Researchers have discovered a new way that melanoma cells may become resistant to treatment with vemurafenib (Zelboraf), a targeted therapy that has produced dramatic, if transitory, results for some patients with advanced disease. In some cases, the drug has caused tumors to shrink and even disappear, but the treatment invariably stops working. Read more > >
Dr. Mason Bond of the University of British Columbia in Vancouver discusses the addition of a novel drug combination to standard therapy in patients younger than 50.
- FDA Commissioner Revokes Approval of Bevacizumab for Metastatic Breast Cancer
- New Form of Asparaginase Approved to Treat Acute Lymphoblastic Leukemia
- Ruxolitinib Approved to Treat the Bone Marrow Disease Myelofibrosis
- National Cancer Advisory Board Will Meet Next Week
- Proposals Sought for Use of PLCO Data and Biospecimens
- Cyber-Seminar Will Address Systems Thinking to Solve Public Health Problems
- NCI Guide on Communicating Data to Lay Audiences Now Available
- Major League Baseball Limits Players' Use of Tobacco
- President Obama Encourages Smokers to Quit
Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.
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Researchers Uncover New Mechanism of Resistance to Melanoma Drug
Researchers have discovered a new way that melanoma cells may become resistant to treatment with vemurafenib (Zelboraf), a targeted therapy that has produced dramatic, if transitory, results for some patients with advanced disease. In some cases, the drug has caused tumors to shrink and even disappear, but the treatment invariably stops working.
By exposing melanoma cells in the laboratory to the drug for extended periods, Dr. David Solit of Memorial Sloan-Kettering Cancer Center and his colleagues have learned that some resistant cells produce a shortened version of the mutant BRAF protein that vemurafenib targets. The shortened protein—which is missing its middle section—is active even in the drug's presence, the researchers reported online November 23 in Nature.
"This is a common mechanism whereby the melanoma tumors overcome the effects of the drug," said Dr. Solit, noting that 6 of 19 patients with resistant tumors had a form of the protein that had been shortened in this way. "We hope that this discovery will lead to more effective treatments."
Vemurafenib blocks growth-promoting signals activated by a mutation in the BRAF gene known as V600E. In August, the Food and Drug Administration (FDA) approved the treatment for patients with unresectable or metastatic melanoma whose tumors have this mutation, which is found in about 60 percent of melanomas.
In their study, Dr. Solit and his colleagues found that the shortened forms of the BRAF V600E protein represent splicing variants—that is, they arose through a change in the processing of the RNA that was transcribed from the gene.
"This is an important study because it identifies the first resistance mechanism to BRAF inhibitors that involves a structural change in BRAF itself," said Dr. Ravi Amaravadi of the Perelman School of Medicine at the University of Pennsylvania, who treats patients with melanoma and was not involved in the study.
It will be important to determine how widespread this resistance mechanism is compared to other proposed resistance mechanisms, Dr. Amaravadi added.
So far, the investigators have found this form of the BRAF V600E protein only in vemurafenib-resistant tumors. They believe that the splicing alteration is specific to BRAF and does not affect splicing in general, suggesting that it could have arisen from a mutation or an epigenetic change.
"Conceptually, we have found a novel form of resistance for any drug," said Dr. Solit. "As happens with other targeted therapies, the drug stops working—but the mechanism is different."
—Dr. Ravi Amaravadi
With drugs such as imatinib (Gleevec) or erlotinib (Tarceva), for example, resistance often occurs when tumors acquire new genetic mutations that prevent a drug from binding to its molecular target. As these resistance mechanisms have been discovered, the knowledge has been used to develop second-generation drugs, such as dasatinib (Sprycel), which can bind to mutant forms of the BCR-ABL kinase to which imatinib cannot bind.
With vemurafenib, the shortened BRAF protein forms complexes within cells that promote growth signals in the presence of the drug. To overcome the resistance, researchers could try to develop more potent drugs and find ways to disrupt the complexes, the authors noted.
Another strategy involves combining drugs that target different proteins, an approach that is already being tried. In June, for example, researchers reported positive preliminary results from an early-phase study testing a BRAF inhibitor in combination with a drug that inhibits a second kinase, MEK, which is part of the same signaling pathway as BRAF. Consequently, the use of a MEK inhibitor could prevent or delay development of a drug-resistant form of BRAF.
"Based on the results of our study, we hypothesize that the combination of the BRAF inhibitor and the MEK inhibitor will be more effective and less toxic than either drug alone," said Dr. Solit. "But we need a randomized study to test this idea."
Studies are also needed to fully characterize the molecular basis for the altered RNA processing that leads to resistance to vemurafenib, as well as to identify additional mechanisms that lead to vemurafenib resistance. If drugs were developed to address the altered RNA processing, these agents could be administered with vemurafenib, Dr. Solit noted.
Dr. Amaravadi agreed. The development of new drugs directed against the molecular changes caused by the BRAF splice variant could "significantly prolong the clinical benefit of BRAF inhibitors," he predicted.
"This study identifies RNA processing as a potentially common resistance mechanism," said co-author Dr. Tom Misteli of NCI's Center for Cancer Research. The findings add to research suggesting the importance of alternative splicing as a mechanism of disease, he added.
"The number of splicing diseases is growing, yet our efforts to target RNA processing as a therapeutic strategy are minimal at the moment," Dr. Misteli said. "RNA therapy offers a largely unexplored, powerful therapeutic strategy."
Cancer Research Highlights
Survey of Oncologists Suggests Lack of Progress in Cancer Pain Management
Results of a national survey show that U.S. medical oncologists receive inadequate training in cancer pain management and perceive numerous barriers to managing pain optimally in their patients. The results of the survey, conducted by Dr. Brenda Breuer and her colleagues at Beth Israel Medical Center in New York, were published online November 15 in the Journal of Clinical Oncology (JCO).
The survey, which was modeled in part after a 1990 survey conducted by the Eastern Cooperative Oncology Group (ECOG), “demonstrated disturbingly little progress” in attitudes and practices related to pain management among medical oncologists over the last 20 years, according to an accompanying editorial. Yet during this time, guidelines for managing cancer pain have been developed and disseminated, continuing medical education on the subject has become common, and access to pain specialists has increased, the study authors noted.
