National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
May 31, 2011 • Volume 8 / Number 11

BREAKING NEWS

XMRV Not Likely Associated with Human Disease

An NCI-led team of  researchers have deciphered the origins of xenotropic murine leukemia virus-related virus (XMRV), undermining claims for the retrovirus's role in human disease. The study results appear online in Science today. For more information, visit the NCI News page.

NEWS

Study Questions Benefit of Surgery versus Watchful Waiting in Some with Prostate Cancer

A series of dates stretching into infinity

Long-awaited results from a U.S. clinical trial indicate that, in men diagnosed with localized prostate cancer, surgery did not improve survival or decrease the risk of dying from prostate cancer. After 12 years of follow-up, there was no difference in overall or prostate cancer-specific survival between men randomly assigned to radical prostatectomy and those assigned to watchful waiting, observation with palliative treatment if the disease begins to progress. Read more > >

A MESSAGE TO READERS

ASCO Coverage

The American Society of Clinical Oncology's 2011 annual meeting will take place June 3–7 in Chicago. This issue of the NCI Cancer Bulletin includes stories on studies released before the meeting. For more ASCO coverage, see the June 14 issue.

  

IN DEPTH

UPDATES

  • FDA Update

    • Sunitinib Approved to Treat Pancreatic Neuroendocrine Tumors
  • Cancer.gov Update

    • Updated Tool More Accurately Estimates Breast Cancer Risk for Asian Americans
    • NCI Recovery Act Web Site Highlights Community-Based Cancer Care and Job Creation
  • Notes

    • NCI's Douglas R. Lowy and John T. Schiller Awarded Sabin Medal
    • Upcoming Cancer Survivors Workshop to Address Stress Management for Caregivers
    • NCI Calls for Applications from Cancer Control Practitioners
    • Spring 2011 NCI CAM News Released

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

Study Questions Benefit of Surgery in Some Men with Early-Stage Prostate Cancer

Long-awaited results from a U.S. clinical trial indicate that, in men diagnosed with localized prostate cancer, surgery did not improve survival or decrease the risk of dying from prostate cancer. After 12 years of follow-up, there was no difference in overall or prostate cancer-specific survival between men randomly assigned to radical prostatectomy and those assigned to watchful waiting, observation with palliative treatment if the disease begins to progress.

A series of dates stretching into infinity

Dr. Timothy Wilt of the Veterans Affairs Center for Chronic Disease Outcomes Research in Minneapolis, MN, presented the findings from the trial, called PIVOT, at the American Urological Association (AUA) annual meeting on May 17.

Several researchers cautioned that reaching firm conclusions will have to await publication of the results in a peer-reviewed journal, particularly when it comes to parsing any differences between patient subgroups. And because the trial was substantially smaller than originally planned, it may lack the statistical power to provide confidence in some of the findings, other experts said.

The trial began in 1994 and enrolled 731 men 75 years of age or younger who had been diagnosed with early-stage prostate cancer. The majority of the cancers were detected based on a PSA test, and all men in the trial had a life expectancy of at least 10 years.

Although overall survival and prostate cancer-specific survival were nearly the same in both groups, Dr. Wilt explained, both outcomes were slightly better in men who received surgery. The absolute differences between the two groups, however, were less than 3 percent.

The finding that surgery offered no survival benefit compared with observation was statistically strongest for men with a PSA level of 10 or less or whose cancer was classified as low risk based on factors that included PSA level, Gleason score, and disease stage. Less than 6 percent of these men died of prostate cancer, and men in the watchful waiting group had slightly better (but not statistically significant) overall and prostate cancer-specific survival than men in the surgery group.

We have to look carefully at the details of the various studies and try to ferret out which patients should be encouraged to have active surveillance and which should receive definitive treatment.

—Dr. J. Erik Busby

“We need to do additional analyses, but we feel confident that our results, overall, show no significant difference in all-cause or prostate cancer-specific mortality in all men enrolled,” Dr. Wilt said in an interview. The research team was also confident, that surgery offers no survival benefit for men with low-risk disease or a PSA level of 10 or below, he continued.

Pouring through the Studies

The PIVOT results come on the heels of findings from two other studies of what has been one of the most contentious issues in oncology: whether men with early-stage prostate cancer should undergo some form of definitive treatment, usually surgery or radiation.

Earlier this month, results from a similar but smaller clinical trial conducted in three Scandinavian countries found that surgery improved survival in men with early-stage disease. Most of the men in that trial, however, had been diagnosed on the basis of symptoms, not PSA screening, which some experts said made the trial findings less relevant to patients in the United States. Meanwhile, recent findings from an observational study conducted at Johns Hopkins University showed excellent long-term survival in men with very low-risk prostate cancer who were treated with active surveillance, which is more aggressive than watchful waiting and entails regular check-ups and screening for disease progression with PSA tests and prostate biopsies.

“We know that we over treat a lot of patients with early-stage prostate cancer,” said Dr. J. Erik Busby of the University of Alabama at Birmingham School of Medicine and Comprehensive Cancer Center. “But we have to look carefully at the details of the various studies and try to ferret out which patients should be encouraged to have active surveillance and which should receive definitive treatment.”

For men with low-risk disease and a PSA score below 10, Dr. Peter Albertsen of the University of Connecticut Health Center said he believes the PIVOT trial results “strongly support active surveillance.”

“In the past,” he continued, “we would look to operate on patients with a PSA [score of] less than 10.”

Surgery did appear to improve survival in some subgroups based on PSA level and tumor-risk category but not those based on patient characteristics (e.g., age, race, other health conditions), Dr. Wilt noted. “But when you look at the different tumor-risk categories, it gets a bit muddier, and we have less confidence in any positive effect,” he cautioned.

The strongest case for a benefit from surgery was in men with a PSA score above 10 and, to a lesser extent, in men with high-risk disease, but only for prostate cancer-specific mortality.

Moving Forward with Caution

The PIVOT trial was initially designed to enroll 2,000 patients. Of the more than 5,000 men who were approached to participate in the trial, 4,300 declined—most, Dr. Wilt said, because they did not want their treatment determined by randomization. Even so, he stressed, PIVOT is the largest randomized trial ever conducted to compare surgery with watchful waiting.

