National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 2, 2012 • Volume 9 / Number 19

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NEWS

Targeted Drug Benefits Some Patients with Advanced Lung Cancer

European Society for Medical Oncology 2012 Congress banner The drug crizotinib (Xalkori) substantially lengthens the amount of time some patients with advanced lung cancer live without their disease progressing, according to findings from the first large clinical trial to test the targeted therapy.

Initial results from the trial were presented Sunday at the European Society for Medical Oncology Congress (ESMO) in Vienna, Austria. Read more > >

COMMENTARY

HHS Secretary Kathleen Sebelius

Statement from HHS Secretary Kathleen Sebelius on Breast Cancer Awareness Month 

The Honorable Kathleen Sebelius is the 21st secretary of the Department of Health and Human Services, which includes NCI. In a statement marking Breast Cancer Awareness Month, Secretary Sebelius highlights some of the successes and challenges in the fight against the disease while stressing the importance of prevention and early detection.

MULTIMEDIA

IN DEPTH

UPDATES

  • Legislative Update

    • President Signs 6-Month Spending Bill
    • Congressional Caucus Holds Childhood Cancer Summit
  • FDA Update

    • FDA Approves Ultrasound Imaging System for Dense Breast Tissue
    • New Treatment for Advanced Colorectal Cancer Approved
  • Notes

    • NCI Director Discusses "What Impedes Cancer Research?"
    • What You Need to Know About Cancer Booklets Updated
    • The Boletín, NCI's Spanish-Language Newsletter, Turns Three


Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

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

Featured Article

Targeted Drug Benefits Some Patients with Advanced Lung Cancer

European Society for Medical Oncology 2012 Congress banner The drug crizotinib (Xalkori) substantially lengthens the amount of time some patients with advanced lung cancer live without their disease progressing, according to findings from the first large clinical trial to test the targeted therapy.

Initial results from the trial were presented Sunday at the European Society for Medical Oncology Congress (ESMO) in Vienna, Austria.

The Food and Drug Administration (FDA) approved crizotinib last year to treat patients with advanced non-small cell lung cancer (NSCLC) whose tumors have a specific genetic mutation. The approval was based on smaller, nonrandomized trials that showed crizotinib could shrink tumors in many patients with the mutation—a genetic rearrangement involving the ALK gene.

Until now, crizotinib had not been shown to prolong progression-free or overall survival compared with standard chemotherapy.

"The results from the phase I and phase II trials were pretty remarkable," said lead investigator, Dr. Alice Shaw of Massachusetts General Hospital. "We had high tumor response rates, which were impressive for just a single agent."

A large randomized trial was necessary, Dr. Shaw explained, to confirm that the tumor responses translated into meaningful outcomes and to answer questions about whether patients whose tumors had this genetic mutation were more sensitive to any therapy, not just crizotinib.

The results from the phase I and phase II trials were pretty remarkable. We had high tumor response rates, which were impressive for just a single agent.

—Dr. Alice Shaw

"Patients who received crizotinib did significantly better," she said. Progression-free survival was more than twice as long in patients treated with crizotinib compared with those who received chemotherapy—docetaxel (Taxotere) or pemetrexed (Alimta)—7.7 months versus 3 months.

Nearly 350 patients were enrolled in the trial, which involved 105 centers in 21 countries and was funded by the drug's manufacturer, Pfizer. Patients in the trial had advanced NSCLC that had returned after their initial treatment and their tumors had the ALK gene rearrangement. A number of studies have shown that tumors in about 4 to 5 percent of patients with NSCLC have the mutation.

The results may be enough to support a change in the drug's regulatory status. The FDA's earlier approval was an accelerated approval, meaning the drug was likely to benefit patients and address an unmet clinical need. 

With such approvals, however, the agency requires data from larger trials to confirm that the drug has a clinical benefit and to ensure that unanticipated side effects do not outweigh any clinical improvements. Pfizer has notified the FDA of the trial results, the company said, and will provide the agency with the complete data when available.