Dr. Breuer and her colleagues mailed the anonymous survey to a randomly selected, geographically representative sample of 2,000 medical oncologists, and 610 usable surveys (32 percent) were returned.
In the survey, oncologists gave their medical specialty good marks (a median rating of 7 on a scale of 0 to 10) for relieving cancer pain but rated their peers as more conservative than themselves in prescribing opioid drugs to manage pain. And although most respondents agreed with the basic principles of pain management, their responses to two challenging clinical scenarios presented in the survey suggest that a majority of oncologists are deficient in knowledge about opioids, the study authors reported.
As in the 1990 survey, “oncologists continue to perceive that the most significant barriers to adequate pain management are poor pain assessment, patient reluctance to report pain, and patient reluctance to take analgesics,” Dr. Breuer and her co-authors wrote. Furthermore, “poor ratings of pain management training [during medical school and residency] have barely changed” in the two decades since the 1990 ECOG survey.
“There is a worldwide outcry for adequate cancer pain management, yet the skills of many oncologists remain inadequate in this domain,” commented the authors of the editorial, Dr. Jamie H. Von Roenn of Northwestern University, who was also the lead author of the ECOG survey, and Dr. Charles von Gunten of the Institute of Palliative Medicine at San Diego Hospice. “If we are to provide patients the care they deserve, we must not just integrate training in pain management into every fellowship program, we must expect oncologists to practice what they learn.”
(For more information, listen to this JCO podcast, in which Dr. Eduardo Bruera, chair of the Department of Palliative Care and Rehabilitation Medicine at the University of Texas M. D. Anderson Cancer Center, discusses the survey’s findings and offers recommendations on addressing some of the problems identified by the survey.)
Trial Confirms Efficacy of HPV Vaccine, Shows Cross-Protection
End-of-trial results from a trial testing Cervarix, a vaccine against human papillomavirus (HPV) types 16 and 18, showed that the vaccine continued to provide substantial protection against cervical precancers 4 years after vaccination. Cervarix provided almost complete protection in young women who had no evidence of exposure to HPV at the time of vaccination. The vaccine provided less protection for the total vaccinated cohort and was less effective with increasing age at vaccination. These findings reflect the vaccine’s lack of effectiveness against infections acquired before vaccination.
The vaccine also partially protected women against four types of HPV that are not targeted by the vaccine. (Although HPV-16 and -18 cause about 70 percent of cervical cancers worldwide, as many as 15 HPV types can cause cancer.) These results from the PATRICIA trial (Papilloma Trial against Cancer in Young Adults) were published online November 9 in Lancet Oncology in two separate papers, available here and here.
The PATRICIA trial enrolled 18,644 young women between the ages of 15 and 25 from 14 countries. The participants were randomly assigned to receive either three doses of Cervarix or three doses of a hepatitis A vaccine as a control. Results from the interim analysis, published in July 2009, showed that the vaccine greatly reduced the risk of grade 2 cervical intraepithelial neoplasias and higher (CIN2+).
The new analysis shows that, 4 years after vaccination, Cervarix provided complete protection against grade 3 cervical intraepithelial neoplasias or higher (CIN3+) associated with HPV-16 and -18 among women who had no evidence of exposure to HPV. The vaccine provided strong protection against CIN3+ caused by other HPV types in this same group of women. Among the total cohort of women who received at least one dose of Cervarix, some of whom may have had prior exposure to HPV, the vaccine provided some protection. (See the table below.)
Cervarix Vaccine Efficacy among Women Who Received at Least One Dose of Cervarix
|Women with no evidence of HPV exposure at baseline||Women who may have had prior exposure to HPV|
|Against CIN3+ associated with HPV-16 and -18||100 percent||45.7 percent|
|Against all CIN3+, regardless of HPV type||93.2 percent||45.6 percent|
|Against all adenocarcinoma in situ||100 percent||76.9 percent|
The vaccine provided cross-protection against HPV-33, HPV-31, HPV-45, and HPV-51, all cancer-causing types of the virus. The researchers speculate that the observed cross-protection may be due either to the vaccine adjuvant (a substance that stimulates the immune system) or to similarities among proteins found on the surfaces of different HPV types.
In an accompanying editorial, Drs. Mark Schiffman and Sholom Wacholder of NCI’s Division of Cancer Epidemiology and Genetics, who were involved with the NCI Costa Rica HPV vaccine trial, noted the importance of the PATRICIA trial results. They also stated that “the practical aspects of vaccine uptake are now the most important issue in HPV vaccine research from a public health perspective.” To increase vaccine uptake in the developing world, where 90 percent of cervical cancer cases occur, next-generation HPV vaccines will need to be less expensive, provide protection in a single dose, and/or be stable without refrigeration, they explained.
Genetic Study Yields Clues to Neuroendocrine Prostate Cancer
Researchers have identified a signaling pathway that may play an important role in neuroendocrine prostate cancer (NEPC), a very rare but aggressive form of the disease. Based on this discovery, the researchers tested a drug that inhibits the pathway and observed anticancer effects in two model systems. The findings appear in the November issue of Cancer Discovery.
Most cases of NEPC, which accounts for a small percentage of prostate cancers, arise following hormone therapy for prostate adenocarcinoma. To better understand the origins of the disease, Dr. Himisha Beltran of Weill Cornell Cancer Center and her colleagues profiled the gene-expression patterns of 7 NEPC tumors, 30 prostate adenocarcinomas, and 5 benign prostate tissue samples.
When they compared NEPCs and prostate adenocarcinomas, the authors found “dramatic differences” in the expression of certain genes, as well as differences in the number of copies of some genes. Two genes emerged as particularly interesting suspects in the disease—the AURKA gene, which encodes a protein called aurora kinase A and has been implicated in other cancers, and MYCN, another cancer-associated gene.
The researchers confirmed the association of AURKA expression with NEPC by analyzing benign prostate tissue and prostate tumors from a separate, larger cohort of patients. They concluded that the protein products of AURKA and MYCN may work together to induce characteristics of NEPC in prostate cancer cells.
