Featured Article

Genome Study Points to Treatments for High-Risk Form of Childhood Leukemia

Genomic tools can help match cancer patients to targeted drugs. (Image by Joshua Stokes, BMC, St. Jude Children’s Research Hospital)

Using genomic tools, researchers have uncovered genetic changes associated with a form of leukemia that recurs in some children. The findings, reported last month in Cancer Cell, suggest that some of these young patients may benefit from targeted drugs that are available but currently not used to treat this particular form of the disease.

The study focused on a subtype of acute lymphoblastic leukemia (ALL) known as Philadelphia chromosome-like ALL. Children with this subtype have a higher risk of a recurrence after standard chemotherapy and lower rates of long-term survival than other children with high-risk ALL.

Since the subtype was first described in 2009 (here and here), researchers have identified genetic changes that could explain about half of these cases. Building on this work, a team led by Dr. Charles Mullighan of the St. Jude Children’s Research Hospital analyzed RNA from 15 patients with the subtype and sequenced the genomes of two of these patients.

The results, Dr. Mullighan said, were “striking.” His team found a diverse set of genetic abnormalities linked to cancer, including DNA mutations and chromosomal rearrangements. The biological effects of these changes, however, appeared to be concentrated primarily on two signaling pathways involved in cell growth and proliferation.

Making Use of Available Drugs 

“We found a wide range of gene fusions, but they converged on a limited number of pathways,” said Dr. Kathryn Roberts of St. Jude, a study author. These pathways included the proteins ABL1, PDGFRB, and JAK2, which all play a role in cell growth.

In the lab, several drugs that inhibit growth-promoting signals through these pathways—including imatinib (Gleevec), dasatinib (Sprycel), and ruxolitinib (Jakafi)—showed anticancer effects against models of Philadelphia chromosome-like ALL.

“These findings are important because these children frequently have very poor outcomes,” Dr. Mullighan said. Future studies could test whether patients with mutations affecting these pathways could be candidates to receive targeted drugs along with chemotherapy, he added.

Overall, children with high-risk ALL have a greater than 80 percent chance of being cured by standard treatments, but only about 60 percent of children with Philadelphia chromosome-like ALL are alive and free of cancer after 5 years. This subtype, which accounts for about 15 percent of childhood ALL cases, shows similar patterns of gene activity as Philadelphia chromosome-positive ALL, but the BCR-ABL1 fusion gene is absent.

Better Diagnostic Tests Needed

The new results are from the TARGET initiative, an NCI-supported project that brings together experts on childhood cancers and genome analysis to identify genetic alterations that could be targeted by new or existing therapies.

“These are exactly the kind of results this initiative was created to generate,” said Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program and an NCI leader of the TARGET initiative.

Dr. Charles Mullighan and his team showed that patients with a high-risk form of leukemia might benefit from existing targeted therapies. (Photo by BMC, St. Jude Children’s Research Hospital)

“At this point there are anecdotal examples of how these findings could be translated for broader application,” Dr. Smith continued. Future challenges include improving diagnostic tests to detect the specific molecular alterations and developing treatments appropriate for each alteration, he noted.

At St. Jude, Dr. Roberts is investigating two approaches for detecting this subtype of ALL at the time of diagnosis. One strategy is to profile the active pathways in the leukemia cells, and the other is to look for signature patterns of gene activity.

These tests could serve as an initial screen for Philadelphia chromosome-like ALL, followed by testing for specific genetic alterations associated with the disease, according to Dr. Christine Harrison of Newcastle University in the United Kingdom, who wrote an accompanying editorial.

She praised the study for providing “a comprehensive genomic definition” of Philadelphia chromosome-like ALL, showing it to be a disease with distinctive genetic alterations that affect a range of proteins involved in cell growth.

The work also illustrates one way that cancer researchers are increasingly using genomic tools, noted co-author Dr. Stephen Hunger of the University of Colorado, who is also chair of the Children’s Oncology Group ALL Disease Committee.

“The first step is to identify the abnormalities driving the development of a particular cancer,” he explained. “Then, you use therapies directed against those abnormalities—either alone or with chemotherapy—to improve the outcomes of patients with the least possible side effects.”

Dr. Smith added, “Targeted agents are already known for some of the molecular alterations in Philadelphia chromosome-like ALL, but for others they will need to be identified.”

Dr. Mullighan agreed that a more complete understanding of the Philadelphia chromosome-like ALL subtype is needed. When his team expanded their analysis to include samples from more than 400 patients, the critical lesions in about 20 percent of the cases were unknown.

“We need to know what the changes are, and no single method of analysis is going to pick up every genetic alteration,” he said.

Knowledge gained from studying Philadelphia chromosome-like ALL in children could prove useful for adolescents and young adults as well. This subtype is thought to be more common with advancing age, and the prognosis may also worsen with age.

Since the study was published, Dr. Mullighan has received inquiries from doctors who want to know whether their patients with ALL might be candidates for the new approach. For the study authors, this has underscored the importance of developing clinically accredited tests.

“We really need to develop the diagnostic tests so that we can identify these patients at the time of diagnosis and direct them to the most appropriate targeted therapy,” Dr. Roberts said.

—Edward R. Winstead

Related articles: “Genome Studies Yield Insights into Childhood Leukemia”

To see Dr. Roberts discussing her findings, please watch this video.