Questions about Overall Survival

The ultimate goal of treatment, of course, is to lengthen overall survival. At this point, the trial has not shown that treatment with crizotinib does that any better than standard chemotherapy. And in large part because of the trial's design, there's a good chance that it won't be able to show an improvement, according to several researchers.

Patients in the trial who were randomly assigned to receive either docetaxel or pemetrexed and whose disease began to progress were allowed to cross over to treatment with crizotinib. The crossover rate, Dr. Shaw noted, was 87 percent.

It's still early in the trial, so nothing definitive about overall survival can be said yet. But with that extent of crossover, "really, the chemo arm is just like the crizotinib arm," Dr. Shaw added.

Dr. Alice Shaw speaking at the European Society of Medical Oncology 2012 CongressDr. Alice Shaw presents results from the first large clinical trial to test crizotinib in patients with advanced lung cancer.

The failure to show an overall survival benefit should not dampen enthusiasm for crizotinib with these patients, stressed Dr. Ramaswamy Govindan of Siteman Cancer Center in St. Louis. It's "entirely possible" that overall survival is improved with crizotinib, Dr. Govindan continued, but the crossover may make it impossible to see in this trial. "Unfortunately, that's just the way things are," he said.

No new concerns about the drug's safety were raised in the trial. Consistent with earlier trials of crizotinib, visual disturbances—often described as floating streams of light in patients' peripheral vision—were the most common side effect, along with diarrhea and nausea. But more patients who received chemotherapy stopped treatment due to side effects.

"At every level, crizotinib was superior to chemotherapy," Dr. Shaw said, including improvements in symptoms, delay in the onset of new symptoms, and general quality of life.

"From an oncologists' standpoint, it's really gratifying to see patients reporting a better quality of life in what is essentially an incurable disease," she said.

Overcoming Resistance

Historically, even following dramatic tumor reductions with crizotinib treatment—including complete tumor eradication—the disease almost always returns.

The situation closely parallels what has been seen in patients with advanced NSCLC whose tumors have mutations in the EGFR gene. Many of these patients initially have excellent responses to gefitinib (Iressa) or erlotinib (Tarceva), but the tumors almost always come back, explained Dr. Giuseppe Giaccone of NCI's Center for Cancer Research.

One potential escape route for tumors may be the development of additional mutations in the ALK gene that interfere with crizotinib's ability to bind to its target. "But that doesn't seem to be the major mechanism," Dr. Giaccone said. Alterations in other key genes that can fuel cancer cell proliferation, including EGFR and MET, also appear to allow tumors to resume growing, he added.

Ways to potentially overcome this resistance are already being studied in human trials.

Data from early stage trials of second-generation ALK-targeted drugs, for example, were also presented at the ESMO meeting. In a small phase I trial testing the experimental drug LDK378, tumor responses were seen in 81 percent of NSCLC patients whose tumors had the ALK mutation and whose disease had returned after crizotinib treatment.

Crizotinib's rapid ascent from the lab to the clinic is 'a great model for modern drug development.'

—Dr. Ramaswamy Govindan

Other approaches include targeting ALK and EGFR, either with a single drug that inhibits both targets or combinations of drugs. For example, Dr. Giaccone and his CCR colleagues are part of a phase I trial testing the combination of crizotinib and the experimental agent dacomitinib in patients with advanced lung cancer, including patients with EGFR and ALK mutations. Dacomitinib inhibits EGFR and other members of the same growth factor family. Early findings from the phase I trial were presented at ESMO.

Combining targeted drugs and further subdividing patients into molecularly defined subgroups will only increase from this point on, Dr. Giaccone stressed.

Dr. Govindan called crizotinib's rapid ascent from the lab to the clinic "a great model for modern drug development." It demonstrates that "patient selection is critical," he said.

NCI cooperative group trials are already being planned to test crizotinib as the first-line therapy in patients with metastatic NSCLC with ALK mutations, he said. Pfizer has also initiated a phase III trial, PROFILE 1014, testing crizotinib as a first-line treatment in patients with ALK rearrangements.

