately $50 million collectively in matching funds from private sources. That’s a nearly threefold leverage for our investment, and these small companies now have the resources to maneuver through the perilous valley of death. This novel public-private partnership initiative is providing a platform to assist small businesses in transitioning to commercially viable entities.

For small businesses, raising funds from investors or strategic partners can still be a very difficult task. For this reason, NCI is now conducting an annual investor forum where potential investors can get a first look at some of the most promising SBIR companies that are developing the next generation of cancer therapeutic, diagnostic, or imaging technologies. The first forum, held last year, was a tremendous success. Our second forum, which will feature 14 awardees, is scheduled for November 9 at Stanford University, and it’s not too late for interested investors to register for this unique event.

Finally, NCI has made significant changes in how the SBIR program is run. Over the last 2 years we have created a development center for managing SBIR and brought on nine program directors who help awardees move through the development and commercialization process. These program directors come from pharmaceutical, biotechnology, and device firms, with both scientific and business expertise and proven track records for getting new technologies to market. They advise SBIR awardees on many aspects of their technology development and business strategies, thus working to accelerate the development and ultimate commercialization of funded technologies.

Interest in NCI’s SBIR program has never been greater. In fact, the number of phase I applications increased nearly 70 percent between 2008 and 2009, a trend that is likely to continue. Much of what the SBIR program does in terms of the development of new technologies goes on outside the view of the public. But the role of NCI SBIR as an engine of innovation is a critical component of improving the science of cancer research and the care of patients with cancer. And, in the end, that’s what NCI’s mission is all about.

Michael Weingarten
Director, NCI Small Business Innovation Research Development Center

Special Report

Hormone Therapy Linked to Modest Increase in Breast Cancer Deaths

Women who used a combination of the hormones estrogen and progestin to treat menopausal symptoms during the Women’s Health Initiative (WHI) study had more cases of invasive breast cancer than non-users, and these cancers tended to involve the lymph nodes, according to an 11-year follow-up report on the participants. In addition, women who received the combined-hormone therapy had a slightly higher death rate from breast cancer and from other causes than women who received a placebo, researchers said today in the Journal of the American Medical Association (JAMA).

Women’s Health Initiative banner

This report is the first from the WHI to include mortality data as well as breast cancer incidence by cancer subtype. “The surprising result was that breast cancer incidence seemed to be increased for all categories of the cancer,” said lead investigator Dr. Rowan T. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.

The original study included more than 16,600 postmenopausal women age 50 to 79 years who were randomly assigned to receive combined hormone therapy or placebo. For the current analysis, the researchers obtained re-consent for additional follow-up from more than 12,700 (83 percent) of the surviving participants. With the longer follow-up, the researchers were able to address some unanswered questions, such as whether hormone use increases breast cancer deaths or influences the type of breast cancer a woman develops.

“This analysis confirms that there is an effect on mortality associated with the hormones,” said Dr. Peter B. Bach of Memorial Sloan-Kettering Cancer Center, who wrote an accompanying editorial. “It also does away with an assumption suggested by some observational studies that hormones are associated with less aggressive cancers.”

Some but not all observational studies have found that although hormone therapy may cause more breast cancers, these cancers, on average, tend to have favorable characteristics and are associated with a lower stage and longer survival than breast cancers in women who did not use hormones. But the findings from the WHI—a randomized controlled trial that is not subject to the same potential biases as an observational study—contradict this idea.

“The WHI results have always suggested that there are elevations in risk for all tumor subtypes,” said co-author Dr. Garnet Anderson of the Fred Hutchinson Cancer Research Center in an e-mail message. “And now the data are increasingly saying that tumors under the influence of estrogen plus progestin are likely to be more advanced and possibly even lethal.”

Compared with placebo, the use of estrogen plus progestin was associated with a statistically significant increase in the incidence of invasive breast cancer overall (295 cases versus 385 cases, respectively). In addition, increased incidence was found among hormone users across all categories of breast cancer examined, but the association was statistically significant only for the presence of positive lymph nodes (43 versus 81, respectively).

In terms of mortality, there were more deaths attributable to breast cancer (2.6 versus 1.3 per 10,000 women per year) and more deaths due to all causes following a diagnosis of breast cancer (5.3 versus 3.4 per 10,000 women per year) in the combined hormone therapy group compared with the placebo group.