Cancer Research Highlights

High Breast Density Does Not Predict Death among Breast Cancer Patients

High breast density is a strong risk factor for developing breast cancer, but it does not affect a breast cancer patient’s risk of death, according to a study recently published in the Journal of the National Cancer Institute.

Denser breasts have more glandular tissue (cells that produce milk during lactation) and supportive connective tissue than fatty tissue. Doctors use a scale called the Breast Imaging Reporting and Data System (BI-RADS) to classify breast density as observed on mammograms on a scale from 1 to 4, with 1 being the least dense and 4 the most dense.

To examine the relationship between breast density and risk of death from breast cancer, Dr. Gretchen Gierach and her colleagues from NCI’s Division of Cancer Epidemiology and ­­­Genetics and the NCI-sponsored Breast Cancer Surveillance Consortium (BCSC) examined medical records from more than 9,000 breast cancer patients collected by the BCSC.

After accounting for age, body mass, treatment, and other factors that could influence the risk of death, the researchers found that among women diagnosed with breast cancer, women with dense breasts were not more likely to die of the disease or of other causes than women with less-dense breasts during nearly 7 years of follow-up, on average.

Unexpectedly, the researchers observed that breast cancer patients with the least-dense breasts had an increased risk of death from breast cancer if they had large tumors or were obese. However, given that this result was based on relatively small numbers of women and has not been previously suggested by other studies, “these findings need to be replicated in larger studies,” said Dr. Gierach.

Obesity is a risk factor for death from breast cancer and is also inversely related to breast density. (That is, obese women are less likely to have dense breasts.) Therefore, obesity could affect associations between breast density and breast cancer death.

“We already know that obesity is a poor prognostic factor for breast cancer in general, but this particular analysis showed that the subgroup of women who were obese and had less-dense, fatty breasts were at greatest risk,” she explained. “Our hypothesis is that the fat content in the breast might be enhancing obesity-related mechanisms that heighten tumor aggressiveness in breast cancer. We are conducting studies to better understand the biology of breast density.”

This research was supported in part by grants from the National Institutes of Health (U01CA63740,U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, and HHSN261201100031C).

Flavored Cigar Use Common among Young Adult Cigar Smokers

Flavored cigar use is common among adults who smoke cigars, and particularly high among young adult cigar smokers, according to the first nationwide survey to assess adult use of these products. Flavored cigar smoking also varies by geographic region, the study found.

Dr. Brian King and colleagues from the Centers for Disease Control and Prevention (CDC) reported the findings online August 27 in Nicotine & Tobacco Research.

Using data from the 2009–2010 National Adult Tobacco Survey, which included about 119,000 landline and cell phone users, the researchers estimated that 6.6 percent of adults in the United States smoke cigars. Cigar smoking was especially high (15.5 percent) among 18 to 24 year olds. Approximately 43 percent of adults who smoke cigars use flavored cigars, they found. Among 18- to 24-year-old cigar smokers, 57 percent use flavored cigars.

Flavored cigar use was also more common among certain groups, including women and Hispanic cigar smokers, as well as cigar smokers with less education and lower incomes. The highest rates of flavored cigar use among cigar smokers were in North Dakota (71.6 percent) and New Mexico (69.0 percent), and the lowest rates were in New Hampshire (11.1 percent) and New Jersey (23.7 percent).

In 2009, the U.S. Food and Drug Administration (FDA) prohibited the use of certain flavors in cigarettes—such as vanilla, chocolate, cherry, and others that have a distinguishable taste or aroma—under authority granted by the Family Smoking Prevention and Tobacco Control Act. However, the FDA does not currently regulate cigars, and flavored cigars may still be manufactured and sold.

Flavorings, the study authors said, “mask the natural harshness and taste of tobacco.” Cigars contain many of the same toxic substances as cigarettes and smokeless tobacco and raise the risk of several cancers, heart disease, and chronic obstructive pulmonary disease.  

Given the high rate of use among cigar smokers, the authors concluded, “efforts to curb flavored cigar smoking have the potential to reduce the prevalence of overall cigar smoking among U.S. adults.”

Gene in Stem Cell Donors May Decrease Relapse Risk in Leukemia Patients

An analysis of patients who had undergone blood stem cell transplants for acute myelogenous leukemia (AML) suggests that certain genetic features of the donors are related to risk of AML relapse. The findings of this retrospective study show that stem cell transplants from genetically similar donors who carry a gene known as KIR2DS1, which can activate cancer-fighting natural killer (NK) cells, appear to be associated with a reduced risk of relapse in AML patients.

The study, by Drs. Katharine Hsu and Bo Dupont of Memorial Sloan-Kettering Cancer Center and their colleagues, appeared August 30 in the New England Journal of Medicine.

KIR genes code for members of a group of proteins called killer-cell immunoglobulin-like receptors, which are found on the surface of NK cells—white blood cells that can kill tumor cells.

Researchers also found that the reduced relapse rate associated with KIR2DS1 was restricted to stem cell donors with specific variants of the gene HLA-C. HLA genes code for cell-surface HLA proteins, which make up a person’s tissue type.

Hematopoietic stem cell transplants (HSCT) are given to patients who have AML to replace the diseased cells in the bone marrow with healthy stem cells that can develop into all types of blood and immune system cells to fight the leukemia. When selecting donors for HSCT, physicians match the HLA tissue type of donor and recipient to reduce the chances that the recipient’s new immune system will damage his or her other tissues and organs.