The bottom line is that treatment of early-stage prostate cancer must be individualized.

—Dr. Julio Pow-Sang

The trial data have to be interpreted cautiously, said Dr. Bhupinder Mann of NCI’s Division of Cancer Treatment and Diagnosis. With inadequate sample sizes, the risks of false-positive and false-negative findings increase, he noted. The survival benefit from surgery suggested in the high-risk group, which accounted for 20 percent of the trial population, “is certainly conceivable,” Dr. Mann said, and is consistent with current clinical practices and guidelines. With more patients in the high-risk group, the possibility of demonstrating a benefit from treatment—if a benefit truly existed—would have been higher and more reliable, he added. But because of the study’s size, “it’s hard to have confidence” in either the positive or the negative results.

Based on the available data, as long as the men have a life expectancy of 10 years or greater, surgery or radiation would still be the preferred first-line treatment in most men with a PSA level higher than 10 or with high-risk disease, said Dr. Julio Pow-Sang of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL.

But even in men for whom surgery is not the preferred first-line treatment, the situation is a bit murky. PIVOT and the recent Scandinavian trial compared surgery with watchful waiting, not with active surveillance. Based on the PIVOT results, Dr. Wilt said, “The data support watchful waiting rather than active surveillance or early intervention with surgery for most men with early-stage prostate cancer, particularly for men with PSA values of 10 or less and those with low-risk disease.”

In the United States, however, even active surveillance has been a tough sell to urologists and urologic oncologists for their patients with early-stage disease; many of these patients still undergo surgery after diagnosis. Given that backdrop, Drs. Albertsen and Busby agree, U.S. doctors are unlikely to recommend watchful waiting to many patients.

“Most of us are a bit nervous with this approach,” Dr. Albertsen said. “We do not yet have confidence that we have not missed higher-grade disease on biopsy.”

The bottom line, stressed Dr. Pow-Sang, is that treatment of early-stage prostate cancer must be individualized. “We know that intervention is good in selected men,” he said, “and that other men will do well without any intervention.”

Carmen Phillips

Cancer Research Highlights

Cabozantinib Shrinks Tumors and Bone Metastases in Prostate and Other Cancers

In a phase II clinical trial, the drug cabozantinib (or XL184) shrank tumors or halted their growth in patients with several types of solid tumors, including ovarian, liver, and prostate cancer. The drug also shrank bone metastases in patients with breast and prostate cancers and melanoma. Dr. Michael Gordon of Pinnacle Oncology Hematology in Scottsdale, AZ, presented the findings at a May 18 press briefing held in advance of the American Society of Clinical Oncology (ASCO) annual meeting.

UPDATE: Deaths from Investigational Drug Announced

Researchers reported the deaths of six participants in the randomized discontinuation trial of the experimental agent, cabozantinib, at the 2011 ASCO annual meeting in Chicago. The cabozantinib-related deaths included patients who had breast, lung, ovarian, prostate, or pancreatic cancer and represent approximately 1 percent of the total number of trial participants.

Cabozantinib is a targeted therapy that blocks the action of the cell-signaling molecules hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and may inhibit other signaling molecules as well. MET signaling can contribute to the growth and spread of cancer cells through the body (metastasis), and VEGFR2 plays a role in tumor blood vessel growth.

Of the 483 patients that Dr. Gordon and his colleagues enrolled in the trial, 398 were evaluated for tumor response during treatment. The trial employed a design called randomized discontinuation. All of the patients received cabozantinib for 12 weeks. Patients whose disease progressed during the first 12 weeks were removed from the trial, those whose tumors shrank remained on the drug, and those whose disease remained stable were randomly assigned to continue taking cabozantinib or a placebo to determine the drug's true role in stabilizing their disease.

The best results were seen in patients with liver, prostate, and ovarian cancer: 22 of 29 patients with liver cancer, 71 of 100 patients with prostate cancer, and 32 of 51 with ovarian cancer experienced either partial tumor shrinkage or stable disease.

Fifty-nine out of 68 patients who had bone metastases had their metastases shrink or disappear during the trial. Many of these patients experienced pain relief and a reduction in the need for narcotic pain medication.

These results show the benefit of "going after not just one pathway but…going after [an] entire network" of signaling molecules, stated Dr. Mark Kris, ASCO's Cancer Communications Committee chair, who moderated the press briefing.

Dr. Gordon explained that the drug's "exceptional activity" in shrinking metastases in patients with prostate cancer and the strong response among ovarian cancer patients led the researchers to expand the study to include 150 patients with each of those cancers in a nonrandomized arm of the trial. Results from those groups will be presented at the ASCO annual meeting next month in Chicago.

Also in the Journals: Cabozantinib May Shrink Some Rare Thyroid Tumors

In a phase I trial of cabozantinib, researchers led by Dr. Razelle Kurzrock of the University of Texas M. D. Anderson Cancer Center found that the targeted drug can shrink tumors in patients with metastatic medullary thyroid cancer (MTC) or MTC that could not be removed surgically. Results from 37 patients with advanced MTC treated with cabozantinib were published online May 23 in the Journal of Clinical Oncology.

Of the 35 patients whose tumors could be measured for response to the drug, 10 had tumors that shrank (a partial response). Fifteen of the 37 patients had tumors that remained stable for at least 6 months. Ninety percent of the 85 patients in the trial experienced at least one side effect, though almost half of those side effects were mild.

The partial responses seen in 10 of the patients "is remarkable…for a disease with essentially no conventional therapeutic options," wrote Drs. Yariv Houvras and Lori Wirth of Massachusetts General Hospital in an accompanying editorial. A phase III trial testing cabozantinib in patients with MTC is currently under way.

End-of-Life Care for Lung Cancer Patients Differs in U.S. and Ontario

Researchers looking at the care received by patients with non-small cell lung cancer (NSCLC) in the United States and in Ontario, Canada, during their last 5 months of life found large differences between the two countries. For example, patients in the United States were more likely to receive chemotherapy in the months before death, and patients in Ontario were more likely to die in a hospital. Dr. Joan Warren and her colleagues in NCI's Division of Cancer Control and Population Sciences collaborated with a group of investigators in Ontario to compare end-of-life care for elderly patients. These findings appeared online May 18 in the Journal of the National Cancer Institute.