“The mortality effects are what we all expected—namely, that they would fall in line with the effects we have seen on incidence,” said Dr. Bach. 

Although the increase in breast cancer mortality among hormone users was modest, it is still an increase, noted Dr. Leslie Ford of NCI’s Division of Cancer Prevention and the Institute’s WHI liaison. “These are real tumors; they are significant tumors. And now the data confirm that you can die from them.”

Last year, WHI investigators reported that, although combined hormone therapy did not increase the incidence of lung cancer, it increased the number of deaths from lung cancer. Together with the current results, it appears that a therapy designed to help women manage menopausal symptoms may increase deaths from the two leading causes of cancer death in women, said Dr. Chlebowski.

“If combined hormone therapy were a new drug, it’s hard to see how you could get it approved,” he added.

If combined hormone therapy were a new drug, it’s hard to see how you could get it approved.

—Dr. Rowan T. Chlebowski

Unless the mortality risks of lung cancer and breast cancer can be mitigated, the use of combined hormone therapy except as short-term therapy in women with symptoms that are not improved by other therapies seems unwarranted, the study authors wrote. They went on to say that it was not possible to reliably define a safe interval for combined hormone therapy.

Dr. Bach echoed this idea in his editorial. Doctors who prescribe brief courses of hormone therapy should be aware that this strategy has not been proven in rigorous clinical trials and that the future negative effects for their patients are unknown, he wrote. So while doctors might discuss the risks and benefits of hormone therapy with patients to help a patient reach an informed decision, the underlying information for making the decision would be speculative.

“The view that these drugs are safe for short periods of time is just not based on evidence or data,” Dr. Bach said in an interview.

Although the potential harms of this treatment have been known since 2002, tens of millions of prescriptions for combined hormone therapy are written for women in the United States each year. Women who are already taking the drugs, Dr. Chlebowski noted, could potentially talk with their doctors about stopping the hormones for a period of time to see if symptoms have improved, as sometimes happens over time.

Meanwhile, non-hormonal treatments for menopausal symptoms are in development. In 2008, NIH established a research network to conduct clinical trials of promising therapies. Preliminary results from the group’s first trial, which tested escitalopram, were presented recently at a scientific meeting and are being submitted for publication, according to Dr. Anderson. Two additional trials are being planned.

After the initial WHI results were reported in 2002, there was a substantial decrease in breast cancer incidence in the United States, which researchers attributed to declines in combined hormone therapy use. Based on the updated findings, the study authors predicted that there would also be a reduction in breast cancer mortality in the United States in the future.

—Edward R. Winstead

Spotlight

Technology
This is the fourth article in a series of stories about new technology for cancer diagnosis or treatment. View a list of articles in this series.

Testing a “Smarter” Biopsy for Prostate Cancer

During an image-guided prostate biopsy, Dr. Peter Pinto and his team place needles to predetermined targets. During an image-guided prostate biopsy, Dr. Peter Pinto (left) and his team place needles to predetermined targets.

The patient, a 63-year-old African American, had undergone 10 separate biopsies for prostate cancer over the previous decade, and each test had come back negative for cancer. Based on the patient’s history of a rising prostate-specific antigen (PSA) level, his urologist suspected cancer but could not find it. Finally, last spring, the urologist referred his patient to Dr. Peter Pinto of NCI’s Center for Cancer Research (CCR) to enroll in a clinical trial testing an experimental image-guided biopsy.
 
Using the new approach, Dr. Pinto and his colleagues identified six lesions in the patient’s prostate that all tested positive for cancer. The lesions were in the anterior prostate, a region that is difficult to assess by conventional biopsy or digital rectal exam. But the lesions showed up on magnetic resonance imaging (MRI) scans, and Dr. Pinto used the image-guided system to collect tissue from the precise locations in the prostate.

“When the patient came to see us, there was considerable frustration on the part of the urologist, who had been repeating the same biopsy technique over and over expecting a different result,” recalled Dr. Pinto, a member of CCR’s Urologic Oncology Branch. “But there really were not any other options until the image-guided approach became available.”

After learning the biopsy results, the patient decided to have his prostate removed surgically, and Dr. Pinto performed the operation at the NIH Clinical Center.  