 “Studies over the last 15 to 20 years have pointed to the fact that the NK cells that emerge after transplant are quite potent in destroying any remaining leukemia cells, particularly in AML,” Dr. Hsu said.

“We know that NK cells are inhibited or activated by the various KIR receptors and their interactions with HLA molecules,” she continued. “The real goal is to figure out which KIR-HLA combinations are going to allow the donor-derived NK cell to have its maximal effects in terms of leukemia control.”

The researchers examined the outcomes of HSCT in 1,277 patients with AML and 427 patients with acute lymphoblastic leukemia (ALL) who had received transplants between 1989 and 2008 from unrelated donors. The donors and recipients were matched for at least 9 of 10 possible versions of the five HLA genes. The researchers used stored blood and DNA samples to test for various types of KIR genes in stem cell donors and for HLA genes in donors and recipients.

They found that patients with AML (but not those with ALL) who received transplants from donors carrying the KIR2DS1 gene had a significantly lower risk of relapse than patients with transplants from donors without KIR2DS1. But KIR2DS1 did not improve outcomes when the donor had two copies, or alleles, of the HLA-C2 gene. This last finding is consistent with studies showing that high levels of HLA-C2 protein reduce the activity of NK cells bearing KIR2DS1 receptors.

Dr. Hsu commented that future studies should examine the effects of other KIR-HLA interactions or combinations in HSCT. “As we do this, we can become more and more refined in our donor selection criteria, with the goal of selecting a donor who is going to give the greatest benefit in terms of reducing leukemic relapse and increasing survival.”

This research was supported in part by grants from the National Institutes of Health (U01 AI69197, KL2 RR024997, R01 HL088134, and P01 CA23766).

Sequencing "Outlier" Genome Suggests Some Patients May Benefit from Cancer Drug

Clinical trials that fail to identify drugs that benefit most patients may still yield valuable information by identifying subsets of patients who would benefit from the drugs. That is the conclusion of a study in which researchers used whole-genome sequencing to salvage a potentially beneficial drug that might have been discarded.

In a report published August 23 in Science, researchers at Memorial Sloan-Kettering Cancer Center describe how they sequenced the tumor genome of a 73-year-old woman with advanced bladder cancer who had a complete response to the drug everolimus (Afinitor) that has lasted for more than 2.5 years. The patient was part of a 45-patient, early-phase clinical trial in which treatment with everolimus failed to improve progression-free survival, the trial’s primary endpoint, among the patient population enrolled in the trial as a whole.

“The patient was a dramatic outlier in terms of her clinical response,” said the study’s senior author, Dr. David Solit.

After targeted sequencing of a few specific genes in the woman’s tumor “didn’t turn up anything revealing,” Dr. Solit continued, the researchers decided to sequence the woman’s entire tumor genome to see if they could discover a molecular basis for her strong response.

Among the many genomic alterations the researchers identified, inactivating mutations in two genes, TSC1 and NF2, stood out. Evidence from laboratory studies had suggested that loss-of-function mutations in TSC1 and NF2 might increase sensitivity to everolimus.

The researchers then analyzed the tumor DNA from 13 other patients enrolled in the trial and found TSC1-inactivating mutations in the tumors of three more patients, two of whom had measurable tumor shrinkage and lived longer without their cancer progressing than patients whose tumors lacked a TSC1 mutation. None of the 13 patients’ tumors had an NF2 mutation.

Sequencing the TSC1 and NF2 genes in tumor samples from 96 other patients with advanced bladder cancer revealed five more patients with TSC1 mutations, but no NF2 mutations.

Dr. Solit and his colleagues hope to launch a small clinical trial testing everolimus in patients with bladder cancer tumors that have mutations in TSC1 or a related gene, TSC2.

“We often see cases where just a few patients in an otherwise negative trial have significant benefit,” Dr. Solit said. “With the in-depth analysis provided by novel technologies like whole-genome sequencing, we can possibly salvage potentially beneficial drugs that were otherwise going to fail.”

Researchers Use Gene Deletions to Find Cancer Treatment Targets

Chromosomal damage that can transform healthy cells into cancer cells may also create weaknesses that can be exploited to kill the cancer cells, a new study suggests. The idea, called “collateral vulnerability,” could be used to identify new targets for drug therapy in multiple cancers, according to researchers from the Dana-Farber Cancer Institute and the University of Texas MD Anderson Cancer Center. The study was published August 16 in Nature.

Directly targeting genetic mutations that drive cancer with drugs is difficult, particularly in the case of mutations that delete tumor suppressor genes. Using data on the brain cancer glioblastoma multiforme (GBM) from The Cancer Genome Atlas (TCGA) initiative, the research team identified a number of “collateral” or “passenger” gene deletions that occurred during chromosomal damage that resulted in the loss of tumor suppressor genes.

The researchers next looked for passenger gene deletions that met two criteria: the deleted genes were involved in functions vital to cell survival, and the deleted genes were closely related to existing genes that perform similar functions. This loss of redundancy caused by passenger gene deletions can potentially be exploited to selectively kill tumor cells, the authors explained.