Aurora kinase inhibitors are being evaluated in clinical trials, and the researchers tested one of these drugs against prostate adenocarcinoma and NEPC cells grown in laboratory culture as well as in mice bearing xenograft tumors derived from these cells. In the laboratory experiments, NEPC but not prostate adenocarcinoma cells were sensitive to the inhibitors; in the mice, the inhibitors caused tumor shrinkage of NEPC but not prostate adenocarcinoma xenograft tumors. In addition, drug treatment suppressed the expression of markers of neuroendocrine cells.
“The next step is to initiate a clinical trial,” said Dr. Beltran, who noted that there are no standard therapies for NEPC and that most patients die within a year of diagnosis. A small percentage of patients with prostate adenocarcinomas also show increased expression of the AURKA and MYCN genes, and these patients could be candidates for aurora kinase inhibitors as well, Dr. Beltran explained.
Previous studies have indicated that NEPCs and prostate adenocarcinomas may share the same cell of origin. It is known, for instance, that a genetic rearrangement often found in prostate adenocarcinomas is present at roughly the same rate in NEPCs. The precise number of cases of NEPC is unknown, however, in part because patients with advancing prostate cancer do not always have a biopsy, which is how NEPC is diagnosed.
The study authors cited evidence that long-term androgen deprivation therapy may promote the transformation of prostate cancer cells into NEPC. This suggests that “with the recent introduction of new highly potent androgen deprivation therapies into the clinical arena, the incidence of NEPC may escalate,” they noted.
“The current study is a stepping stone toward identifying neuroendocrine prostate cancer that is usually missed using regular screening modalities,” commented Dr. Sudhir Srivastava, who heads NCI’s Early Detection Research Network. “Understanding the biology of neuroendocrine prostate cancer will lead to better clinical management of this rare form of the disease.”
A Conversation With
A Conversation with Dr. Mason Bond on Improving the Treatment of Patients with Ewing Sarcoma
Dr. Mason Bond of the Department of Pediatrics at the University of British Columbia in Vancouver serves as the principal investigator of a Children's Oncology Group (COG) clinical trial. The phase III trial, which is still recruiting patients, is testing the addition of a novel drug combination to standard therapy in patients younger than 50 years who have localized Ewing sarcoma.
How is your treatment trial different from earlier trials?
The basic structure of the trial is similar to that of past trials, but we are testing the addition of vincristine, cyclophosphamide, and topotecan to the standard drug combinations for first-line treatment. In phase II studies, patients with metastatic and relapsed disease showed better responses to this combination than to any other combination recently tested. Since the topoisomerase I inhibitors, like topotecan, are not part of the current standard combinations, we hope that adding a combination that works in a slightly different way can improve progression-free survival. Patients can also receive this experimental combination as an outpatient therapy, which makes it easier for patients to get treated.
We have also modified the definitions of surgical margins, for example, to clarify how far a lesion can be from a margin, and we've incorporated up-to-date radiation oncology techniques. We are looking at other prognostic factors and studying whether PET imaging might help predict either tumor response or patient outcome.
Is this trial only for pediatric patients?
No, this is the first COG trial to enroll young adults through the Clinical Trials Support Unit. Nearly 20 percent of the people in the trial are 18 years or older, but all of them have been enrolled through pediatric centers.
I would like more young adults to participate in this trial. One goal of the pediatric oncology cooperative groups is to encourage older adolescents and young adults to get into clinical trials in any way we can. We have seen with pediatrics how participation in clinical trials leads to improvements in outcomes; young adult participation in clinical trials is the best and fastest way to make improvements for this age group.
How have treatments for Ewing sarcoma been changing?
The treatment changes, in general, have been a little slow. We were quite excited when a trial published in 2009 showed that treatment given every 2 weeks yielded better results than treatment given every 3 weeks, because other ways of intensifying treatment that we tested had not produced better results. The last time there was a big step forward like this was in 2003, with the addition of ifosfamide and etoposide.
Since then, we have been looking for new agents to add to first-line treatment that would improve progression-free survival. There has been a lot of effort looking for new biologic agents, but we have not been able to identify one to test in Ewing sarcoma just yet. The best chemotherapy combination for which there is quite a lot of information in phase II trials, and in patients with relapsed, refractory, and metastatic disease, was cyclophosphamide and topotecan. That is why we decided to test that combination in our study.
Researchers are still hoping to identify more specific agents for Ewing sarcoma, such as new agents that target signaling pathways. It just takes a long time for agents to be tested in pediatric populations and for agents with an adult indication to be identified for use in pediatric patients. I think the identification of new and effective agents to test in [early-phase] trials is the key to moving treatment forward.
Are there certain patients who still have a poorer prognosis?
People who have metastatic disease at the time of diagnosis have poor outcomes. Trying to find an effective treatment for them, and even trials for them, has been challenging, but they are also the people who are more likely to be part of clinical trials testing new agents at an earlier stage.
In general, older adolescents and young adults also have a poorer prognosis than younger people, and one of the challenges has been enrolling young adults in trials. It is important to capture older adolescents and young adults in these kinds of trials, because enrolling them in trials could improve progression-free survival in that age group in a way that has not really happened in recent years.
Study Raises Concerns about Using Cancer Cell Lines to Test Drug Resistance
Cancer cells grown in culture and stored for use in laboratory studies—known as cell lines—are the workhorses of basic cancer research. A new study from NIH and NCI researchers suggests, however, that established cancer cell lines may have important limitations when used to investigate resistance to chemotherapy drugs. The findings indicate the need for better in vitro models of cancer that more accurately represent how tumors behave in the body, they said.
In the study, published November 15 in the Proceedings of the National Academy of Sciences, Dr. Michael Gottesman, NIH deputy director for Intramural Research, and his colleagues showed that, in various cancer types, the expression of a specific set of genes associated with drug resistance was very different in cell lines than it was in tumor samples representing the same cancer types.