The researchers used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database and from several linked databases in Ontario, the most populous Canadian province. The study included 13,533 patients from the United States and 8,100 patients from Ontario, all of whom had been diagnosed with NSCLC and died of cancer at age 65 or older between 1999 and 2003.

After adjusting for demographic differences in the two populations, the researchers found substantial differences in patterns of care near the end of life. In addition to differences in chemotherapy use and place of death, the researchers found that the majority of U.S. patients used hospice care in the last months of life. No formal hospice programs exist in Ontario, which instead provides palliative care in the home, in outpatient clinics, and in hospitals.

For patients in both countries, the use of emergency room services and hospitalization rose near the time of death. But during the last 30 days of life, 12 percent fewer U.S. patients visited an emergency room compared with those in Ontario. And fewer U.S. patients were admitted to the hospital during the last 30 days of life.

More than 60 percent of patients in Ontario who were hospitalized during the last month of life received palliative care as an inpatient, with over 80 percent of the hospitalized Ontario patients dying in the hospital. "It appears that most [of these patients] were admitted for supportive care," wrote the authors. About the same percentage of U.S. patients were in hospice during their last month of life, allowing them to die outside of the hospital.

"Despite relatively high use of community supportive care, the rates of inpatient death are too high in the United States and much too high in Ontario," wrote Dr. David Goodman of the Dartmouth Medical School in an accompanying editorial. But he cautions against expanding enrollment in hospice programs blindly without attention to the wishes of individual patients. Currently, he concluded, patients in both countries "do not yet adequately participate in end-of-life care decisions."

Researchers Identify New Way Tumor Cells May Adapt to Stressful Conditions

Some tumor cells may use a protein normally found only in the brain to help them survive and grow under stressful conditions, according to new findings. The protein, an enzyme known as carnitine palmitoyltransferase 1C (CPT1C), enables tumor cells to generate energy using fatty acids instead of glucose, which is the chief energy source for living organisms.

An international team of researchers led by Dr. Tak Mak of the University of Toronto published its findings May 15 in Genes & Development. The study suggests that CPT1C could be a new target for cancer therapy.

Cells within solid tumors, such as breast, lung, or colon cancers, can survive and grow under conditions that would kill normal cells. Tumor cells gain this survival advantage through alterations in their metabolism, a phenomenon known as metabolic transformation. Researchers have long known of this phenomenon but only recently uncovered evidence that fatty acids might be an energy source for tumor cells.

"It's like when the pipelines are cut for Middle East oil. You've got to tap all kinds of alternative sources for energy," explained Dr. James Phang of NCI's Center for Cancer Research, who studies cancer cell metabolism but was not involved in the current study.

The first hint that CPT1C could play a role in metabolic transformation came when Dr. Mak and his colleagues found that expression of the CPT1C gene was correlated with mouse mammary tumor cells' resistance to the anticancer drug rapamycin. The drug blocks glucose entry into cells and thus creates starvation conditions.

The researchers next asked whether CPT1C gene expression is increased in human cancers. They found that in 13 of 16 patients with non-small cell lung cancer, the levels of CPT1C messenger RNA (mRNA), which is used to make the CPT1C protein, were notably higher in tumor tissue than in normal lung tissue from the same patient.

In further experiments, the researchers showed that depriving tumor cells of nutrients or oxygen led to increased levels of CPT1C mRNA. They also showed that depleting CPT1C protein from human breast and colon cancer cells impaired the cells' ability to grow under low-oxygen and low-glucose conditions. CPT1C depletion also slowed the growth of tumors formed when the cancer cells were transplanted into mice.

Taken together, the study authors wrote, the results "suggest that a CPT1C inhibitor, used either…[alone] or in combination with other anticancer agents, may be a promising new avenue of cancer treatment."

In an interview, Dr. Mak said the larger implication is that rather than targeting oncogenes to treat cancer—a task that is daunting because of the sheer number of known oncogenes—it may be "time for us to try to exploit therapeutic targets, or combinations of therapeutic targets, that are a result of metabolic adaptation by a cancer cell...because there are fewer ways to rearrange the metabolic pathways of a cancer cell than there are oncogenes."

Dr. Phang agreed and noted that targeting CPT1C in particular "is promising as an approach to treating some cancers. But how efficient that could be and under what conditions remains to be seen," he said.

Special Report

HPV and Pap Co-Testing Safely Extend Cervical Cancer Screening Intervals

For many women, the yearly visit to their gynecologist or primary care physician includes a Pap test to screen for cervical cancer or lesions that are precursors to the disease. A growing body of evidence, however, has shown that for many women, annual cervical screening—particularly if it also includes a test that detects the presence of cancer-causing types of human papillomavirus (HPV)—is unnecessary.

Several gynecologic health and oncology groups have recommended 3-year intervals for cervical cancer screening in women age 30 and older who have a normal Pap test and negative HPV test. The recommendations, however, have not been widely implemented in common clinical practice.

A reconstruction of a papillomavirus (Image courtesy of Dr. Benes Trus, NIH Center for Information Technology) The HPV test used for cervical cancer screening detects the presence of high-risk HPV types, similar to the papillomavirus pictured above. (Image courtesy of Dr. Benes Trus, NIH Center for Information Technology)

Results from a large study of routine clinical practice at Kaiser Permanente Northern California, presented May 18 during a press briefing for the upcoming American Society of Clinical Oncology (ASCO) annual meeting, provide perhaps the strongest confirmation yet that an annual Pap test is no longer a necessity. In women 30 years of age or older who had a normal Pap test and a negative HPV DNA test result, very few cancers or precancerous changes were detected in the following 3-year period, the study found.

“To the extent that there is fear about cancer risk in a 3-year screening interval, our study reassures clinicians and their patients that this interval is safe,” said the study’s lead investigator, Dr. Hormuzd Katki of NCI’s Division of Cancer Epidemiology and Genetics (DCEG).

The study found that the Pap test did not substantially modify the extremely low cancer risk for HPV-negative women. But for HPV-positive women, the Pap test did help better identify women at high risk of cancer. As such, Dr. Katki said, the findings also “present a strong hypothesis” that the HPV test could be conducted first, and, if it is negative, women could be asked to return in 3 years. If the HPV test is positive, the Pap test could help determine whether a woman should undergo a colposcopy to examine the cervix for signs of cancer.