One gene that met these criteria is ENO1. ENO1 produces enolase 1, an enzyme that plays a central role in a process cells use to make energy. Human cells have a closely related gene (ENO2) that produces the enzyme enolase 2, which acts as a back-up for enolase 1 in brain tissue. Brain cells normally have a high level of enolase 1 activity and a small amount of enolase 2 activity. In some patients with GBM, however, the tumor cells lack enolase 1 activity because ENO1 was deleted when a tumor suppressor gene was deleted. This lack of enolase 1 activity could make these tumor cells more vulnerable to enolase inhibition.

This idea was tested using two targeting strategies. First, in GBM cell lines that lacked ENO1, the investigators showed that silencing ENO2 gene expression with a short hairpin RNA (a short RNA sequence that blocks the production of enolase 2 protein from ENO2 messenger RNA) sharply reduced cell growth, and tumors failed to form in mice injected with the treated cells.

The second approach involved a drug that targets the enolase 1 and enolase 2 proteins. Treatment of GBM cell lines lacking ENO1 with the drug caused the cancer cells to die because of the low overall enolase levels in these cells. But drug treatment had little effect on normal brain cells or GBM cells that had ENO1, since these cells have high levels of ENO1 gene expression and are, therefore, less sensitive to the drug.

The collateral vulnerability concept is similar in some respects to the idea of synthetic lethality, which uses genetic mutations in cancer-associated genes to identify other potential cellular vulnerabilities, explained the study’s co-lead author, Dr. Florian Muller of MD Anderson.

There are many more passenger gene deletions than tumor suppressor gene deletions, “and some of these passenger-deleted genes perform functions critical for cell survival,” Dr. Muller continued. “So, by expanding the concept to passenger genes, we vastly expand the possibility of finding these relationships, and, in the case of essential-redundant gene pairs like ENO1 and ENO2, we also provide a rational, knowledge-based method of drug-target discovery.”

The researchers are extending their work to other passenger gene deletions in GBM, Dr. Muller said.

This research was supported in part by the National Institutes of Health (CA95616-10 and CA009361).

A Conversation With

A Conversation with Dr. Louis Staudt about Targeting New Treatments for Burkitt Lymphoma

Dr. Louis Staudt of NCI’s Center for Cancer Research and his international colleagues used RNA sequencing technology to confirm that Burkitt lymphoma is molecularly distinct from other types of non-Hodgkin lymphoma and to identify promising new targets for treatment. These new targets may be particularly important for lymphoma treatment in the developing world. Dr. Staudt described the findings, published August 12 in Nature, in a conversation with the NCI Cancer Bulletin.

What recent developments in technology allowed you to do this study?

Dr. Louis Staudt

The main development was next-generation sequencing, which gave us a very high-throughput way of determining the sequence of RNA. So, in a very rapid way, in a large number of lymphomas, we could identify likely mutations that could cause the cancer. Sequencing has become more affordable, and, at the same time, it’s become even more high-throughput, so we get more information. For a modest investment, we can survey a large number of tumors.

Did you identify any mutated genes in Burkitt lymphoma that may be targets for new treatments?

We found frequent mutations affecting a transcription factor, TCF3, which might not be a therapeutic target itself. But then we determined what [cellular] pathways were activated or reinforced by these mutations, and that led us to therapeutic targets with available drugs that are being tested in the clinic for other cancer types.

So, our focus turned to a pathway leading from the B-cell receptor to the PI(3) kinase pathway, which is arguably the most commonly mutated and activated signaling pathway in human cancer. In our lymphoma cases, this pathway was activated indirectly, but the end result is that, if you throw drugs at the tumor cells that inhibit the PI(3) kinase pathway, the cells die a swift and horrible death.

We also found a relationship between the transcription factor TCF3 and one of the many genes that it activates, called CCND3, which encodes the protein cyclin D3, an important regulator of the cell cycle. We found that not only does TCF3 activate CCND3 but that CCND3 was itself mutated frequently, and those mutations turn it into an oncogene, a cancer-causing gene.

So, this was another high-frequency mutation that led us to try a drug that inhibits its signaling pathway, and what we observed initially was exactly what we’d expected: the cells stopped dividing at a precise point in the cell cycle. However, the big surprise was that after the cells stopped proliferating, in a matter of days they all started dying, meaning that we will have another potential way of not just stopping the tumor cells from growing but eliminating them.

How will this study affect patients?

With the high-dose chemotherapy regimens that we can use here in the United States and in developed countries in general, we can already cure a high percentage of people with Burkitt lymphoma, maybe 85 percent of patients.

The situation is quite different in developing countries. In Africa, there’s a high incidence of Burkitt lymphoma, and the high-dose therapies that we use in the developed world cannot be safely delivered in Africa, in those less-developed settings, because they suppress the immune system. That leaves patients highly susceptible to infections, and because of the lack of supportive care in Africa, those infections will end up killing people.

What’s being used to treat Burkitt lymphoma in Africa is a minimal chemotherapy regimen, which thankfully cures about 30 to 50 percent of patients, but that’s way too low a rate. So, we hope that we might be able to supplement that minimal chemotherapy with some of these new targeted agents and improve the outcomes for patients there.

But there’s also still a role for new therapies in the developed world for the 15 percent of Burkitt lymphoma patients who are not treated adequately with current therapies. There’s also a potential role for these new therapies in elderly patients, because high-dose chemotherapy can cause overwhelming infections in older individuals, even with great supportive care.