Carmen Phillips

Beyond ALK and EGFR

Patients with a different gene rearrangement may also benefit from crizotinib, according to another early-phase study presented at the ESMO meeting. In the trial, patients with advanced NSCLC whose tumors had rearrangements in the ROS1 gene, which occur in less than 2 percent of patients, also had substantial tumor responses.

Crizotinib "has remarkable activity [in these patients], nearly identical to what's been seen in patients with ALK rearrangements," explained Dr. Shaw, who was also an investigator on the trial.

Another gene, KRAS, is among the most frequently mutated genes in patients with the most common type of NSCLC, adenocarcinoma, and some studies suggest that KRAS mutations are associated with a poor prognosis. Results from the phase II GALAXY trial, also presented at the ESMO meeting, suggested that the drug ganetespib may have greater efficacy than standard chemotherapy in patients with adenocarcinoma and in patients with KRAS mutations whose disease has returned following initial treatment.

Ganetespib targets heat-shock protein (HSP) 90, a "chaperone" protein that helps other proteins carry out their functions. The drug is a second-generation HSP90 inhibitor that does not appear to have the toxicity issues of the first-generation HSP90 inhibitors, said the trial's lead investigator, Dr. Suresh Ramalingam of the Winship Cancer Institute in Atlanta.

Further follow-up is needed before investigators can confirm a benefit, Dr. Ramalingam cautioned. Earlier this year, results from a clinical trial of another targeted therapy, selumetinib, also suggested it may improve survival in NSCLC patients with KRAS mutations.

Both trials offer some much-needed hope. "This is the biggest molecular subset of lung cancer patients," Dr. Ramalingam said. "They're in serious need of good treatment options."

Cancer Research Highlights

Drug Combination More Effective than Single Drug for Advanced Melanoma

The combination of two targeted drugs—dabrafenib and trametinib—may delay the progression of advanced melanoma longer than dabrafenib alone, a new study suggests. These results, presented September 29 at the 2012 European Society for Medical Oncology Congress (ESMO) and published concurrently in the New England Journal of Medicine, add to a growing body of evidence that combinations of targeted drugs for melanoma are more effective and less toxic than a single targeted drug.

Dabrafenib and trametinib target different parts of a cell signaling pathway altered in melanoma by a mutation called BRAF V600. Single drugs that block BRAF activity shrink melanoma, but the tumors inevitably develop resistance. Researchers hoped that adding a second drug with a different target would slow the development of resistance and disease progression.

In the first part of the randomized phase II trial, which enrolled 85 patients, the researchers determined the combination’s safety and the doses to be used in the trial. The researchers then randomly assigned 162 patients to one of three treatment groups: dabrafenib alone, dabrafenib plus a low dose of trametinib, or dabrafenib plus a higher dose of trametinib. Patients whose disease progressed with dabrafenib alone were allowed to add the higher dose of trametinib to their treatment.

Patients receiving the higher dose of trametinib plus dabrafenib had a median progression-free survival of 9.4 months compared with 5.8 months for patients receiving dabrafenib alone. After 1 year of follow-up, 41 percent of patients receiving the higher-dose of trametinib plus dabrafenib had no disease progression, compared with 9 percent of those who received dabrafenib alone.

Overall, 79 percent of patients in the higher-dose combination group were alive after 1 year, explained Dr. Georgina Long of the Melanoma Institute Australia, one of the study’s authors, at an ESMO press conference. “We have never, ever seen a 12-month survival of that level in metastatic melanoma to date,” she said.

Side effects differed among the treatment groups, and patients in all arms of the trial frequently required temporary or permanent dose reductions. More patients receiving dabrafenib alone (19 percent) developed a secondary squamous-cell skin cancer than patients receiving the higher-dose combination (7 percent), though this difference was not statistically significant. Most patients in the higher-dose combination group (71 percent) experienced a fever compared with a minority of those receiving dabrafenib alone (26 percent).

The trial was funded by GlaxoSmithKline, the drugs’ manufacturer. Two company-sponsored phase III trials of the drug combination are currently under way (here and here).