“But we’ll need more study and evaluation of this possibility in routine clinical practice before we can be sure,” he said.

A Real-World Study

The study is particularly important because it comes from a “real-world experience,” said ASCO President Dr. George Sledge during the press briefing. It involved more than 330,000 women in the Northern California region of Kaiser Permanente, a large managed care organization, making it the largest analysis of its kind to date.

“This study tells us where we’re going with cancer screening,” he continued, with the practice transitioning from “an ancient technique such as cytopathology to more molecularly based techniques that allow us to actually look at the specific cause of cancer in patients with cervical carcinoma.”

The women in the study had voluntarily enrolled in an HPV/Pap co-testing program launched by Kaiser in 2003. Every woman in the program was screened annually. Women with a normal Pap test result and a negative HPV test result had an extremely low 5-year cancer rate, 3.2 cancers per 100,000 women per year. Screening with just the HPV test was nearly as effective, with 3.8 cancers per 100,000 women per year. Risk estimates for women with a normal Pap test alone were nearly double: 7.5 cancers per 100,000 women per year.

Compared with a positive Pap test done alone, a single positive HPV test done alone was associated with a greater likelihood of finding cancer or a precancerous lesion after 5 years, meaning that the HPV test allowed for the earlier detection of cervical cancer or precancers.

However, Dr. Katki stressed, a positive Pap test did provide important information in women who also had a positive HPV test, increasing the likelihood of finding women with established cancer or the types of cervical lesions most likely to become cancer.

Enough to Tip the Balance?

Even with clinical guidelines recommending co-testing and longer screening intervals and the continued accumulation of data in support of these recommendations, changing physician behaviors has been very difficult, said Dr. Howard Jones, director of Gynecologic Oncology at Vanderbilt-Ingram Cancer Center in Nashville, TN. Although there is some evidence to suggest that clinicians have modestly increased their use of HPV testing in concert with the Pap test, studies also indicate that many have been reluctant to stretch screening intervals beyond 1 year.

Both the slow uptake of HPV testing and the failure to expand screening intervals can be attributed to several factors, Dr. Jones continued. One of the most prominent reasons for the latter is that many women have come to expect an annual Pap test.

Physicians can tell their patients who have negative results on both tests that they don't need to be screened again for cervical cancer for 3 years.

—Dr. Howard Jones

Physicians can tell their patients who have negative results on both tests that they don’t need to be screened again for cervical cancer for 3 years, he said, but “when those patients come back the next year, and I tell them we don’t have to do a Pap test, they often say ‘No, I want the test.’” He continued, “As a physician, I can argue with a woman for 10 minutes, but I’ve got 10 more patients to see that morning. Many physicians will just do the test and save the time and frustration.”

Physician reluctance to expanding screening intervals has also been linked to fears that women won’t come in for annual check-ups.

“The problem that many OB/GYNs [obstetrician/gynecologists] have [with longer intervals] is that many women largely think the only reason to go to a doctor is for a Pap test,” said Dr. Ellen Smith, a gynecologic oncologist with Texas Oncology in Austin. “For many women, that’s the only time they get their blood pressure checked, their weight checked, just get a general physical.”

A substantial proportion of women already fail to see a primary care physician or OB/GYN regularly, Dr. Smith continued. “So what will it be like if the [cervical cancer] screening interval is every 3 years?”

In the meantime, Dr. Smith stressed, there also needs to be an intense focus on the other side of the coin: ensuring that girls and young women get the HPV vaccine to help prevent cervical cancer in the first place and increasing the number of women who are screened regularly. More than half of women diagnosed with cervical cancer haven’t been screened in the previous 5 years, she said.

Because the current HPV vaccines will prevent only about 70 percent of cervical cancers, Dr. Katki stressed, current guidelines recommend that women who are vaccinated should still be screened.

On all of these issues, Dr. Jones said, “We really do need to educate the doctors, educate the patients, and keep pushing forward.”

Carmen Phillips

Further Reading: Cervical Cancer Screening Approach Slowly Shifting

Current Cervical Cancer Screening Recommendations  

The three most commonly cited sets of recommendations for cervical cancer screening were developed by the American Cancer Society (ACS), the American Congress of Obstetricians and Gynecologists (ACOG), and the U.S. Preventive Services Task Force (USPSTF). The chart below, adapted from a CDC resource, compares key aspects of all three guidelines.

Screening Method & IntervalsACS
2002
USPSTF
2003
ACOG
2009
Conventional cytologyAnnually; every 2–3 years for women age ≥ 30 years with a history of 3 negative cytology tests.* Sexual history should not be used as a rationale for more frequent screening.At least every 3 yearsEvery 2 years from age 21–29 years; every 3 years for women age ≥ 30 years with a history of 3 negative cytology tests.*
Liquid-based cytologyEvery 2 years; every 2–3 years for women age ≥ 30 years with a history of 3 negative cytology tests.* Sexual history should not be used as a rationale for more frequent screening.Insufficient evidenceEvery 2 years from age 21–29 years; every 3 years for women age ≥ 30 years with a history of 3 negative cytology tests.*
HPV co-test (cytology + HPV test)Not recommended under age 30. Age ≥ 30 years, no more than every 3 years if HPV negative, cytology normal. Sexual history should not be used as a rationale for more frequent screening.Insufficient evidenceAge ≥ 30 years, no more than every 3 years if HPV negative, cytology normal, even with new sexual partners. Not recommended for women younger than 30 years.
Primary HPV testingNot FDA approvedNot FDA approvedNot FDA approved

* Some exceptions apply (e.g., women who are immunocompromised, have a history of prenatal exposure to the synthetic hormone DES, are HIV positive, have previously been treated for CIN 2 or 3, cancer, etc.)

A Closer Look

Despite Early Skepticism, HPV Vaccines Prove Effective

Reader Suggested

Cervical cancer is the second most deadly cancer in women worldwide. Although incidence has fallen dramatically in the United States and other developed countries, where routine screening measures—most notably the Pap test—are widely available, the disease remains a major public health concern in the developing world. Fortunately, the group of viruses responsible for virtually all cases of cervical cancer has characteristics that make the viruses particularly amenable to vaccine development.