What does this study add to the overall field of cancer genomics?

I think one of the most remarkable findings is that the frequencies of the mutations we found in this type of lymphoma were extraordinarily high compared to other forms of cancer. For example, [one] transcription factor…was activated by mutations in 70 percent of cases. If you look in many of the other cancer genome projects, you find a much lower frequency of recurrent mutations.

If we can divide cancer into narrowly defined subtypes, we’ll find that within those subtypes there is a very clear, common way for cells to become malignant. That mechanism, that pathway will be used in a high percentage of those cases.

If you were to take all breast cancers, you would not find any mutations that occur at anywhere near the frequency that we found in Burkitt lymphoma. That is simply because breast cancer is not one disease; it’s many diseases rolled into one diagnosis. So, our job in cancer genomics is to divide cancer into precisely defined molecular categories. That will enable a much more rapid understanding of essential pathways that could be responsive to drugs.

—Interviewed by Sharon Reynolds

For more information, please visit NCI’s Center for Cancer Research and the Office of Cancer Genomics

Featured Clinical Trial

Targeting Invasive Glioma Cells

Name of the Trial
Phase I Trial of AZD7451, a Tropomyosin-Receptor Kinase (TRK) Inhibitor, for Adults with Recurrent Gliomas (NCI-12-C-0005). See the protocol summary.

Dr. Katharine A. McNeill and Dr. Howard Fine

Principal Investigators
Dr. Katharine McNeill, NCI Center for Cancer Research, and Dr. Howard Fine, New York University Cancer Institute

Why This Trial Is Important

Glioblastoma is the most common malignant brain tumor in adults, with about 12,000 new cases diagnosed each year in the United States. It is also one of the deadliest, with a median survival following diagnosis of about 14 months.

Surgery to remove as much of the tumor as possible is the standard primary treatment for glioblastoma. After surgery, doctors use radiation therapy and treatment with the chemotherapy drug temozolomide to try to delay the growth of the remaining cancer. Although these measures may delay disease progression for a while, they cannot prevent it, and death usually occurs within a few months. Currently, the only therapy that has proven effective in delaying death in patients with progressive glioblastoma is bevacizumab, which helps block the tumor's ability to induce the formation of new blood vessels.

Glioblastoma is particularly difficult to treat because of its highly invasive nature. Although the bulk of the tumor may be well defined, malignant cells have usually migrated away from the tumor by the time it is discovered. Some of these cells inevitably remain behind after surgery and, if left unchecked, will eventually kill the patient.

Progress in the treatment of glioblastoma has been hampered by the absence of preclinical tumor models that mimic the invasiveness of the cancer. However, NCI researchers recently developed new cell lines from a subset of glioblastoma tumor-initiating cells that more accurately replicate the invasiveness of human glioblastoma in animal models. Using the new models, they were able to determine that cells near the edge of glioblastoma tumors express a set of proteins that help make them highly invasive. Subsequently, they identified a compound that may be effective in blocking the function of one of these key proteins.

A protein called tropomyosin-receptor kinase, or Trk, is commonly found on brain cells and helps regulate the development, function, and survival of nerve cells. In glioblastoma, Trk is highly expressed on the cells around the edges of the tumor and on the infiltrative cells that have migrated away from the tumor mass, whereas those cells in the bulk of the tumor show lower levels of Trk expression. Doctors want to see if inhibiting the function of Trk will help block the invasiveness of glioblastoma cells and reduce the likelihood that the tumor will progress.

In this first-in-class phase I trial, patients with glioblastoma that has not responded to standard postoperative therapy or that has progressed will be treated with varying amounts of a Trk inhibitor called AZD7451 to determine the maximum tolerated dose and the side effects of this drug. Doctors will also look for signs of clinical activity.

“Regardless of the extent of tumor resection, there are always residual tumor cells because these cells are highly invasive and infiltrate normal brain tissue,” said Dr. Fine, former chief of NCI’s Neuro-Oncology Branch. “So surgery is never curative in this disease; some type of postoperative therapy is always required to try to address these remaining infiltrative tumor cells.

“We became interested in trying to study this invasive process in the laboratory in hopes of identifying new molecular targets for therapy,” he continued. “We were able to find that this molecule called Trk was expressed specifically on glioblastoma cells that were invading and [that] Trk was signaling to these tumor cells in a way that was important for the cells to move within the brain. Further, by inhibiting Trk we were able to shut off the invasive process in these models.”   

The trial is taking place at the NIH Clinical Center in Bethesda, MD, and at the New York University Cancer Institute in New York City.

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

Spotlight

Clinical Pathways in Cancer Care Catching On

For a woman diagnosed with HER2-negative, estrogen-receptor negative breast cancer that has spread to the lymph nodes, guidelines from the National Comprehensive Cancer Network (NCCN) recommend chemotherapy following surgery.

Within this recommendation, however, is a lot of room for variation. In fact, there are 16 possible chemotherapy regimens, explained Dr. Bruce Feinberg, chief medical officer of Cardinal Health Specialty Solutions, based in Dublin, OH. Many of these regimens are similar, “but most of them will never be tested head to head” to determine which are the most effective, least toxic, and least costly, he said.

Clinical pathways can help physicians choose the best treatments for individual patients from several possible regimens.

As a result, even within the same oncology practice, two similar patients may get very different treatments, often because their oncologists prefer or are more comfortable with one particular regimen than another.