Fusing MRI and Ultrasound Images

Developed by a multidisciplinary team that includes clinicians, researchers, engineers, and computer scientists, the image-guided biopsy represents a kind of global positioning device. A patient’s initial MRI serves as a template for directing needles to specific places in the prostate and mapping the locations of suspected cancer. Prior to the biopsy, the MRI data are merged, or fused, with real-time ultrasound imaging data, and together these data guide the procedure.

“This technology gives you a smarter, truer biopsy,” said Dr. Bradford Wood, who directs the NIH Center for Interventional Oncology and is leading the research with Drs. Pinto and Peter Choyke of CCR. “All too often the standard biopsy is inadequate. A suspicious area may be hidden from the standard technique, and this approach offers another way of mapping the tissue.”

With a conventional prostate biopsy, 6 to 12 needles are inserted into selected regions of the gland. (The sites of these insertions are not recorded.) This approach is not comprehensive and may miss cancer. What’s more, a needle that hits cancer may not strike the center of a lesion, which could lead doctors to underestimate the stage of a patient’s disease.

You must have flash installed and enabled to view the video.


Howard Silby, a prostate cancer survivor, talks about his experience with NCI's Molecular Imaging Program at NIH. One of his doctors and director of the Molecular Imaging Clinic, Dr. Peter Choyke, explains the science behind one molecular imaging study under way at the NIH Clinical Center and what the results will mean for the future of prostate cancer diagnosis and treatment. (Video produced and edited by Sarah Curry)

“Patients in this trial recognize that the needle biopsy gives an incomplete picture of what’s going on in prostate cancer,” said Dr. Choyke, chief of NCI’s Molecular Imaging Program. “They are happy to come in for an MRI because they want to have a better picture of their disease.”

Dr. Pinto added: “It seems to me that prostate cancer is the only solid tumor that doctors find by randomly sampling an organ.”

The image-guided system adds about 5 to 7 minutes to a conventional prostate biopsy, said Dr. Baris Turkbey, a radiology fellow in CCR, who has overseen the MRI scans for many of the nearly 260 men in the trial. Although the technique is still experimental, the NIH researchers are working with their partners at Philips Healthcare to transform the research platform into a commercial tool that could be used by urologists on an outpatient basis.

In a recent study, the researchers described the technology and reported results for 50 patients. The system, they concluded, may be useful for documenting the location of prior biopsies as well as directing subsequent biopsies to regions of the prostate not previously sampled. Because the needles are equipped with tracking devices, the precise locations of each sample could be recorded for patients undergoing active surveillance (formerly known as watchful waiting).

Toward Targeted Treatments

In addition to finding cancers, the system could also lead to more targeted treatments for the disease. “This platform may play a role in allowing us, one day, to offer patients focal therapy for prostate cancer,” said Dr. Pinto. Focal therapy involves techniques such as freezing or burning lesions within the prostate gland while sparing healthy tissue.

The techniques for freezing and burning lesions in the prostate exist now, Dr. Choyke noted. “But the critical question for the field has been: how do you identify the targets?”

Another challenge for researchers is finding ways to distinguish lethal prostate cancers from those that may never cause harm in a man’s lifetime. Current treatments for prostate cancer—including prostatectomy, radiation, and ablation—target the entire prostate gland, and all have potential side effects such as incontinence, rectal injury, and loss of sexual function.

Along with the image-guided biopsy, the researchers are also testing molecular imaging agents that could provide information about the biology of the cancer rather than just the location. (See video above.) The two approaches are complementary and could lead to ways to distinguish the lethal and nonlethal forms of the disease, the researchers said.

A goal of the current work, said Dr. Wood, is to “narrow the gap between diagnosis and treatment.” Instead of merely diagnosing a patient’s cancer, the researchers want to be able to use the information they collect at diagnosis during treatment. Toward that end, the imaging system could be modified to target lesions in the prostate, and clinical trials are being designed using focal prostate therapy, he noted.

In the current trial, after Dr. Pinto surgically removes a patient’s prostate, it is placed in a specially designed mold and sent to NCI’s Laboratory of Pathology. There, Dr. Maria Merino examines the specimen according to the same “cut lines” that were used on the imaging studies to confirm that suspicious lesions on an MRI really are cancerous. This process could eventually reveal associations between lesions found on MRI and certain types of disease.