The study included cell lines from NCI's Human Tumor Cell Line Screen, commonly called the NCI-60 panel, a collection of 60 cancer cell lines derived from 9 common tumor types. Cancer cell lines from the NCI-60 panel and other sources are used for many types of studies, such as testing experimental drugs for anticancer effects or investigating how specific genes influence tumor development.
The researchers focused on 380 genes associated with drug resistance. They compared the activity of these genes in cancer cell lines representing six tumor types with the activity of the same genes in clinical samples of the same six tumor types. There was "no correlation between clinical samples and established cancer cell lines," the researchers found.
In addition, when the researchers profiled the activity of these genes associated with drug resistance across all the cell lines of the NCI-60 panel, they made "the striking observation that all of the cell lines…bear more resemblance to each other, regardless of the tissue of origin, than to the clinical samples that they are supposed to model," the researchers wrote.
"We thought we might see some similarities among the cancer cell lines," said the study's lead author, Dr. Jean-Pierre Gillet of the Laboratory of Cell Biology in NCI's Center for Cancer Research. But the extent of the differences in the activity of these drug-resistance genes between the cell lines and tumor samples was "impressive" and "definitely surprising," Dr. Gillet added.
In cell lines, the researchers found changes in gene expression that may be the result of "selection pressure and culture conditions" that the cells acquired during extended growth in culture so they can thrive in an artificial environment. These same genes are also involved in drug resistance. "In other words, the cancer cell lines are highly selected during their establishment for expression of genes associated with [multidrug resistance]," the researchers wrote.
The research team initially focused on ovarian cancer. They compared the gene expression profile of the drug-resistance genes for 15 ovarian cancer cell lines—including five from the NCI-60 panel and 10 other commonly used lines—with the profiles of 80 tumor samples obtained from patients before treatment began. Not only were the cell line and tumor sample profiles "strikingly different," the researchers reported, but the ovarian cancer cell line profiles were similar.
The research team also found that the drug-resistance profiles of the other cell lines in the NCI-60 panel were very similar to those of the ovarian cancer cell lines. Moreover, the profiles of the cell lines for five other cancer types were also different from those of the tumor types they are meant to model.
These findings should be interpreted with caution, noted Dr. Cyril Benes, director of the Center for Molecular Therapeutics at Massachusetts General Hospital. "The functional significance" of the similar gene expression profiles, or clustering, "is unclear," Dr. Benes wrote in an e-mail. "The transcriptional profile is different, but does that translate into an important biological outcome in terms of drug response?"
No one believes that cancer cell lines are perfect, said Dr. Edward Sausville, associate director for clinical research at the University of Maryland Greenebaum Cancer Center. Other studies have hinted at these types of issues with cell lines, and it's not surprising that cells grown in a plastic dish and stored for long periods evolve to handle the stress of the conditions, he continued.
"Whether it's a set of cell lines or other models, they're not one size fits all," Dr. Sausville said. "They are good for some things and not good for others."
Studies like this one, that molecularly characterize the NCI-60 panel and other commonly used cell lines, are welcome and needed, said Dr. Susan Holbeck of NCI's Developmental Therapeutics Program, the program through which the NCI-60 panel is managed. But even with their shortcomings, she stressed, cancer cell lines are still highly valuable tools.
For example, some of the early suggestions that the targeted therapies vemurafenib (Zelboraf) and crizotinib (Xalkori)—both of which were recently approved by the Food and Drug Administration—may be highly effective in patients with mutations in the BRAF and ALK genes, respectively, came from studies of cell lines with those mutations, she noted.
"Each cell line can be seen as a bag full of molecular targets," Dr. Holbeck continued. "They're excellent tools for generating hypotheses that can then be tested in other models," such as genetically engineered mouse models that more closely mimic how tumors develop and progress in humans.
Studies like this "are certainly valuable," Dr. Benes said, in part because they demonstrate that the entire undertaking of modeling human cancer "is a learning process…. Understanding what predicts translation from results in models to patients is also an important part of it, as well as making different, possibly better models."
Unexpected Complications: Treating Cancer during Pregnancy
Trina Pockett of Fortuna, CA, was 23, the mother of a 2-year-old, and pregnant with her second child when she noticed a lump under her collar bone. The lump wasn't painful, so for a while she ignored it. When the lump didn't go away, she showed it to her doctor, who ordered an emergency biopsy.
The diagnosis was devastating. She had Hodgkin lymphoma, an immune-system cancer that is one of the most commonly diagnosed cancers in young adults. Because the cancer had already spread to her neck, chest, and stomach, her doctors advised starting chemotherapy immediately.
Pockett suddenly found herself a member of an extremely small club: the estimated 3,500 women in the United States who each year receive a diagnosis of cancer during pregnancy. For each woman and her doctors, the diagnosis creates an exquisite dilemma: delaying treatment may risk her life, but proceeding with therapy may risk harming her unborn child.
No Rigorous Studies
Cancer—most commonly breast cancer, cervical cancer, lymphoma, and melanoma—occurs in about one pregnancy in a thousand. Because cancer during pregnancy is a rare event, most doctors have encountered few if any cases, and the medical literature offers few rigorous studies to provide guidance.
"It's extraordinarily difficult to do meaningful research in patients with cancer who are pregnant," said Dr. Clifford Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center, who estimates that in more than two decades of practice he has seen one pregnant patient with breast cancer "every year or 2."
In addition to the rarity of cancer in pregnancy, concerns about the risks of chemotherapy to the fetus pose a significant barrier to conducting clinical research in pregnant women with cancer, explained Dr. Ted Trimble, former head of gynecological cancer therapeutics with NCI's Cancer Therapy Evaluation Program.
"Most trial sponsors are not comfortable encouraging pregnant women to participate in a trial of any agent whose mechanism of action might cause birth defects or fetal death," Dr. Trimble said.
As more women delay childbearing until their 30s or 40s—ages at which cancer risk, while still low, begins to creep up—some researchers predict that cancer diagnoses during pregnancy will increase. Swedish researchers have estimated that the incidence of breast cancer diagnosed during pregnancy or within 2 years of delivery more than doubled between 1963 and 2002.