The discovery that human papillomaviruses (HPV) are responsible for cervical cancer initiation led long-time collaborators Dr. Douglas Lowy, chief of NCI’s Laboratory of Cellular Oncology (LCO), and Dr. John Schiller, head of the LCO’s Neoplastic Disease Section, to begin studies in the early 1980s to understand how these viruses infect cells. The goal of designing a vaccine to prevent HPV infection and, thus, cancer wasn’t adopted until the early 1990s.

“When we started this work,” said Dr. Schiller, “there was no greater optimism for an HPV vaccine than there was for an HIV vaccine. In fact, there was skepticism that it could work at all.”

A cross section of the cervical epidermis showing human papillomaviruses infecting the basement membrane and stimulating the release of antibodies. Human papillomaviruses (blue spheres) can initiate infection only at sites where the normal cell layers of the cervical epidermis have been disrupted, exposing the underlying basement membrane. In women who have received the HPV vaccine, this damage stimulates the release of antibodies (black Ys) that bind to the virus and prevent infection. (Image courtesy of Drs. Douglas Lowy and John Schiller, NCI)

The researchers’ persistence paid off when, in 2006, Gardasil became the first prophylactic vaccine against HPV to be approved for cervical cancer prevention in females in the United States. Approval for a second vaccine, Cervarix, followed in 2009. Women and girls who complete all three doses of either vaccine before becoming sexually active receive nearly 100 percent protection from infection by select HPV types. The duration of immunity is not known, but it has been shown to last for at least 5 years. Both vaccines protect against infection with HPV-16 and HPV-18, two high-risk, or carcinogenic, HPV types that cause approximately 70 percent of all cervical cancers. Gardasil also protects against infection with HPV-6 and HPV-11, which cause 90 percent of genital warts.

“There was a poor track record for developing vaccines against local genital infection,” commented Dr. Lowy, citing the long history of unsuccessful attempts to develop a herpes simplex virus vaccine as an example. “I think the surprise was really how well the HPV vaccine works,” Dr. Lowy continued, “and we now think several different factors account for this very high level of protection.”

A Combination of Serendipity and Good Science

Drs. Schiller and Lowy and their colleagues began their studies by examining the proteins on the surface of the HPV virus, which presumably were responsible for binding to target epithelial cells to initiate an infection.

“The best way to make antibodies that will neutralize a virus is to give the body something that looks like the real virus,” explained Dr. Schiller. “We couldn’t give killed or live attenuated HPV because it has oncogenes, so we decided to try to make something that looks like the outer shell of the virus.” The key discovery was that the major HPV surface protein, L1, alone or in combination with the minor surface protein, L2, spontaneously forms noninfectious particles that closely resemble the original virus structure and can induce the body to produce high levels of antibodies that prevent infection of cells in culture.

To begin studying the HPV infection process, the researchers incubated the L1 or L1 plus L2 virus-like particles (VLPs) with cells in culture. Both types of VLP were able to attach to the surface of the cells, suggesting that L1 was responsible for this attachment. This realization led the researchers to begin vaccine development with the L1 VLPs. Remarkably, the highly repetitive structure and the spatial arrangement of the L1 VLPs are ideal for activating the immune receptor that controls the production of antibodies, explaining the robust levels of antibodies observed following HPV vaccination.

The antibodies produced by intramuscular injection of the HPV vaccine circulate in the blood. Because HPV infections occur on the surface of the cervix, however, it was unclear how these circulating antibodies would come into contact with the virus to prevent infection. Further research into the virus’ life cycle shed light on this apparent conundrum.

 The need for multiple injections and the vaccines' high cost pose significant barriers to their widespread use, especially for people in the developing world.

Using a mouse model, Drs. Schiller and Lowy and their colleagues found that the virus must attach to the basement membrane of the cervix, a layer beneath the epithelial cells, to initiate infection. The basement membrane is exposed only after the cells above it are physically or chemically damaged. This disruption (or “microtrauma”) stimulates the body to release antibodies at the sites of trauma, where the antibodies can then come into contact with the virus.

The animal studies also illuminated the mechanism by which HPV infects cervical epithelial cells. Binding of the viral L1 protein to the basement membrane causes the proteins on the viral surface to reorganize, revealing the L2 protein. An enzyme on the basement membrane then clips off a piece of L2, exposing a previously hidden portion of the L1 protein. This L1 domain binds to a receptor on the epithelial cell surface, allowing the virus to enter the cell.

“For most viruses, the first step in the viral life cycle is the binding to the cell-surface receptor, whereas papillomaviruses apparently spend several hours on the basement membrane before they bind to the cell surface. This gives the antibodies more opportunities to bind to the virus particle and prevent infection,” Dr. Lowy explained.

One other characteristic of HPV that has lent itself well to vaccine development, Dr. Schiller explained, is its double-stranded DNA genome, which makes it difficult for the DNA to accumulate mutations. This prevents the HPV virus from evading the immune system as effectively as viruses that have rapidly evolving single-stranded RNA genomes, like HIV.

More Work to Be Done

Although the current HPV vaccines are important advances in the prevention of HPV infection and cervical cancer, there is still room for improvement.

Gardasil and Cervarix target only a few types of HPV because they were developed using the unique L1 VLPs of those types. To expand the number of HPV types targeted by Gardasil, Merck is adding L1 VLPs of the five types known to cause the most cervical cancers after HPV-16 and HPV-18 to its next-generation vaccine. Other companies are taking a new approach by developing vaccines that use the L2 protein. A portion of L2 appears to trigger the generation of antibodies that will block infection by most known HPV types, not just the type from which the L2 was derived.

There are also more practical obstacles to overcome. The need for multiple injections and the vaccines’ high cost pose significant barriers to their widespread use, especially for people in the developing world. “Right now, most of the girls and women getting vaccinated will get screened [for cervical cancer], so they are really pretty low risk; we’re mostly preventing premalignant lesions,” said Dr. Schiller. “The real impact will be if you can get this vaccine to the group of women who aren’t going to get adequately screened. That will be the real payoff for this vaccine.”