Further reading:

Health Care Costs a Major Barrier for Young Adult Cancer Survivors

Many young adult cancer survivors do not seek routine medical care because of cost concerns, according to a new study. Even after accounting for health insurance status, survivors of adolescent and young adult (AYA) cancers were much more likely to forgo care in the prior year because of cost concerns, researchers reported September 24 in Cancer.

The results point to potentially serious consequences for AYA cancer survivors, the authors explained. “Medical care in the years following cancer therapy is particularly important to screen survivors for late effects, such as secondary cancers, infertility, and cardiac conditions,” they wrote.

Although the greater availability of health insurance for young adults as a result of the Affordable Care Act will help, they continued, the study indicates “that improvements in post-treatment health care access must be prioritized for this population.”

The study focused on long-term survivors diagnosed and treated between the ages of 15 and 34.

To conduct the study, the researchers used 2009 data from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System, a nationwide, state-based system of health surveys conducted each month by telephone. The study included responses from 979 AYA cancer survivors between the ages of 20 and 39 who were at least 5 years past their cancer diagnosis (case subjects) and approximately 67,000 people in the same age range who did not have a history of cancer (control subjects).

Overall, 34 percent of survivors reported forgoing routine care because of cost, compared with 20 percent of control subjects. The groups most affected by cost concerns were survivors between the ages of 20 and 29 and female survivors, Dr. Anne Kirchhoff of the Huntsman Cancer Institute in Utah and her colleagues reported.

AYA survivors also reported being in poor or fair health more often (27 percent versus 9 percent for control subjects) and experiencing frequent mental or physical distress. Forty percent of survivors had not had a routine medical visit in the past year, and 22 percent did not have a personal medical care provider.

Further reading: 

Many Women whose Tumors Disappear after Chemotherapy Have Mastectomies

Many women with breast cancer whose tumors disappear after presurgical chemotherapy have a mastectomy instead of breast-conserving surgery, according to a re-analysis of data from the NeoALTTO trial. The results were presented September 30 at the 2012 European Society for Medical Oncology Congress (ESMO).

In the phase III trial, investigators randomly assigned women with HER2-positive breast cancer to receive trastuzumab, lapatinib, or both drugs for a total of 18 weeks prior to surgery. (Both drugs target the HER2 receptor.) After the first 6 weeks, paclitaxel chemotherapy was added to the anti-HER2 treatments.

In 160 of 429 women, the tumors disappeared (a pathologic complete response). But whether a woman had a pathologic complete response did not influence the type of surgery she had later. Although women receiving all three drugs were up to twice as likely to have their tumors disappear as women who received only a single anti-HER2 drug plus paclitaxel, they were no more likely to have breast-conserving surgery than a mastectomy.

Instead, the ultimate choice of surgery type was more strongly influenced by the characteristics of the tumor before chemotherapy, including the initial tumor size and whether the tumor expressed the estrogen receptor, as well as the type of surgery originally planned and whether the cancer was multifocal or multicentric.

One of the main goals of presurgical (neoadjuvant) chemotherapy is to “downstage” larger tumors to allow less-aggressive surgery. Therefore, “there is a need for a clear consensus on the role of breast-conserving surgery, especially in patients who respond to neoadjuvant therapy,” said lead investigator Dr. Carmen Criscitiello, of the European Institute of Oncology in Milan, Italy, at an ESMO press conference.

“This will ultimately translate…into improved breast-conservation rates, [and] could spare more women from receiving radical treatment like mastectomy,” she concluded.

Guest Commentary by HHS Secretary Kathleen Sebelius

Statement on Breast Cancer Awareness Month

The Honorable Kathleen Sebelius is the 21st secretary of the Department of Health and Human Services, which includes NCI. Secretary Sebelius released the following statement to mark Breast Cancer Awareness Month.

Secretary Kathleen SebeliusSecretary Kathleen Sebelius

In October, during National Breast Cancer Awareness Month, we remember those who have lost their lives to breast cancer, and those who are battling it now, by recommitting ourselves to their fight and spreading the word of the importance of prevention and early detection.

Despite significant advances in treatment and prevention, breast cancer remains the second leading cause of cancer death for women in the United States. However, because of the Affordable Care Act, it's a new day for women's health and the fight against breast cancer.