Toxic to DNA
Chemotherapy agents are known to cause malformations in laboratory animals. The risk of birth defects is highest during the first trimester of pregnancy when organs are forming.
"Chemotherapy agents are meant to interfere with rapidly dividing cells; they are supposed to be toxic to DNA," explained Dr. John J. Mulvihill, a specialist in cancer genetics at the University of Oklahoma Health Sciences Center.
—Dr. Elyce Cardonick
Since 1984, Dr. Mulvihill has maintained the Registry of Pregnancies Exposed to Chemotherapeutic Agents, which has accumulated data from the medical literature since 1950 on the outcomes of 845 pregnancies in women treated for cancer. "It's not great population-based data," he said. "It's more a collection of rare clinical experience.
"We do see an excess of malformations, 19 percent, with first-trimester exposure to chemotherapy," Dr. Mulvihill continued. "Exposure in the second and third trimesters seems to have no increased adverse effects except when therapy is given very late in pregnancy, when it can cause transient effects like low white-blood-cell counts."
Given the obstacles to conducting clinical trials in pregnant women, studies based on data from registries—with all their limitations—provide the best evidence available about outcomes for children prenatally exposed to chemotherapy, according to Dr. Trimble.
Reason for Optimism
"After the first trimester, the concern is less about birth defects and more about potential for impaired organ or brain function, since the brain continues to develop throughout pregnancy, " said Dr. Elyce Cardonick, a maternal-fetal medicine specialist at Cooper University Hospital in Camden, NJ.
Dr. Cardonick maintains the Pregnancy & Cancer Registry, which since 1997 has compiled information on nearly 300 pregnancies in women with cancer, and is following 247 mothers and children over the long term. Findings from her studies and others offer some reason for optimism: In general, children prenatally exposed to chemotherapy do not appear to have higher rates of birth defects or developmental abnormalities than other children.
Mexican researchers closely followed 84 children whose mothers received chemotherapy for hematologic cancers during pregnancy, including 38 who were treated during the first trimester, for a median of 18 years. All the children were normal, physically and neurologically, and performed normally at school. Some gave birth to their own children, adding 12 second-generation offspring to the study cohort.
Premature birth is more likely than chemotherapy to impair the cognitive development of children prenatally exposed to chemotherapy, an international research group reported in September at a European oncology meeting. Of the 70 children they studied, who ranged in age from 18 months to 18 years, 47 were born prematurely. Although most of the children were normal, most of those with cognitive development problems were born early.
Lead researcher Dr. Frederic Amant, of University Hospitals Leuven in Belgium, said it was not clear whether chemotherapy caused the early deliveries, but in many cases preterm delivery was induced. "Our results suggest [inducement of early delivery] should be avoided," he said.
At the 2011 American Society of Clinical Oncology annual meeting, Dr. Jennifer Litton, a medical oncologist specializing in breast cancer at the University of Texas M. D. Anderson Cancer Center, reported on 41 children born to women who were treated during the second or third trimester with a standardized multidrug chemotherapy regimen in a prospective registry trial.
Overall, the children, now ages 1 to 21, are doing well, she said. Three to four percent have birth defects, equivalent to the national average for children not prenatally exposed to chemotherapy. The cohort has now increased in size to nearly 90 children, whom Dr. Litton and her colleagues are still following.
The M. D. Anderson study has enrolled 81 pregnant women with breast cancer since 1989 and has used the same chemotherapy regimen of 5-fluorouracil, doxorubicin, and cyclophosphamide since its inception. Pregnant patients are generally treated with older anticancer agents because of a lack of safety data for newer therapies, according to Dr. Trimble.
Don't Ignore a Lump
Data from the Pregnancy & Cancer Registry indicate that in about one in five cases doctors recommended terminating the pregnancy before starting cancer treatment, according to Dr. Cardonick. Anecdotally, she has heard of pregnant women who didn't tell their doctors about a lump or other abnormality because they feared they would be advised to terminate the pregnancy.
"Women and oncologists need to know it's possible to successfully treat cancer while continuing with a pregnancy," she said. "Women should not be afraid to bring a breast mass or mole to their doctor's attention.
"Most oncologists want to treat the patient as if she's not pregnant, and, for the most part, in the second and third trimester, they can," she continued. "But they need to make some adjustments. For example, you should not give chemo after the 34th week of pregnancy because, if the patient goes into labor while her white blood cell counts are low, the baby could be born with neutropenia."
Trina Pockett's doctor suggested she consider termination but supported her decision to continue with the pregnancy. She underwent four cycles of chemotherapy before her daughter, Kate, was born 6 weeks prematurely. After the birth she completed chemotherapy, followed by radiation treatment.
She has been cancer-free since 2001. Kate, who spent nearly 4 weeks in neonatal intensive care, is now a healthy 11-year-old who aspires to be a veterinarian. Pockett gave birth to a third child, Noah, in 2004.
In 2009, she achieved a personal goal when she competed in a half-marathon in San Diego. "To run in the same city where I had chemotherapy was very special," she said.
A Closer Look
Interpreting Risk: Direct-to-Consumer Genetic Testing
In the winter of 2009, Shannon Behrman ordered a genetic test online because she was curious to know whether she had inherited her family's increased risk for melanoma. The direct-to-consumer (DTC) genetic test revealed an increased risk for melanoma, as well as for autoimmune disorders, but average risk for breast cancer, Parkinson disease, and most other diseases.
She received the test results without ever speaking with a doctor or a genetic counselor. Unlike most customers, however, Dr. Behrman has a Ph.D. in molecular biology and is a health communications fellow in NCI's Office of Cancer Genomics.
DTC genetic tests are DNA tests that are marketed and sold directly to the customer without a doctor's order or a consultation with a genetic counselor. In recent years, the tests have become more accessible as many new genetic testing companies have emerged. Moreover, prices for DTC genetic tests have continued to drop, increasing their availability to the general public.
With greater public access to DTC genetic tests, researchers are examining whether members of the public will be able to accurately interpret their test results without the aid of genetic counselors.
A recent study in Public Health Genomics reported that although members of the general public are likely to think that DTC genetic test results are easy to understand, they may not interpret them correctly. The authors also found that the general public thinks DTC genetic test results are more helpful in making decisions about medical care than genetic counselors think they are.