Enter “clinical pathways”—programs that are being designed and implemented by large networks and smaller practices to limit such variation. The programs do this by helping doctors select what the available evidence indicates are the best regimens for a particular patient. That evidence is derived from sources that can include clinical trial data and professional guidelines.

In the breast cancer example above, the clinical pathway used by many Michigan oncologists narrows the first-line treatment options from 16 to 4 regimens, explained Dr. Feinberg, who ran a large Atlanta-based oncology practice for 23 years.

Pathways programs that Cardinal Health has helped to establish in Michigan, Maryland, Pennsylvania, and several other states have “reduced variation, and allowed those oncologists to gain more refinement and better knowledge of the treatments,” Dr. Feinberg said. And that, proponents of clinical pathways believe, can improve the quality of care.

Pathways may also save money, by reducing treatment complications and the unnecessary use of some drugs, for example. And with annual direct costs of cancer treatment in the United States estimated to reach $173 billion by 2020, any way of cutting costs—without sacrificing quality—is under serious consideration.

Building a Pathway

The pathways concept appears to be picking up steam. In a small survey conducted at NCCN’s 2012 annual conference, for example, nearly 60 percent of respondents said they had implemented or were considering implementing clinical pathways.

Clinical pathways are just one route the oncology community is pursuing to improve the quality and efficiency of care, explained Dr. Steven Clauser, chief of the Outcomes Research Branch in NCI’s Division of Cancer Control and Population Sciences (DCCPS).

“In the last few years, we’ve begun to see a real emphasis on trying to improve and measure quality,” Dr. Clauser said. That includes efforts to track adherence to clinical guidelines, “and using [the resulting] data to better understand an organization’s clinical environment and how they’re treating their patients,” he continued.

Clinical pathways are similar to clinical guidelines, but they take the concept one step further.

The US Oncology Network, a nationwide network with approximately 1,000 oncologists, develops its clinical pathways following a specific formula, explained Dr. Roy Beveridge, chief medical officer for McKesson Specialty Health. (McKesson acquired US Oncology in 2010.)

“First, we look at randomized controlled trials...which we believe are the most important data,” Dr. Beveridge said. “We want to see the manuscript, and we look for definitive trials.”

When a randomized trial shows that one treatment is significantly better than “anything else out there,” he continued, “then that is the top choice in the pathway. Period.”  In cases where two treatments are equally effective but differ in toxicity, the less-toxic regimen is favored. And in cases where efficacy and toxicity are similar, then cost—in the form of what insurers pay—is taken into account.

Cardinal Health and Via Oncology, a spinoff of a clinical pathways program developed at the University of Pittsburgh Medical Center (UPMC) Cancer Center, follow similar criteria. All three companies rely on physician-led committees to review clinical trial results, published studies, and, with the exception of Via Oncology, professional clinical guidelines to develop each pathway.

In the physician networks that implement pathways, oncologists can review and comment on draft pathways before they’re finalized. These committees convene regularly to review the latest data and determine whether a pathway needs to be updated.

The pathways are not iron clad, nor should they be, explained Dr. Peter Ellis, Via Oncology’s medical director. In all of the major pathway programs, the rule of thumb for adhering to a pathway is 80 percent, a threshold that appears to be based primarily on clinical experience, not firm data.

If an individual oncologist has an adherence rate above 80 percent, “we’re worried about it,” said Dr. Ellis. Adherence above 80 percent “could mean that they’re not thinking through the needs of individual patients. There are going to be circumstances when a patient really should be on something other than the pathway choice.”

UPMC, Dr. Ellis said, has a compliance rate of 77 percent with its available pathways, which now cover approximately 90 percent of cancer treatment decisions, as well as tests, post-treatment surveillance, radiation therapy, and supportive care.

The pathways concept isn’t always welcomed with open arms, though. Practicing oncologists must “deal with reality, where variances [to pathways] go by different names, such as vomiting, fever, drug shortages, pulmonary emboli, frustration, grief,” Dr. Craig Hildreth, an oncologist in St. Louis, wrote last year on his Cheerful Oncologist blog. (Free registration is required to access the blog.)

In some cases, medical practices within a health care network that has implemented a pathways program have refused to use them.

At practices in the US Oncology Network, Dr. Beveridge said, the response has been good. “Our Level I Pathways is an evidence-based medicine initiative,” he said. “The buy-in has been high because these treatment guidelines are physician-led and developed based on proven evidence.”

A practice's setting will also likely influence the decision to implement clinical pathways, said Dr. George Weiner, director of the University of Iowa Holden Comprehensive Cancer Center. Academic medical centers with tumor boards and “strong in-house multidisciplinary programs,” where there is a significant amount of collaboration and discussion among the different clinicians involved in patient care, may be less likely to go the pathways route, he believes.

Do Pathways Improve Care, Save Money?

The concept of clinical pathways is a strong one, said Dr. Stephen Taplin, chief of the Process of Care Research Branch in DCCPS. But, he cautioned, it’s unclear whether clinical pathways improve quality.

“The idea that adherence to a guideline or a pathway is a measure of quality is complicated,” Dr. Taplin said. “That’s the part we have to be careful about.”

Oncologists must consider factors like patient preference and suitability for treatment when making decisions about care, he stressed.