In the meantime, participants in the trial are helping to advance the research. As one patient told Dr. Pinto, “My father had prostate cancer, and I have prostate cancer. By participating in this study, I know that my son may have better care if he gets the disease.”

Edward R. Winstead

A Closer Look

Partners in Crime: Using Synthetic Lethality to Identify New Cancer Targets

One of the big stories of the past year in cancer research has been the emergence of several agents that target an enzyme known as PARP1. Early-stage clinical trials involving women who have particularly difficult-to-treat types of breast cancer, including tumors with a mutated form of either the BRCA1 or BRCA2 gene, have shown that treatment with drugs that block PARP1 produced promising results. (See the “Also in the News” sidebar below.)

Diagram showing a mechanism for cancer cell death in cells with a BRCA mutation and DNA repair blocked by a PARP1 enzyme A cancer cell with mutations in the BRCA gene has a limited capacity for repairing damaged DNA, but can still remain viable. If another route of DNA repair is also blocked, such as the type performed by the PARP1 enzyme, the cancer cell loses an important fail-safe and is more likely to die.

Similar to PARP1, the two BRCA genes produce proteins that help repair damaged DNA. When these genes are mutated, they can transform a healthy cell into a cancerous one. However, combining a BRCA mutation with a PARP1 enzyme that is under therapeutic assault eliminates one potential fail-safe mechanism that the genetically unstable but still-thriving cancer cell needs to survive. The mutated genes and PARP1 enzyme have what is called a “synthetic lethal” relationship: when either one alone is blocked or damaged, the cancer cell is all right; when both are blocked or damaged, the cancer cell dies.

A number of oncology research groups are using relatively new tools such as heavy-duty bioinformatics and small-molecule or RNA interference (RNAi) screens to identify synthetic lethal relationships between well-established therapeutic targets and, in some cases, lesser-known components of cancer cells’ signaling networks. They believe these discoveries could lead to new treatment options that overcome age-old problems in oncology, such as excessive toxicity, treatment resistance, and “undruggable” targets.

Prior to the clinical trial results with the PARP1 inhibitors, synthetic lethality was “a promising theoretical concept that people thought should work [in humans] because it works in model organisms,” said Dr. William Hahn of the Dana-Farber Cancer Institute. Now, he continued, it’s been “taken all the way to the patient” and shown “to have a clinical benefit, and that’s why people are excited about it.”

Finding a Hit in a Signaling Network

The concept of synthetic lethality is very attractive, said Dr. Igor Astsaturov, a researcher at Fox Chase Cancer Center who is involved in several synthetic lethality-related projects. Most normal cells are dormant for long periods, he explained, and they use growth-related signaling pathways only intermittently. Genetically unstable cancer cells, on the other hand, “are continuously exploiting these signaling systems to their advantage, so they are vulnerable to inhibition.”

Also in the News: PARP Inhibitor Shows Promise in Difficult-to-treat Breast Cancer

An investigational drug that targets PARP-mediated DNA repair improved survival in women with metastatic, triple-negative breast cancer, U.S. researchers reported last week at the European Society for Medical Oncology Congress in Milan. Updated results from a 121-patient phase II clinical trial showed that a combination of chemotherapy and the PARP inhibitor iniparib improved overall survival by 5 months (12.3 months versus 7.7 months) in women with this difficult-to-treat type of breast cancer compared with women who only received chemotherapy.

Women in the trial who received iniparib also had superior response rates and longer progression-free survival compared with women who only received chemotherapy. The addition of iniparib to chemotherapy did not appear to produce any additional side effects, the researchers reported.

“These data are promising and suggest that iniparib may provide a potential new treatment option for patients with metastatic triple-negative breast cancer, which currently has limited therapeutic options,” said the trial’s lead investigator, Dr. Joyce O’Shaughnessy, who directs the Breast Cancer Research Program at the Baylor Charles A. Sammons Cancer Center in Texas, in a news release.

Based in large part on findings reported by Dr. Astsaturov and his colleagues in Science Signaling last month, several human trials testing treatments based on synthetic lethality are being planned at Fox Chase. Their study was centered on the epidermal growth factor receptor (EGFR), a protein that is overexpressed in a number of cancers and is the target of several FDA-approved cancer drugs.