President Proclaims October National Breast Cancer Awareness Month

The White House has issued a Presidential Proclamation designating October National Breast Cancer Awareness Month. As the federal government's leading funding institution for cancer research, NCI supports a wide range of research to improve breast cancer prevention, detection, and treatment. NCI also funds research on follow-up care for the growing number of breast cancer survivors.

We know that the chance of successful treatment is highest when breast cancer is detected early. While not a perfect tool, mammogram screenings are key to early detection. Yet, only about 75 percent of women aged 40 or older have had a mammogram in the last 2 years. If we could boost that number to 90 percent, thousands more lives could be saved. But budgets are tight, and even moderate copays can deter many women from getting those important screenings.

Because of the Affordable Care Act—the health care law signed by President Obama 2 years ago—many private health plans and Medicare now cover mammograms and certain other preventive services with no copays or other out-of-pocket costs. This means that women can get the potentially life-saving services they need to detect breast cancer before it spreads, without worrying how a copay would affect their family budget. Last year, more than 6 million women with Medicare got a free mammogram.

Under the health care law, other services to help prevent breast cancer are also covered, such as a well-woman visit—at no additional cost—so women have the opportunity to talk to their doctor about their health care needs, their personal risk for breast cancer, and their best options to reduce their risk. The Affordable Care Act gives women, not insurance companies or the government, control over their health care.

Women also have new rights and protections under the law against insurance company abuse. If diagnosed with breast cancer or another illness, women cannot have their coverage taken away when they need it the most simply because of a mistake made on paperwork. And beginning in 2014, it will be illegal for insurers to discriminate against anyone with a pre-existing condition, such as breast cancer.

The health reform law is also helping women who are going through costly breast cancer treatment by preventing insurance companies from imposing lifetime dollar caps on coverage. This means that women fighting breast cancer can focus on their health, their families, and living their lives, and not worrying that their insurance will run out while they still need treatment.  

We have made substantial progress in reducing the burden and toll of breast cancer on American women and their families. Initiatives under the Affordable Care Act, along with ongoing research, are making real differences in the lives of American women and their families.

Kathleen Sebelius
Secretary 
U.S. Department of Health and Human Services

Multimedia

NIH Research Radio: Building a Biobank

A technician dissects and preserves a tissue sample using the GTEx PAXgene tissue preservation system. (Image from the National Disease Research Interchange GTEx Team)

In the first segment of a series being featured on NIH Research Radio, NCI Cancer Bulletin writer Edward R. Winstead talks about his recent story on the Genotype-Tissue Expression project.

Click to Listen

Type: (MP3) | Time: 5:39 | Size: 3.23 MB | Read Transcript

Special Report

Turning Genes Up, Not On: A New View of the Myc Protein

Francis Barraud's painting of a dog looking into a phonograph Acting as an amplifier, the Myc protein may increase the expression of all active genes in a cell.

One of the best studied proteins in cancer research is also one of the most mysterious.

Myc helps control genes involved in cell growth and is associated with many cancers. But, after thousands of studies, researchers still do not know important details about how Myc operates in normal cells and in cancer cells.

Two new studies, however, cast this large body of work in a new light, providing some answers and raising new questions. Myc, the studies found, apparently boosts the expression of nearly all active genes in a cell, rather than activating specific genes.

"Whatever a cell is doing, it will do that more intensely under the influence of Myc," said Dr. David Levens of NCI's Center for Cancer Research, who co-led one study with Dr. Keji Zhao of the National Heart, Lung, and Blood Institute. Both studies appeared in Cell last week.

A New Perspective

Dr. Levens and his colleagues tracked the activity of Myc in white blood cells using molecular "tags." This approach revealed that Myc does not preferentially interact with any specific gene; instead, the protein is present at nearly every gene that is already expressed.

Using different methods and types of cells, Dr. Richard Young of the Whitehead Institute for Biomedical Research and his colleagues reached a similar conclusion in a second study. "We came to realize that the primary role of Myc is to go to all the genes that are active in a cell and act like a rheostat, turning up their expression," said Dr. Young.  