For the study, the researchers asked members of the general public—in this case, the Facebook friends of the lead researcher—and members of the National Society of Genetic Counselors to interpret mock DTC genetic test results. The Facebook friends of the principal investigator were not a representative sample of the public, however. On the whole, the subjects were young, white, female, highly educated, and mostly employed in the health care field. Because this is a skewed population, the results of the study may underemphasize the challenges the general public may face when interpreting DTC genetic test results.
Although most subjects correctly interpreted whether the test results meant more or less risk, overall, they did less well than the genetic counselors. Members of the general public also trusted the test results more than the genetic counselors did.
The researchers note that if members of the general public misunderstand the meaning of their DTC genetic test results they may experience unnecessary anxiety or feel falsely reassured about their health. Both outcomes could ultimately cause harm if, for example, they led to unwarranted changes in screening behavior.
A Third Possibility
The study findings did not surprise Dr. Jean Claude Zenklusen of NCI's Office of Cancer Genomics. In his experience, most people hear what they want to hear. "If you tell them their risk is lower, but not zero, they think 'OK, I'm great!'" he explained. He added that many people don't pay attention to a test result that shows they have increased risk, but those who do can become overly concerned.
Dr. Gillian Hooker of the Johns Hopkins Bloomberg School of Public Health/National Human Genome Research Institute (NHGRI) Genetic Counseling Training Program noted a third possible outcome: A finding of an increased risk on a DTC test could cause the person to change his or her behavior. For instance, she said, if someone received a test result that showed higher risk for a disease, and if evidence-based interventions were available to reduce that risk, that person could choose to change his or her behavior to reduce the risk of that particular disease.
For Dr. Behrman, the DTC genetic test results didn't reveal new information. "[My increased melanoma risk] is in line with my family history," she said. She has yet to make health changes or seek a genetic counselor for interpretation. "I just try to be healthy and slather on the sunscreen," she said.
—Dr. Jean Claude Zenklusen
A major obstacle in interpreting DTC genetic test results is numeracy. Numeracy, analogous to literacy, is a person's ability to correctly read and interpret numbers. Dr. Hooker noted the challenges of numeracy. "It's really hard to imagine what a difference of 1 or 2 percent means for your health," she said. "There's a fair amount of data in the risk communication literature that says that people translate risk much as the paper described."
Dr. Behrman noted a similar issue in her DTC genetic test results. "If I look at the results for my melanoma risk, it shows I have a twofold elevated risk of 2.4 percent. For the average person, when they see these numbers, they may just think, 'that's a twofold risk!'" But people receiving such a result should note that even though the risk may be double the average person's risk, it is still, at 2.4 percent, a fairly small risk.
Communication scientists recognize that the way risk information is reported influences how it is perceived. Indicating that "2 in every 1,000" people with a genetic predisposition for a disease will develop it, compared to "1 in every 1,000" people in the general population, provides more complete information than saying that an individual is "twice as likely" than the average person to contract a disease. The former presentation is referred to as absolute risk, the latter as relative risk. Most risk communication experts argue for using absolute risk estimates when communicating risk information to patients to provide greater context and more meaningful information.
Given the challenges in interpreting genetic results and the serious possible consequences of misunderstanding, some companies are offering testing only through a doctor or genetic counselor. "I understand how [a result indicating higher risk] could be alarming to people who aren't familiar with biology or statistics," explained Dr. Behrman. "If all you see is elevated risk, you panic." She added that ordering her DTC genetic test through a doctor would not have been a significant barrier.
Some argue that going through a doctor could be a barrier to accessing one's own genetic information. "There is some concern about medical paternalism," said Dr. Hooker, referring to the philosophy that certain health decisions are best left to health care providers. "It's something I struggle with myself. To what extent do people have the right to access DTC genetic testing directly, or is allowing the consumer that access irresponsible?"
Dr. Zenklusen also takes a moderate path. "Your genome is yours," he said. "You should have full access to your genome, but companies bear a responsibility to report [genetic test results] in a responsible way." He added that the method of returning results should not be "over-reassuring or over-scaring."
The Public Health Genomics study suggests that research must be continued in several areas: risk communication, the best formats for communicating genetic information to patients, the connections between SNPs and disease, algorithms to find causative mutations, calculations to interpret genetic data, and other modifiers of our genomes.
—Emma J. Spaulding
More information: Cancer Genetics Risk Assessment and Counseling (PDQ)
Featured Clinical Trial
Novel Combination Chemotherapy for Localized Ewing Sarcoma
Name of the Trial
Phase III Randomized Study of Adding Vincristine Sulfate, Topotecan Hydrochloride, and Cyclophosphamide to Standard Chemotherapy in Patients with Non-Metastatic Extracranial Ewing Sarcoma (COG-AEWS1031). See the protocol summary.
Dr. Mason Bond, Children’s Oncology Group (COG)
Why This Trial Is Important
Ewing sarcoma is a rare cancer of the bone or soft tissue that occurs primarily in adolescents and young adults. In fact, it is the second most common malignant bone tumor diagnosed in patients younger than 20 years of age. Most Ewing sarcomas have a characteristic chromosomal alteration that results in the expression of a fusion protein (EWS-FLI1) that inappropriately turns on cell-growth-promoting genes. Thus, these tumors tend to grow rapidly and often metastasize to the lung, bone, or bone marrow. The presence of metastases at diagnosis and being diagnosed at an older age are associated with a poorer prognosis.
Treatment for patients with Ewing sarcoma includes surgery, radiotherapy, or both, along with systemic chemotherapy. Until the introduction of combination chemotherapy, the 3- to 5-year survival rate for patients with Ewing sarcoma was less than 10 percent. However, results from several clinical trials have demonstrated improved survival for patients without metastases who were treated with a chemotherapy combination called VDC-IE, in which administration of the drugs vincristine, doxorubicin, and cyclophosphamide (VDC) is alternated with administration of the drugs ifosfamide and etoposide (IE), and by reducing the interval between cycles of VDC-IE.