To conduct the study, explained co-investigator Dr. Erica Golemis, the team exhaustively mined gene and protein databases to construct a large but still limited “library” of 638 proteins that make up a broad intracellular signaling network in which EGFR is a critical component. Using an RNAi-based screen, they identified synthetic lethal relationships between the products of several genes and EGFR: when EGFR was inhibited by a drug and expression of each of the other genes was simultaneously “knocked down” by small interfering RNAs, there was an increase in cancer cell death. (See the box at the end of this article.)

“The study generated a lot of solid leads,” Dr. Astsaturov said. Most of the gene products that had a robust synthetic lethal relationship with EGFR tended to cluster near to EGFR or had direct or indirect interactions with it. Several of the strongest hits “pointed directly to logical targets for clinical exploration of combination therapies,” he continued, including Aurora kinase A and STAT3, both of which are targets of available investigational drugs. The Fox Chase trials will combine an EGFR inhibitor with an Aurora kinase A inhibitor in patients with metastatic lung cancer and head and neck cancer.

Getting Around the Shortcomings of Current Treatments

One of the theoretical advantages of cancer treatments based on synthetic lethality—now with some clinical evidence to support it—is that they should have minimal toxicity, because only cells with the “impairments” that comprise the synthetic lethal relationship (e.g., a mutated gene and a therapeutically inhibited enzyme) should be affected. Those cells should almost exclusively be cancer cells. In trials that tested PARP1 inhibitors, the drugs appeared to add little in the way of side effects.

Treatments based on synthetic lethality, stressed Dr. Hahn, may also help to overcome the problem of targets that, either due to underlying biology or the targets’ actual physical makeup, are “undruggable” with small molecule and biologic drugs; a number that, according to one recent estimate, could represent as much as 75 percent of the identified molecular targets for cancer.

A prime example of a potentially valuable undruggable target is the oncogene KRAS, which is commonly mutated in a number of cancers, including pancreatic, lung, and colon. But synthetic lethality may offer a route around the problem.

Last year, Dr. Hahn and colleagues published studies in Cell and Nature in which they used RNAi screens in cancer cell lines with mutant KRAS to identify a synthetic lethal relationship between KRAS and two kinase enzymes, STK33 and TBK1. Kinases have proven to be highly druggable targets. In the same issue of Cell, Dr. Steven Elledge from Harvard Medical School and colleagues identified another kinase called PLK1 that had a strong synthetic lethal relationship with mutant KRAS.

Although many synthetic lethality studies rely on small-molecule and RNAi screens, the synthetic lethal relationship between PARP1 and BRCA mutations was actually deduced from previous research on DNA repair and then validated in cell lines and animal models before moving into human trials. (Researchers are already searching for similar relationships between PARP1 and other DNA-repair targets.) While it is possible that other synthetic lethal relationships can and will be identified in this way, it will be difficult to do, said Dr. William Kaelin from the Dana-Farber Cancer Institute.

Although the understanding of the biology that underlies cells’ molecular networks has improved substantially, it is “far from complete,” Dr. Kaelin said. “The lesson from the screens in model organisms, such as yeast, is that it’s difficult to predict synthetic lethal interactions.”

And although Dr. Kaelin believes that identifying and targeting individual “drivers” of disease is and will continue to be a fruitful therapeutic avenue, synthetic lethality research underscores the importance of the context in which those targets reside. “At the end of the day, we are dealing with molecular networks rather than simple linear pathways,” he said.

Improved understanding of how those networks operate may yield yet another benefit: preventing the emergence of resistance to therapy, something that can be achieved “by using combinations of agents that are not cross resistant and have unique mechanisms of action,” Dr. Kaelin said.

The parallel that is often raised is the “cocktail” therapy approach used to treat HIV. The idea is to “hold things down so that the tumor can’t select for resistance,” Dr. Golemis explained. “Whether you do that by sequential treatments or by developing good combination treatments that hit multiple hubs in the signaling network, we’re gradually accumulating the tools to be able to do this.”