Jennifer Crawford

Featured Clinical Trial

Metformin to Treat Early-Stage Breast Cancer

Dr. Pamela J. GoodwinDr. Pamela J. Goodwin

Name of the Trial
Phase III Trial of Metformin versus Placebo in Early-Stage Breast Cancer (CAN-NCIC-MA.32). See the protocol summary.

Principal Investigators
Drs. Pamela J. Goodwin, Karen Gelmon, Kathleen Pritchard, Timothy Whelan, Lois Shepherd, Jennifer Ligibel, Dawn Hershman, Ingrid Mayer, Timothy Hobday, National Cancer Institute of Canada Clinical Trials Group; and Dr. Priya Rastogi, National Surgical Adjuvant Breast and Bowel Project

Why This Trial Is Important  
Patients with early-stage breast cancer are usually treated with surgery to remove the affected breast (mastectomy) or just the tumor and a small amount of surrounding normal tissue (lumpectomy). Post-surgical, or adjuvant, therapy may include local treatment (radiation therapy) and/or systemic treatment (chemotherapy, hormone therapy, or both), depending on the type of surgery received and the clinical features of the tumor, such as its size, grade, and whether it has spread to nearby lymph nodes (lymph node-positive disease). In addition, if the tumor tests positive for overexpression of the HER2 gene, the patient will likely be treated with a drug or biological agent that targets the HER2 protein

Although these treatments are effective in curing many patients with early-stage breast cancer, some patients will experience a relapse, and some will ultimately succumb to their disease. Consequently, doctors are eager to find new treatments for early-stage breast cancer or ways to improve the effectiveness of existing treatments.

The drug metformin (Glucophage) has been used for decades to treat people with diabetes. Researchers have found that diabetics taking metformin are less likely to develop cancer or die from the disease than diabetics who do not take metformin. In addition, women with early-stage breast cancer taking metformin for diabetes have higher response rates to presurgical, or neoadjuvant, therapies than diabetic patients not taking metformin or patients without diabetes. Recent results of studies in women with breast cancer who are waiting for surgery have shown that metformin may slow tumor cell growth. These observations have suggested that metformin may be helpful in preventing recurrences in women treated for early-stage breast cancer.

In this trial, nondiabetic women or men younger than age 75 who have been diagnosed with early-stage breast cancer within the previous 12 months and who have undergone surgery to remove their tumor will be randomly assigned to take metformin or placebo pills twice a day for 5 years. Participants in the trial may also receive adjuvant hormone and/or radiation therapy, but any chemotherapy (adjuvant or neoadjuvant) must have been completed prior to joining the study. Doctors will monitor the study participants to see if metformin improves disease-free survival, overall survival, and a number of other medical, biological, and quality-of-life endpoints.

“We think metformin may act against breast cancer through insulin-mediated or insulin-independent mechanisms of action, or both,” said Dr. Goodwin. “First, it may lower insulin levels, thereby reducing signaling through the PI3K [signaling] pathway, which is a growth/proliferation pathway in breast cancer cells. Secondly, independent of insulin, metformin alters metabolism in the mitochondria and turns on the [enzyme] AMP kinase, which then inhibits mTOR, a protein that helps regulate cell division and survival,” she explained.

“So, metformin is biologically a very interesting drug, and because it’s been used so widely, its side effects are well known,” Dr. Goodwin added. “In general, it’s a very safe and well-tolerated drug if you avoid its use in patients older than 80 and those with abnormal liver, kidney, or cardiac functions. The most common side effects are mild bloating and diarrhea that usually go away on their own after a few months, but we are starting off at half the dose of metformin for the first 4 weeks to help participants adjust.”

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

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

Community Update

Scientific Meetings through the Lens of Twitter

Poster presentations at a scientific conference At conferences, Twitter can help drive traffic to poster presentations. (Image courtesy of AACR)

When cancer doctors and researchers gather in Chicago this weekend to discuss the latest advances against the disease, people at the meeting and around the world will join a conversation that started on Twitter 2 weeks ago.

The discussion began in earnest on May 18, when the American Society of Clinical Oncology (ASCO) released 4,000 scientific abstracts online ahead of its annual meeting this weekend. People on Twitter began to post short messages, or tweets, about abstracts they found interesting. This sparked more chatter, including, just for fun, a flurry of tweets in Haiku.

On Saturday, after much anticipation, the conversation will turn to research results. During the plenary, members of the audience will share findings from the talks on Twitter in real time; these messages, in turn, will prompt people following online to share their views.

“One of the most useful things about Twitter at meetings is the real-time feedback from colleagues who come at the talks from different angles,” said Dr. David Kroll of North Carolina Central University. “The additional perspectives can really help you to interpret a talk.”

Less Solitary, More Enjoyable

Before social media, these kinds of conversations took place between sessions or over drinks afterward. One’s perception of a presentation can change, however, with the passage of time and additional talks, Dr. Kroll noted. In contrast, Twitter captures information and first impressions in real time.

A common criticism of Twitter is that it’s a distraction, and for some users this may be true. Yet, for Dr. Kroll and other researchers, tweeting can enhance the conference experience by making it less solitary and more enjoyable.

“Twitter immediately adds value to the information you’re getting from a talk,” he said. “Someone may tweet in the middle of a presentation: ‘The new finding is interesting, but did you know about this other study?’” The tweet would likely include a link to the study.

The premise of Twitter is that you “follow” (receive updates from) people whose interests you share. At the Chicago meeting, with more than 30,000 attendees and many concurrent sessions, tweets from people whose opinions you respect could be useful information.

“Twitter is particularly effective for large meetings,” said Dr. Brent Stockwell of Columbia University. “There is no way to make every presentation. But you can gain insights into the talks you miss by hearing what other people are saying about those sessions on Twitter.”  

He added, “It’s sort of like having a few of your friends go to the talk and report back to you.” 

One of the most useful things about Twitter at meetings is the real-time feedback from colleagues who come at the talks from different angles.

—Dr. David Kroll

Building Community

ASCO will be tracking the Twitter traffic during the event and plans to analyze the data, said Dr. Robert Miller of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, who serves on several ASCO committees associated with new media and technology.