In this clinical trial, which is being conducted in the United States, Canada, and Australia, researchers will test whether the addition of the drug combination vincristine, topotecan, and cyclophosphamide (VTC) to VDC-IE improves overall survival and event-free survival (survival without cancer progression or recurrence) in newly diagnosed patients with non-metastatic Ewing sarcoma of the bone or soft tissue (excluding the soft tissue of the skull). Eligible patients will be randomly assigned to receive six cycles of VDC-IE or VTC-IE-VDC followed by surgery, radiation therapy, or both and 11 more cycles of the initial chemotherapy.
“Because topotecan and cyclophosphamide are active in patients when Ewing sarcoma recurs or relapses, our thinking is that the combination may contribute to improving survival or preventing relapse in newly diagnosed patients,” said Dr. Leo Mascarenhas, vice chair of the trial.
“This trial is unique in that it is the first COG trial available through NCI’s Cancer Trials Support Unit (CTSU) that will enroll both adolescents and young adults,” added Dr. Mascarenhas. “It provides broader access to patients who may not be treated at a pediatric center, which is the case for a significant number of patients with Ewing sarcoma.”
Secondary aims of the trial include assessing the importance of initial tumor volume, tumor histology, and response to treatment as measured by PET scans as prognostic factors for localized Ewing tumors. Additionally, the effect of the type of local therapy (surgery, radiotherapy, or both) on associated complications and survival will be evaluated. “There are a lot of issues we hope to address in this trial to help us understand this disease better to improve the outcome of patients,” said Dr. Mascarenhas.
FDA Commissioner Revokes Approval of Bevacizumab for Metastatic Breast Cancer
On November 18, Food and Drug Administration (FDA) Commissioner Dr. Margaret Hamburg announced her decision to revoke the agency’s approval of the drug bevacizumab (Avastin) for the treatment of metastatic breast cancer. The FDA Center for Drug Evaluation and Research (CDER) granted bevacizumab accelerated approval for this indication in February 2008 with the condition that Genentech, the drug’s manufacturer, perform two confirmatory clinical trials.
“Unfortunately, the additional studies failed to confirm Avastin’s initial promise,” said Dr. Hamburg at a press briefing explaining the revocation. The two trials showed that bevacizumab delayed tumor growth slightly but did not improve survival or patients’ quality of life.
Based on these findings, CDER’s Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 in July 2010 to recommend that the FDA withdraw its accelerated approval for metastatic breast cancer. Following an appeal from Genentech in July of this year, ODAC upheld its recommendation to withdraw approval for the indication.
“Sometimes, despite the hopes of investigators, patients, industry, and even the FDA itself, the results of rigorous testing can be disappointing,” said Dr. Hamburg at the press briefing. “This is the case with Avastin when used for the treatment of metastatic breast cancer.” In light of the potentially severe side effects of bevacizumab, including heart attack or heart failure, severe high blood pressure, and bleeding or hemorrhaging, “it is clear there is no proof of a benefit in breast cancer patients that would justify those risks,” Dr. Hamburg explained.
Bevacizumab is still approved for the treatment of metastatic colorectal cancer and kidney cancer, advanced non-small cell lung cancer, and glioblastoma. Dr. Hamburg stressed that the “FDA doesn’t regulate the practice of medicine,” so a final decision on whether to use bevacizumab for metastatic breast cancer will be up to a patient and her doctors. “I urge women who are currently taking the drug for breast cancer to discuss the risks and benefits…with their oncologist,” she added.
Future studies may identify subsets of patients with metastatic breast cancer who would benefit from bevacizumab. “I would really be very pleased to see Genentech pursue those studies, and we would of course be very open to the submission of a new application that would include additional data, including support for the notion of a subset of responders to the use of Avastin,” Dr. Hamburg concluded.
Further Reading: “Progression-free Survival: Patient Benefit or Lower Standard?”
New Form of Asparaginase Approved to Treat Acute Lymphoblastic Leukemia
On November 18, the Food and Drug Administration (FDA) approved Erwinaze, an alternate form of asparaginase that is derived from the bacterium Erwinia chrysanthemi, to treat acute lymphoblastic leukemia (ALL) in patients who have become allergic (hypersensitive) to other forms of asparaginase derived from the bacterium Escherichia coli.
Asparaginase kills leukemia cells by breaking down the amino acid asparagine in the plasma. Asparagine depletion is selectively toxic to leukemia cells, which, unlike normal cells, cannot synthesize asparagine. The level of asparaginase activity is known to correlate with leukemia control and survival.
The FDA approval was based on the results of a single-arm trial involving 58 patients between the ages of 2 and 18 and a safety analysis of 574 patients between the ages of 1 and 66 who participated in a program to expand access to the drug. Patients in both studies had developed allergic reactions to asparaginase and pegaspargase, another modified form of asparaginase, both of which are derived from E. coli.
In the single-arm trial, the main outcome measure was the proportion of patients in whom a prespecified threshold level of asparaginase activity was maintained at 48 or 72 hours after dosing. All evaluable patients in the trial achieved this outcome.
Erwinaze is given as an injection three times per week. Side effects associated with Erwinaze treatment include serious allergic reactions, inflammation of the pancreas, high blood levels of liver enzymes, blood clotting, bleeding, nausea, vomiting, and high blood sugar.
Erwinaze has been designated as an orphan drug, a designation given to drugs for the treatment of diseases affecting fewer than 200,000 people in the United States.
Ruxolitinib Approved to Treat the Bone Marrow Disease Myelofibrosis
On November 16, the Food and Drug Administration (FDA) approved ruxolitinib (Jakafi) for patients with intermediate- or high-risk myelofibrosis. Ruxolitinib is the first drug approved specifically to treat patients with this bone marrow disease.
In patients with myelofibrosis, fibrous tissue replaces the bone marrow, causing blood cells to be made in organs such as the liver and the spleen. This disease is marked by an enlarged spleen, anemia, and decreased numbers of white blood cells and platelets. Symptoms include fatigue, abdominal discomfort, pain under the ribs, feelings of fullness, muscle and bone pain, itching, and night sweats.