The best way to develop and use pathways will need to be closely studied, noted Dr. Weiner.  “How rigorous should they be? How much flexibility should they include?”

Dr. Ellis acknowledges that it’s difficult to prove that clinical pathways improve care quality.  Even so, he argued, “If a pathways system can document that evidence-based care is given, then it naturally follows that the quality of care will improve.”

But at this point, Dr. Feinberg noted, the idea that pathways improve care quality is “largely an act of faith.... You have to look for behavior changes that you believe represent better care.”

Some documented behavior changes include less use of combination chemotherapy as third- and fourth-line treatments. Patients treated on a pathway also have fewer emergency room and hospital admissions because of chemotherapy side effects, the US Oncology Network and Cardinal Health have reported.

The US Oncology Network is, thus far, the only group to publish data on potential cost savings. Using electronic medical record data from eight of its affiliated practices, they found that, over 1 year, outpatient treatment costs were 35 percent lower ($18,000 versus $28,000) for patients with non-small cell lung cancer treated on-pathway than off-pathway.

Some insurers have been skeptical about whether pathways can improve care or reduce costs, Dr. Beveridge acknowledged. “That’s why we conducted the study,” he said. “Because of our study results, I believe most payers are now interested in learning more about a pathways approach.”

Insurers are central to the model used by Cardinal Health, which facilitates collaborations with insurers and oncology groups on pathway development. As part of that collaboration, the insurers provide financial incentives to practices that participate in the program and meet compliance benchmarks.

Even with the uncertainty, clinical pathways are proliferating. The US Oncology Network has licensed its pathways to several hospital systems and practices, Dr. Beveridge said. Hospitals and oncology practices in 11 states are using Via Oncology’s pathways. The most recent addition came just last month with Indiana University Health System, which will implement the pathways at the central site and its affiliated oncology practices.

With the advent of accountable care organizations and other efforts to measure quality of care and reduce costs, clinical pathways—or something like them—may very well be part of the future for all hospitals and medical practices, Dr. Ellis believes.

“There’s got to be more accountability and proof of quality of care,” he said. “You’re not going to be able to say to patients and payers, ‘Trust me, I’m a good doctor.’”

—Carmen Phillips

FDA Update

FDA Approves First Drug Developed for Children with Rare Brain Tumor

Last week, the U.S. Food and Drug Administration approved Afinitor Disperz—pediatric doses of everolimus (Afinitor) tablets—to treat a rare brain tumor called subependymal giant cell astrocytoma (SEGA). Afinitor Disperz is the first approved form and dose of a drug developed to treat pediatric tumors.

Afinitor Disperz dissolves easily in a small amount of water, making the treatment easy to administer to patients who are unable to swallow whole tablets. It is also available in smaller doses than everolimus, the adult form of the drug.

Afinitor Disperz is recommended to treat patients 1 year of age and older who have tuberous sclerosis complex (TSC) and are diagnosed with SEGA but who are ineligible for surgery. Prior to the approval of this new dosage form, everolimus was recommended only for patients 3 years of age and older.

TSC is a rare genetic disease that causes tumors to grow in the brain and other vital organs. SEGA is a slow-growing tumor that can cause life-threatening complications by blocking the flow of fluid in the brain. These tumors occur in 6 to 9 percent of TSC patients, generally children and young adults.

Everolimus blocks the uncontrolled activity of a protein called mTOR kinase, which plays a critical role in the development and growth of SEGA tumors occurring in patients with TSC.

Everolimus was granted accelerated approval in 2010 to treat SEGA in patients with TSC.
Everolimus and Afinitor Disperz remain under accelerated approval for the treatment of SEGA in patients with TSC. Everolimus’ manufacturer, Novartis, updated safety and efficacy data from the single-arm study of 28 pediatric and adult patients used to support the drug’s accelerated approval in 2010 for the treatment of SEGA in patients with TSC.

In a more recent study involving 117 pediatric and adult patients who were randomly assigned to take everolimus or a placebo daily, 35 percent of patients treated with everolimus experienced tumor shrinkage compared with none who were treated with placebo. The most common side effects observed in patients with SEGA were mouth ulcers and respiratory tract infections.

Studies continue to evaluate the long-term safety and effectiveness of everolimus and Afinitor Disperz in pediatric and adult patients with SEGA. Afinitor Disperz is classified as an orphan drug because it is intended to treat a rare disease or condition. Afinitor Disperz’s application was granted priority review, which the FDA completed in 6 months.

New Treatment for Severe Neutropenia Approved

The U.S. Food and Drug Administration approved a drug called tbo-filgrastim to shorten bouts of severe neutropenia, a condition that leads to decreased levels of infection-fighting white blood cells (neutrophils). Some patients with cancer who receive chemotherapy develop severe neutropenia.

Tbo-filgrastim is intended for adults who have cancers other than blood or bone marrow cancers and who are taking chemotherapy drugs that substantially decrease the production of neutrophils in the bone marrow. This reduction in neutrophils may lead to infection and fever (febrile neutropenia).

Injections of tbo-filgrastim stimulate the bone marrow to increase the production of neutrophils and are administered 24 hours after chemotherapy treatment.

A randomized clinical trial showed that patients treated with tbo-filgrastim recovered from severe neutropenia in 1.1 days compared with 3.8 days for those who received the placebo. The study involved 348 patients with advanced breast cancer who were being treated with doxorubicin (Adriamycin) and docetaxel (Taxotere).