To make this easier, the society designated an official keyword (or hashtag) that people can attach to conference-related tweets. Messages that include “#ASCO11” can be viewed together on the Web.

“We’re interested in seeing how the attendees use the hashtag and whether there are conversations about clinical discussions using Twitter,” said Dr. Miller, who was speaking as an individual and not on behalf of ASCO. “My expectation is that attendees will use Twitter to have a dialogue with one another in real time about the implications of what’s being presented.”

Dr. Miller, who will be tweeting from Chicago, added: “I don’t view Twitter as a distraction; I view it as a way to build community.”

In recent years, Twitter traffic has increased at another big cancer conference—the annual meeting of the American Association for Cancer Research (AACR), according to Ron Vitale, the group’s associate director of Web site communications. “Twitter is a great resource before, during, and after the meeting,” he wrote in an e-mail. “There is a thirst for knowledge out there.”

While there does not appear to be much published research on Twitter at scientific meetings, a recent study assessed the activity of 260 self-identified physicians on Twitter during a month last year. On the whole, physicians were sharing medical information that could have a positive effect on public health, the researchers found.

The authors noted, however, that some of the self-identified physicians seemed to be promoting specific products using unproven health claims. For the public, this finding underscores the importance of knowing which physicians are providing reliable health information on Twitter, said lead author Dr. Katherine Chretien of the Washington, DC, Veterans Affairs Medical Center.

Challenges and Concerns

Twitter is still relatively new, and tweeting from meetings is a work in progress.

The Twitter feed of a large meeting can be “a mishmash of messages,” particularly if one is not familiar with the topic and doesn’t know the jargon, noted Jody Schoger, a Texas-based writer who blogs and tweets about cancer. Rather than follow a meeting’s hashtag, she prefers to read updates from a few people she regularly follows and trusts.

“Twitter updates can be helpful, but they will never replace the electricity of actually being at the meeting,” she added in an e-mail.

When it comes to communicating complex science, Twitter’s 140-character limit leaves little room for explanation. In April, as the AACR annual meeting was under way in Florida, Dr. Naoto T. Ueno of the University of Texas M. D. Anderson Cancer Center singlehandedly tried to provide some context.

While traveling abroad, Dr. Ueno sent out a series of educational tweets with basic concepts in cancer biology (for example, here and here). The messages may have helped some readers interpret the research advances being reported over Twitter.

Dr. Ueno acknowledged, though, that many scientific tweets are flawed. Too often, he said, a message is not understandable or does not contain useful information. For instance, tweets from meetings routinely report that a presenter is now talking about a specific drug.

“This is not useful information,” Dr. Ueno wrote in an e-mail. “I would like to know what the [presenter] is saying about it, the take-home message, and where I can find more information.”

Some of this information, of course, may eventually emerge over time. For this reason, Dr. Sally Church, a pharmaceutical company consultant who blogs about cancer research, will capture the stream of ASCO tweets and make the compilation publicly available online.

Dr. Church will also tweet from presentations, relying, as she often does, on the help of medical oncologists. “Many of the oncologists I chat with on Twitter during meetings are responsive and helpful,” she said. Their tweets, she added, tend to be accurate and precise.

“An Honest Discussion about Blogging Policies”

When a barrage of tweets appears in real time, it can be difficult to assess the accuracy of individual messages. Yet, as several researchers noted, when many people are tweeting about the same findings at the same time, a consensus emerges and errors become evident.

 When many people are posting about the same findings at the same time, a consensus emerges and errors become evident.

Concerns about the accuracy of tweets may contribute to the reluctance of some presenters to have their work tweeted during meetings, particularly unpublished findings that have not been through peer review. (At some meetings, such as the Biology of Genomes conference at Cold Spring Harbor Laboratory, presenters must grant permission to have their talks tweeted.)

Presenters may also worry that coverage in a blog or “microblog,” such as Twitter, could limit where the work could be published later, noted a recent editorial in Nature Methods about blogging and microblogging at meetings. But this “seems unlikely because journals do not count talks as prepublication, and unsolicited coverage in blogs also falls under this category,” the authors wrote.

Nonetheless, the editorial called for “an honest discussion about blogging policies to ensure that the needs of the scientific community for information are met while addressing a presenter’s concern about premature exposure of sensitive work.”

AACR has posted guidelines for the use of social media at meetings, and ASCO has information about social networking opportunities in Chicago. In comparison, Twitter is rarely used at smaller meetings, and host organizations, such as universities, do not always have clear policies on the use of social media, according to Dr. Stockwell.

The Serendipity of Twitter

Among the many uses for Twitter at scientific meetings, driving traffic to poster presentations that may otherwise be missed seems to be a clever innovation. After reading an intriguing tweet from a cancer advocate at a recent meeting, Dr. Church investigated. “The poster turned out to be one of the coolest of the day, so I blogged about it,” she recalled.

Social media can enable these kinds of unexpected connections. In another example, Scott Hensley, who writes and edits NPR’s health blog Shots, learned a few weeks ago “through the miracle of Twitter” that a prostate cancer meeting was under way across the street from his office building in downtown Washington, DC.  

The miracle was actually a tweet about the meeting from Dr. Church, who was there. Hensley crossed the street to join her and ended up covering a major study reported that day

On Twitter, meanwhile, people have been talking about this weekend’s meeting in Chicago. The person who started the flurry of Haiku tweets even had one last poem. “Haiku trend slowing/Fun was had, but back to work/Chicago awaits,” tweeted Geoffrey Curtis.

Edward R. Winstead

Disclosure: The writer follows the people mentioned in the article on Twitter and has met several of them at scientific meetings.

Follow the NCI Cancer Bulletin on Twitter at http://twitter.com/#!/NCIBulletin

FDA Update

Sunitinib Approved to Treat Pancreatic Neuroendocrine Tumors

The Food and Drug Administration (FDA) has approved sunitinib (Sutent) to treat patients with pancreatic neuroendocrine tumors (PNET) that cannot be removed by surgery or that have metastasized. This is the second new drug approval for this disease in a month; the FDA approved everolimus (Afinitor) to treat PNET in early May.

The FDA based its approval on the results of a study that showed that patients who received sunitinib lived longer without their disease spreading or worsening than those who received a placebo—a median of 10.2 months compared with 5.4 months.