These are very well done studies, noted Dr. Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania and a Myc researcher who was not involved in the work. "They provide an additional view of how a relatively powerful cancer gene works when it is deregulated."

We came to realize that the primary role of Myc is to go to all the genes that are active in a cell and act like a rheostat, turning up their expression.

—Dr. Richard Young

But the model, he added, does not account for some well-documented observations about Myc.

"We know, for instance, that Myc inhibits the differentiation of cells," Dr. Dang said. "So that means that instead of only amplifying the expression of active genes, the protein has to inhibit something in cells. These studies acknowledge that not all active genes are turned up; in fact, up to one-third are repressed."

Another important question, Dr. Dang noted, is how high levels of Myc might contribute to cancer. "If you crank up Myc to very high levels and it still behaves as an amplifier, does that cause the expression of genes to occur in an imbalanced way and alter  [RNA in a way] that could lead to cancer?" he asked.

These and similar questions could keep researchers busy for a long time, noted the authors of an accompanying editorial. These "seminal" studies provide a first "glimpse of a coherent and holistic view of Myc," wrote Dr. Gerard Evan and two colleagues at the University of Cambridge in the United Kingdom in the editorial.

This view of Myc suggests there will never be a single transcriptional signature—a set of genes consistently activated by the protein. This is because the activity of Myc depends entirely on the type of cell and which state the cell is in when Myc is activated, according to the new model.

Implications for the Future

If the new results are confirmed, they could have implications for cancer researchers. Drug developers might want to disrupt the cellular machinery involved in the amplification effect of Myc rather than focusing on specific genes, noted Dr. Young.

"If Myc is amplifying all of the active genes in a cell, the idea of targeting just some of those genes appears unlikely to succeed," he said. "Going after Myc may be more fruitful." He predicted that the new results could "reinvigorate efforts to drug Myc itself," though Myc, like other transcription factors, has proven to be an elusive target.

Researchers have been looking for a pathway through which Myc operates for many years. "Our results suggest that Myc will cooperate with any oncogenic process," said Dr. Levens.

Before launching this study, Dr. Levens wondered whether he could add anything new to the large scientific literature on Myc. He now sees the new model as bringing together and explaining many puzzling and often contradictory observations about the biology of Myc.

"Our study is more integrative than it is novel," he said. "It's hard to say something really new about this protein."

Edward R. Winstead

Spotlight

With CellMiner, Researchers Prospect for Cancer Discoveries

Cell plate with small wells holding pink liquidCellMiner can easily compare patterns of gene expression, microRNA expression, and drug activity in the NCI-60, a panel of 60 human cancer cell lines.

Researchers have updated a web-based application that makes a wealth of genomic and pharmacologic data obtained from a panel of human cancer cell lines available to anyone with access to a computer and the Internet.

Known as CellMiner, the publicly available application lets researchers rapidly retrieve data on the expression of more than 22,000 genes and 360 microRNAs, and the growth-inhibiting activity of more than 26,000 compounds in NCI's Human Tumor Cell Line Screen, also known as the NCI-60 panel of cell lines. The compounds include 102 FDA-approved drugs, as well as others being studied in clinical trials.

Tapping into a Wealth of Information

The NCI-60 consists of 60 human cancer cell lines (laboratory-grown cells) derived from nine different tissues. These cell lines were acquired by NCI's Developmental Therapeutics Program (DTP) to screen compounds for anticancer activity. In addition to testing about 100,000 compounds on these cells, NCI researchers have amassed an extensive database of genomic information for these widely used cell lines.

Working with such large data sets often means dealing with unwieldy databases that make it difficult to analyze and integrate data. But with CellMiner, researchers can easily compare patterns of gene expression, microRNA expression, and drug activity in the NCI-60. By means of a novel pattern-matching tool, users can also explore relationships between these parameters and any pattern of interest they choose to input (for example, cell lines that lack mutations in the commonly mutated tumor suppressor gene TP53), enabling them to define their own questions.