In three clinical trials evaluating the drug’s safety, the most common side effect observed was bone pain.

FDA Approves Drug to Treat Rare Type of Leukemia

Last month, the Food and Drug Administration (FDA) approved vincristine sulfate liposome (Marqibo) to treat adults with a rare disease called Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL).

Vincristine sulfate liposome is approved for patients whose leukemia has returned at least twice or whose leukemia has progressed following two or more prior treatments. The drug contains vincristine, a common anticancer agent, encased within a liposome, a drug delivery vehicle composed of material similar to that of cell membranes. It is an injection administered once a week by a health care professional.

The drug’s effectiveness was evaluated in a clinical trial of adults whose leukemia had relapsed at least twice despite standard treatments and who had responded to at least one previous treatment for at least 90 days. Ten of the 65 enrolled patients (15.4 percent) had a complete remission or a complete remission with an incomplete blood count recovery. In these 10 patients, the remissions lasted for a median of 28 days. The median time to the first post-remission event (relapse, death, or next therapy) was 56 days.

The drug’s safety was evaluated in two single-arm trials that included 83 patients whose leukemia had relapsed at least twice. Serious adverse events, such as low white blood cell counts with fever, low blood pressure, respiratory distress, and cardiac arrest, occurred in 76 percent of the patients studied. The most common side effects included constipation, nausea, low blood cell counts, fever, nerve damage, fatigue, diarrhea, decreased appetite, and insomnia.

A warning that the drug must be administered intravenously because it is deadly if given in other ways, such as into the spinal fluid, will be included in the prescribing information. The warning also states that the dosage recommendations for vincristine sulfate liposome and vincristine sulfate are different. To avoid overdosing, health care professionals must verify the drug name and the dose before administration.

The drug was approved under the accelerated approval program, which allows the FDA to approve a drug based on clinical data showing that it is reasonably likely to provide a clinical benefit to patients. The manufacturer must conduct more clinical studies to confirm the drug’s benefit and safety. Vincristine sulfate liposome also received orphan-product designation because it is intended to treat a rare disease.

Cancer.gov Update

New Website Highlights NCI-Designated Cancer Centers

NCI recently launched a website that provides an in-depth focus on the NCI-designated cancer centers. The site highlights the recent accomplishments of the nationwide research and patient care network in four areas: targeted cancer therapies, advanced medical technologies, cancer survivorship programs, and initiatives to reduce disparities in research and treatment of cancer in medically underserved populations and communities.

Sixty-seven U.S. cancer centers have earned recognition as NCI-designated cancer centers, indicating that they have met rigorous criteria for world-class programs in multidisciplinary cancer research. These centers develop research programs, faculty, and facilities that are focused on developing better approaches to cancer prevention, diagnosis, and treatment.

One section of the updated site focuses on the development of one of the first targeted cancer therapies, imatinib (Gleevec), and describes how researchers at several NCI-designated cancer centers were involved in the initial research and, later, clinical trials for the drug. After the first clinical study was reported in 1999, imatinib moved quickly toward Food and Drug Administration approval for chronic myelogenous leukemia. By 2011, it had been tested and approved to treat several other cancers.

Another feature of the new website is an interactive map of NCI-designated cancer centers across the United States, with links to detailed profiles for each center. There is also a list of top scientific and medical awards for cancer center scientists, including 45 Nobel Prize winners, and a section describing what it takes for an institution to become an NCI-designated cancer center.

2011/2012 Cancer Trends Progress Report Available

NCI released its 2011/2012 Cancer Trends Progress Report last week. The report summarizes the nation’s progress against cancer in relation to the Healthy People 2020 targets developed by the U.S. Department of Health and Human Services. The revised report, published every other year, is intended for policy makers, researchers, clinicians, and public health service providers. It offers updated national trends data in a user-friendly format that is fully accessible to people with disabilities.

The report features

• A quick tutorial to ease navigating and downloading materials within the report;
• Updated “Trends-at-a-Glance” snapshot;
• Links to NCI’s State Cancer Profiles’ state- and county-level data;
• Data, graphs, and slides that are easy to download;
• Links to Healthy People 2020 materials;
• Links to colorectal cancer mortality projections; and
• Custom print reports.

The Cancer Trends Progress Report: 2011/2012 Update can be viewed online. General questions about the report may be directed to progressreporthelp@mail.nih.gov.

Website for NCI’s Geographic Information Systems & Science Updated

The recently updated website for NCI’s Geographic Information Systems (GIS) & Science for cancer prevention and control boasts a streamlined design to help users more easily navigate the site.

Geographic and spatial contexts are important factors in health. They can influence the risk of getting a disease, the ability to adopt a healthy lifestyle, and the ease of access to medical services for disease prevention, diagnosis, and treatment.

GIS systems capture, manage, analyze, and visualize geographic information, including cancer data, making it easier for researchers to observe and interpret relationships, patterns, and trends in complicated data sets.

The redesigned website features a “Why Spatial Context Matters” screen with rotating images that depict geographic and environmental factors that affect cancer risk, as well as four entry routes to the main elements of the GIS site.

Please visit the GIS website to

• Learn about GIS initiatives and research at NCI;
• Explore the tools and data used in GIS research; and
• Find out about NCI and NIH funding and training opportunities.