Sunitinib is a small-molecule tyrosine kinase inhibitor that blocks cell proliferation and tumor blood vessel formation. Commonly reported side effects included diarrhea, vomiting, fatigue, high blood pressure, abdominal pain, stomatitis, and neutropenia. The FDA has also approved sunitinib to treat late-stage kidney cancer and gastrointestinal stromal tumors.

Cancer.gov Update

Updated Tool More Accurately Estimates Breast Cancer Risk for Asian Americans

Screenshot of Breast Cancer Risk Assessment Tool

NCI researchers have updated a model for estimating breast cancer risk so that it is more accurate for Asian and Pacific Islander American (APA) women. The updated Breast Cancer Risk Assessment Tool (BCRAT) can now better estimate risk for American women who identify themselves as Chinese, Japanese, Filipino, Hawaiian, other Pacific Islander, or other Asian. The model is described in a paper published online May 11 in the Journal of the National Cancer Institute.

Dr. Mitchell H. Gail, of NCI's Division of Cancer Epidemiology and Genetics, and his colleagues used data from the Asian American Breast Cancer Study (AABCS), combined with data from NCI's Surveillance, Epidemiology, and End Results program, to update the model. The resulting algorithm was tested using data from approximately 4,000 APA women in the Women's Health Initiative, a study of health issues among postmenopausal women.

Intended for use by health professionals, the BCRAT calculates 5-year and lifetime estimates of a woman's risk of developing invasive breast cancer based on her medical history, reproductive history, and family history of the disease. In the updated model, the weight of individual factors and the calculations used to assess the interactions of multiple factors have been adjusted to more accurately predict the risk of breast cancer for APA women.

NCI Recovery Act Web Site Highlights Community-Based Cancer Care and Job Creation  

The NCI Recovery Act Web site features a new article highlighting how Recovery Act funding is driving science-based cancer care and research in hospitals at the local level. Community cancer centers have an enormous impact on cancer care in the United States, so in 2007 NCI created the NCI Community Cancer Centers Program (NCCCP), a network of 16 community hospitals that deliver an enhanced level of care and support in local settings.

Recovery Act funding has enabled the expansion of the NCCCP network to 30 cancer centers in 22 states, creating nearly 300 new jobs in the process. This expansion is allowing NCCCP hospitals to focus additional resources on preventive care and on bringing the latest scientific advances directly to cancer patients where they live.

Notes

NCI’s Douglas R. Lowy and John T. Schiller Awarded Sabin Medal

Drs. Douglas R. Lowy and John T. Schiller (Photo by R. Baer) Drs. Douglas R. Lowy and John T. Schiller (Photo by R. Baer)

The NCI scientists whose discovery provided the technology for commercially developed human papillomavirus (HPV) vaccines received the Albert B. Sabin Gold Medal Award from the Sabin Vaccine Institute.

Drs. Douglas R. Lowy and John T. Schiller of the Laboratory of Cellular Oncology in NCI’s Center for Cancer Research are the first and second inventors on government-owned patents for HPV vaccines licensed to Merck & Co., Inc., and GlaxoSmithKline. As a direct result of their work, vaccines now exist that prevent infections with high-risk, or cancer-causing, HPV types and with HPV types that cause genital warts.

The Sabin Medal is given annually to acknowledge extraordinary contributions made by scientists in the field of vaccine research. The award commemorates Dr. Albert B. Sabin, who developed the oral polio vaccine.

Upcoming Cancer Survivors Workshop to Address Stress Management for Caregivers

The third of four telephone workshops in NCI’s annual “Living With, Through, and Beyond Cancer” series will be held June 14 from 1:30 to 2:30 p.m. EDT. Part III of the series is titled “Stress Management for Caregivers: Taking Care of Yourself Physically and Emotionally.”

The free series offers cancer survivors, family members, friends, and health care professionals practical information to help them cope with concerns and issues that arise after treatment ends. The workshops are presented by CancerCare, in collaboration with NCI, LIVESTRONG, the American Cancer Society, the Intercultural Cancer Council, Living Beyond Breast Cancer, and the National Coalition for Cancer Survivorship.

Speakers for the June 14 workshop include Dr. Guadalupe Palos, a clinical research manager at the University of Texas M. D. Anderson Cancer Center; Dr. David Kissane, chair and attending psychiatrist at Memorial Sloan-Kettering Cancer Center; and Dr. Laurel Northouse, professor of nursing at the University of Michigan and co-director of the sociobehavior program at the University of Michigan Comprehensive Cancer Center.

Part IV, “Fear of Recurrence and Late Effects: Living With Uncertainty,” will take place on July 12.

These workshops are free; no phone charges apply. To register, visit CancerCare. If you missed part I or II of the series, podcasts are available here and here.

NCI Calls for Applications from Cancer Control Practitioners

Screenshot of: https://researchtoreality.cancer.gov/mentorship

NCI is accepting applications for a new pilot mentorship program as part of the Research to Reality (R2R) online community of practice. The purpose of the program is to help cancer control practitioners develop the knowledge, understanding, and skills needed to identify, adapt, implement, and evaluate evidence-based cancer control and prevention interventions in community or clinical settings.

The 12-month mentorship program is designed as a distance-learning opportunity that will link mentees with experienced public health professionals through in-person meetings and training sessions, video conferencing, e-mail, and webinars. With guidance from their mentors and ongoing technical assistance and training from NCI, mentees will work on year-long cancer control and prevention projects relevant to their current jobs.

The mentor–mentee teams will also share their work and lessons learned with the R2R online community through discussion forums, cyber-seminars, and other interactive features as a way to extend the program’s reach.   

The application process is competitive, and a maximum of six mentees will be selected to participate. More information and applications are available on the mentorship page of the R2R Web site. The application deadline is June 30.

Spring 2011 NCI CAM News Released

Spring 2011 NCI CAM News cover

NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM) released the spring 2011 issue of NCI CAM News, a twice-yearly newsletter with information on NCI’s latest complementary and alternative medicine (CAM) activities. The newsletter highlights NCI-sponsored CAM research, resources for researchers such as funding opportunities and grant writing workshops, and upcoming meetings and lectures.

Articles in this issue include:

Past newsletters are available online.