Myelofibrosis and other myeloproliferative disorders are associated with the increased activity of tyrosine kinase enzymes called JAK 1 and 2, which play key roles in a signaling pathway that is involved in cell proliferation and growth, hematopoiesis, and the immune response. Ruxolitinib, a pill taken twice daily, binds to and inhibits JAK 1 and 2, which may lead to reduced inflammation and cell proliferation.
The safety and effectiveness of ruxolitinib were evaluated in two clinical trials with a total of 528 patients. Patients in both trials had myelofibrosis that was resistant or refractory to available myelofibrosis therapy or ineligible for allogeneic bone marrow transplantation. All patients had enlarged spleens and needed treatment for disease-related symptoms. Patients in one study received ruxolitinib or the best available therapy; in the other study patients received ruxolitinib or a placebo. The primary endpoint in both trials was the proportion of patients whose spleen size was reduced by at least 35 percent.
In both studies, a significantly higher proportion of patients taking ruxolitinib saw their spleen shrink by 35 percent or more—29 percent of patients receiving ruxolitinib compared with zero percent of those receiving the best available therapy, and 42 percent of patients taking the drug compared with 1 percent of those taking the placebo. In the placebo-controlled study, a greater proportion of patients receiving ruxolitinib than receiving the placebo had their myelofibrosis-related symptoms reduced by 50 percent.
The most serious side effects seen in patients treated with ruxolitinib include low blood platelet levels, anemia, fatigue, diarrhea, shortness of breath, headache, dizziness, and nausea.
Ruxolitinib was reviewed under FDA’s priority review program, an expedited 6-month review of drugs that may offer significant advances in treatment over available therapy or that provide a treatment when no adequate therapy exists.
The treatment has been designated an orphan drug, a designation given to drugs for the treatment of diseases affecting fewer than 200,000 people in the United States.
National Cancer Advisory Board Will Meet Next Week
The National Cancer Advisory Board (NCAB) will meet December 5–6 in Building 31 on the NIH main campus in Bethesda, MD.
Videocasts of past meetings are available here.
Proposals Sought for Use of PLCO Data and Biospecimens
Data and biospecimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial are available to qualified researchers through a peer-review process. The Etiology and Early Marker Studies (EEMS) program accepts proposals for access to PLCO biospecimens twice a year, with the current cycle ending on January 16, 2012, at 5:00 p.m. ET.
By collecting biologic materials and risk factor information from trial participants before the diagnosis of disease, EEMS—a component of the PLCO—provides a resource for cancer researchers who are studying cancer etiology and early detection. Etiologic studies investigate the environmental, biochemical, and genetic risk factors for cancer. Early detection studies aim to develop reproducible, reliable biomarkers of early disease.
Proposals will be accepted for the next EEMS review cycle starting December 1. Details of the review process and application materials are available online. Questions may be directed to firstname.lastname@example.org or 240-314-2313. Proposals for the next cycle will be accepted in June or July 2012.
Cyber-Seminar Will Address Systems Thinking to Solve Public Health Problems
The December 14 NCI Research to Reality (R2R) cyber-seminar will feature an overview by Dr. Allan Best on systems thinking and practical tools to help solve complex population health issues.
Addressing these health issues often requires intervention and engagement with key stakeholders and organizations across many levels, ranging from local entities (schools, churches, and work environments), to regional systems (health departments and hospital networks), to entire countries (national agencies). This multilevel, multiparticipant view is at the heart of systems thinking, a process of understanding how parts influence one another within a whole.
Drs. Ross Brownson and Ken McLeroy will provide real-world examples of how systems models can be applied in a variety of settings. Dr. Brownson will highlight the use of concept mapping and discuss the different levels that should be considered when implementing evidence-based programs within organizations or developing public health policies. Dr. McLeroy's presentation will focus on the use of social network analysis as a tool to analyze community capacity and ensure that organizations and communities are working together to develop, implement, evaluate, and sustain effective programs.
For more information and to register for this event, visit the R2R website, where you can watch presentations and join discussions. This cyber-seminar will be available on the R2R website approximately 1 week after the presentation.
If you missed any of the past cyber-seminars, you can view them in the R2R archive.
NCI Guide on Communicating Data to Lay Audiences Now Available
Making Data Talk: A Workbook helps public health practitioners, scientists, health educators, clinicians, researchers, students, and statisticians effectively communicate data to lay audiences.
The workbook, based on the book Making Data Talk: Communicating Public Health Data to the Public, Policy Makers, and the Press, by Drs. David E. Nelson, Bradford W. Hesse, and Robert T. Croyle of NCI's Division of Cancer Control and Population Sciences, provides key information, practical suggestions, and examples on how to successfully communicate health-related scientific data.
The workbook also offers recommendations about selecting and presenting data and introduces the OPT-IN (organize, plan, test, integrate) framework, which guides public health practitioners on how to present health data to lay audiences. Many chapters also include practice exercises that use real-world examples to reinforce and apply key concepts.
Major League Baseball Limits Players' Use of Tobacco
The agreement prohibits players, managers, and coaches from using smokeless tobacco during televised interviews, club appearances, or other events where fans are permitted. In addition, players, managers, and coaches may not carry tobacco packages or tins when fans are in the ballpark. Individuals who violate the policy will be subject to discipline.
The agreement also expands tobacco education programs for players and calls for a program of education and public outreach on the dangers of smokeless tobacco.
The effort to promote "tobacco-free baseball" is supported by numerous national health and medical organizations, including the American Cancer Society, the American Medical Association, and the American Academy of Pediatrics, as well as many youth organizations, researchers, public health organizations and others. More information about the effort can be found online.
Further reading: "House Committee Convenes Hearing on Smokeless Tobacco"
President Obama Encourages Smokers to Quit
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November 17 marked the American Cancer Society's 36th annual Great American Smokeout, a day set aside every year to encourage smokers to make a plan to quit smoking for good and to remind nonsmokers not to start.
President Barack Obama congratulated those participating in the Great American Smokeout in a short video message.
Visit NCI's smoking home page to see the video and for information and resources on quitting smoking.