Carmen Phillips

Anatomy of an RNAi Screen for Synthetic Lethality

From the initial library of 638 proteins chosen for the screen in the Fox Chase study, the team identified more than 60 proteins that cancer cells under assault with an EGFR inhibitor rely on to survive. The screens use RNA interference in several cancer cell lines to, one at a time, knock down the expression of the genes that produce these proteins. The cell lines are simultaneously treated with an EGFR inhibitor or a control drug that does not affect cancer cell viability. The team then looked at the effect of the knockdown of each individual gene on the extent of cell death in both EGFR-inhibitor treated and non-treated cells. From the initial group of “hits”—genes that, when silenced, yielded increases in cancer cell death in the inhibitor-treated cells—the team did additional validation testing with other small interfering RNAs to confirm the findings and isolate the most robust synthetic lethal relationships.

The entire study took more than 3 years to conduct, Dr. Golemis explained. Although it is a cumbersome process, she added, “RNAi screening is becoming a dominant way of approaching biological networks.”

One of the first groups to use this approach was the laboratory of Dr. Lou Staudt in NCI’s Center for Cancer Research. As described in a paper published in 2006 in Nature, they used the approach—what they called an “Achilles’ heel genetic screen”—in cell lines of diffuse large B-cell lymphoma to identify genes aside from known oncogenes and tumor suppressors that cancer cells need to survive.

Featured Clinical Trial

Eliminating Hairy Cell Leukemia Minimal Residual Disease

Name of the Trial
Cladribine with Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia (NCI-09-C-0005). See the protocol summary.

Dr. Robert Kreitman Dr. Robert Kreitman

Principal Investigator
Dr. Robert Kreitman, NCI Center for Cancer Research

Why This Trial Is Important
Hairy cell leukemia is a rare type of cancer in which the body produces a large number of abnormal B lymphocytes. These lymphocytes appear “hairy” when viewed under a microscope and can be found in the bone marrow, spleen, and blood. Although hairy cell leukemia usually grows slowly, it does require treatment if symptoms and signs develop, such as low blood cell counts, recurrent infections, or a swollen spleen. Initial treatment with the chemotherapy drug cladribine usually induces a remission. However, there’s no evidence that, with remission, the disease is cured. Given time, it appears that all patients will relapse unless they die from something else first.

“If you follow patients over time (now about 20 years since the introduction of cladribine), you don’t find a plateau in the disease-free survival curve, which means that over time patients are still relapsing at a constant rate,” said Dr. Kreitman. “So eventually the disease will come back, at least for most, and, for younger patients in particular, this is a significant problem.”

Minimal residual disease can be found in a very high percentage of patients. The residual hairy cells often display an unusually high number of CD20 proteins. CD20 is an antigen found on the surface of all B lymphocytes, but the antigen is typically overexpressed in B-cell cancers like hairy cell leukemia. Consequently, CD20 is an important target for the treatment of these cancers. A monoclonal antibody called rituximab targets CD20 and has helped improve responses and survival in patients with several different types of B-cell diseases. Doctors want to see if the addition of rituximab to cladribine will eliminate minimal residual disease in patients with hairy cell leukemia.

In this trial, patients with hairy cell leukemia who have disease-related symptoms that require treatment, and who have not been treated or have had only one prior treatment with cladribine, will be randomly assigned to receive cladribine with either concurrent rituximab or rituximab at least 6 months after completing cladribine therapy. The primary endpoint of the study is to determine whether rituximab given at the same time as cladribine decreases minimal residual disease. Six months after initial treatment, patients given rituximab and cladribine together will be compared with those in the delayed-rituximab group to see if the rituximab is having a detectable effect.

“In terms of eradicating minimal residual disease long term, we don’t know whether it’s better to give rituximab at the same time as cladribine, or after 6 months,” said Dr. Kreitman. “Giving both agents concurrently may lead to a synergistic effect, with each agent enhancing the other. However, delaying rituximab until the cladribine has had time to eliminate most of the hairy cells may lead to a better possibility of eliminating disease altogether.

“It’s possible that patients receiving rituximab up front may fare better in the short term but that the delayed rituximab group will eventually catch up in terms of keeping the disease at bay,” he explained. “So both arms of the trial may end up producing equivalent outcomes, but those outcomes should be better than if the patients had received cladribine alone. Ultimately, we hope that eliminating minimal residual disease will lead to patients being cured or at least delaying any relapse until further into the future.” 

For More Information
See the lists of eligibility 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/ft-all-featured-trials.

FDA Update

Regulatory Science Initiative Will Prepare FDA for New Technologies

On October 6, FDA Commissioner Dr. Margaret Hamburg released a report that outlines plans to modernize the agency’s product safety review and approval procedures through its Regulatory Science Initiative.

The report notes that recent breakthroughs in science and technology, including the mapping of the human genome and applications of nanotechnology, “have the potential to transform our ability to prevent, diagnose, and treat disease.” The FDA’s regulatory procedures have not kept pace with new scientific developments, the report continues, and the agency’s initiative seeks to address that gap by advancing “regulatory science to develop new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products.”

The President’s FY 2011 budget request would provide the FDA with $25 million for the initiative to “expand ongoing efforts within the agency and build additional partnerships with academia, industry, and government agencies,” the report says.

As an example of such partnerships, NIH and the FDA recently announced joint awards to advance regulatory science through four research projects. NIH will contribute $9.4 million over 3 years to the projects, while the FDA will provide $950,000. “These projects show the potential breadth of opportunity that comes from advancing regulatory science,” Dr. Hamburg said. “The results are likely to have broad application to researchers across scientific disciplines and will result in better-informed regulatory decision-making and faster drug development and approval processes.”

Warning about Carboplatin Dosing for Physicians and Principal Investigators

Based on recommendations from NCI’s Cancer Therapy Evaluation Program (CTEP), the FDA sent a communication October 8 to the U.S. oncology community warning of recent changes in the methods of measuring serum creatinine that may affect the dosing of carboplatin cancer therapy.

The new standardized Isotope Dilution Mass Spectrometry (IDMS) method, which all U.S. clinical diagnostic laboratories will use by the end of 2010 to measure the metabolic marker creatinine in blood serum, appears to underestimate creatinine at low levels (e.g., ~0.7 mg/dL) compared with older methods. This discrepancy could result in an overestimation of kidney function and lead to inappropriate dosing of carboplatin.

Thus, the notice states: “If a patient’s [glomerular filtration rate] is estimated based on serum creatinine measurements by the IDMS method, [the] FDA recommends that physicians consider capping the dose of carboplatin for desired exposure….”

The notice provides guidance on how to determine the maximum dose and adds that principal investigators of ongoing clinical trials that involve carboplatin should determine whether the dosing in those trials needs to be adjusted based on the new information.

HHS Update

Advisory Committee Will Work to Heighten Breast Cancer Awareness

During an October 16 teleconference marking Breast Cancer Awareness Month, HHS Secretary Kathleen Sebelius announced the formation of a new federal advisory committee that will work with the CDC to heighten awareness among women under the age of 40 about breast health and breast cancer. The 15-member committee will be chaired by Dr. Ann Partridge, clinical director of the Breast Oncology Center at the Dana-Farber Cancer Institute.

The new advisory committee is a result of the Patient Protection and Affordable Care Act, which was signed into law by President Barack Obama earlier this year and charged the CDC with developing initiatives to improve knowledge of breast health and breast cancer, with a specific focus on younger women.

During the teleconference, Secretary Sebelius was joined by Second Lady Dr. Jill Biden, and they discussed other aspects of the law designed to help improve the detection and treatment of breast cancer, including requirements for new insurance plans to cover preventive screenings, such as mammograms, without charge and outlawing the denial of insurance coverage because of pre-existing conditions.

Notes

NCI’s Ira Pastan and Carl Wu Elected to Institute of Medicine

Drs. Ira Pastan and Carl Wu Drs. Ira Pastan and Carl Wu

Two researchers from NCI’s Center for Cancer Research were recently elected to the Institute of Medicine (IOM): Dr. Ira H. Pastan, chief of the Laboratory of Molecular Biology, and Dr. Carl Wu, chief of the Laboratory of Biochemistry and Molecular Biology. They were among 65 new inductees announced at the IOM’s annual meeting on October 11 at the National Academy of Sciences in Washington, DC.

Dr. Pastan joined NCI in 1969 and established the Laboratory of Molecular Biology the following year. His early studies focused on the mechanisms of hormone action, endocytosis, and the regulation of gene expression in bacteria and animal cells.

In the 1990s, he initiated a new targeted cancer therapy program. He has used genetic engineering to create novel proteins he named recombinant immunotoxins. Several recombinant immunotoxins are now in clinical trials for various cancers, and one has produced many complete remissions in drug-resistant hairy cell leukemia.

Dr. Pastan obtained his M.D. from Tufts University School of Medicine, completed his medical training at Yale University, and received research training at NIH. He is a member of the National Academy of Sciences and has co-authored over 1,100 scientific publications.

Dr. Wu joined NCI in 1982 and initiated studies on the biochemical mechanism of chromatin remodeling. As a junior fellow at Harvard University under Nobel laureate Dr. Walter Gilbert, Dr. Wu provided the first evidence that chromatin is remodeled to induce or erase DNase hypersensitive sites at cellular gene promoters. His group reported the discovery of an ATP-dependent chromatin remodeling activity in cell-free extracts and the purification and characterization of the responsible enzyme, named NURF.

Dr. Wu’s studies have led to the characterization of a large family of ATP-dependent chromatin remodeling enzymes now known to be involved in many aspects of DNA metabolism. He is currently studying histone dynamics and the role of chromatin in organizing centromeres and kinetochores for proper chromosome segregation.

Dr. Wu received his Ph.D. from Harvard University and has been recognized by a number of awards and by election to the National Academy of Sciences, the American Academy of Arts and Sciences, the Academia Sinica, and the European Molecular Biology Organization.

Membership in the IOM is considered one of the highest honors in the fields of health and medicine, and it recognizes individuals who have demonstrated outstanding professional achievements and commitment to service. Current active members elect new members from among candidates nominated for their accomplishments and contributions to the advancement of the medical sciences, health care, and public health.

Meet NCI Experts at APHA

Visit Us at APHA

NCI will conduct several Meet the Experts sessions at the American Public Health Association’s (APHA) 138th Annual Meeting November 6–10 at the Colorado Convention Center in Denver. Visit booth #1220 and talk with NCI experts about the wide range of collaborative opportunities available through NCI.

Sunday, November 7

2:00 p.m.

Jeff Swarz
Making Web Content Interactive

3:00 p.m.Leslie Cooper
Opportunities for Research and Training through NCI’s Center to Reduce Cancer Health Disparities
4:00 p.m.Nina Ghanem
Health Communications Internship Program

Monday, November 8

10:00 a.m.

David E. Nelson
Cancer Prevention Fellowship Program

11:00 a.m.Isis Mikhail
NCI Research Funding Opportunities in Cancer Complementary and Alternative Medicine
12:00 p.m.Amy Sanders
Informatics for Consumer Health (ICH)
1:00 p.m.Richard Moser and Lila Rutten
Health Information National Trends Survey (HINTS)/Grid-Enabled Measures (GEM)
2:00 p.m.Margaret Ames
NCI Interactive Budget Analysis Tool
3:00 p.m.Emmanuel Taylor and James Hadley
Opportunities for Research and Training through NCI’s Center to Reduce Cancer Health Disparities
4:00 p.m.Special NCI Networking Session

Kelly Blake
Communicating Breast Cancer Screening Guidelines

Alissa Gallagher
Creating Virtual Cancer Communities

Anne Hartman 
Identifying Solutions to Survey Problems, Examples from Tobacco Control

Harry Kwon
Increasing Awareness of Cancer Information among Minorities

Salma Shariff-Marco
Measuring Racial/Ethnic Discrimination in Health Surveys

Tuesday, November 9

10:00 a.m.Karen Parker 
International Cancer Research Partnership
11:00 a.m.Robin Harrison
NCI's Evidence-based Cancer Information (PDQ) - Relevance for Public Health Practitioners
12:00 p.m.Richard Moser and Lila Rutten
Health Information National Trends Survey (HINTS)/Grid-Enabled Measures (GEM)
1:00 p.m.Russell Glasgow
Dissemination and Implementation of Cancer Control Science
2:00 p.m.April Oh
Classification for Laws of School Students/Attitudes and Behavior (C.L.A.S.S.)
3:00 p.m.Ryan Patrick
State Cancer Legislative Database
4:00 p.m.Antoinette Percy-Laurry
Surveillance, Epidemiology, and End Results (SEER) Program