A Case Study of CellMiner-Aided Discovery

A study led by Dr. Gabriele Zoppoli of NCI's Laboratory of Molecular Pharmacology and published September 11 in the Proceedings of the National Academy of Sciences, exemplifies the discoveries that can be made with CellMiner.

The researchers used the tool to search for genes whose expression correlates with the cell-killing activity of anticancer drugs called topoisomerase inhibitors in the NCI-60.

"At the very top of the list there was one gene, which we knew nothing about, called Schlafen-11 (SLFN11)," Dr. Pommier said.

Pursuing this lead, the researchers found that SLFN11 expression is causally associated with the activity of a broad and widely used group of chemotherapy drugs known as DNA-damaging agents (DDAs). In a series of experiments they showed that the gene sensitizes cancer cells to DDAs, has a wide expression range in colon and ovarian cancer samples from The Cancer Genome Atlas, and may act as a biomarker for predicting the response to DDAs in patients.

"No one had heard of this gene before or knew anything about it" until it turned up in the CellMiner results, noted Reinhold, who was a co-author on the study. "It shows how you can discover things [with CellMiner] that you could never have anticipated."

Such pattern comparisons can, for example, reveal new connections between drug activity and gene expression, pick out compounds or drugs that work through similar—or complementary—mechanisms, or identify genes that may predict the response of cancer cells to specific drugs, noted Dr. Yves Pommier, chief of the Laboratory of Molecular Pharmacology (LMP) in NCI's Center for Cancer Research (CCR).

No Bioinformatics Expertise Needed

"Our goal is to have this database used by people who do not have bioinformatics expertise, including M.D.s and anyone else who wants to explore the database without having a bioinformatics team next to them," said Dr. Pommier, who co-authored a recent report in Cancer Research that detailed CellMiner's features and provided case examples of its use. The lead author and lead developer of CellMiner, William Reinhold, is a molecular biologist in LMP.

Reinhold, Dr. Pommier, and their colleagues developed CellMiner so that researchers could avoid the time-consuming data processing previously required to work with information in the NCI-60 database. The suite of web-based tools provides "a quick and easy way for people to start doing systems biology and pharmacology—which is to say, comparing big data sets of disparate types to ask scientific questions," explained Reinhold.

"Without specialized expertise, there's been a huge wall between people who want to ask these questions and the people who have access to the information," he continued. "We're trying to take that wall down."

Users of CellMiner simply input their query online and, within minutes, receive an e-mail containing the results in the form of tables and bar graphs in a single Excel spreadsheet. The application calculates the correlation between all parameters and identifies statistically significant correlations.

And, because data are provided in a spreadsheet, Dr. Pommier noted, users can archive the results and continue working on them, even without Internet access. Researchers "can use Excel tools to search and organize the data, which makes it very versatile," he added.

One-Stop Shopping

"CellMiner is a powerful tool that allows you to generate hypotheses about the ways in which different genes or patterns of gene expression can affect cell behavior [in cancer],"  said Dr. Michael Gottesman, chief of CCR's Laboratory of Cell Biology. His lab, which was not involved in developing CellMiner, is using the tool to study gene expression patterns that correlate with resistance to specific anticancer drugs.

Investigators in Dr. Susan Bates's lab, in CCR's Molecular Oncology Branch, were among the first to use CellMiner's predecessor—a computer program called COMPARE—to probe the NCI drug-screen database. Using COMPARE, they identified a drug with anticancer activity called romidepsin, which turned out to be effective against T-cell lymphoma.

Because only one-third of patients with T-cell lymphoma responded to romidepsin in clinical trials, Dr. Bates's team is using CellMiner to help find a biomarker that predicts which patients will respond favorably to the drug.

"The CellMiner program builds on COMPARE by providing a much easier-to-use interface," Dr. Bates said. "People in my laboratory…have found it very easy to adapt to CellMiner."

Working with CellMiner "is one-stop shopping, whereas, before, working with the drug screen data required multiple queries," confirmed Dr. Robert Robey, a chemist in Dr. Bates's lab who works with the tool. "I read the paper and within a few minutes I was pulling up drug profiles. The interface makes it easy to put in your own data and pull meaningful things out of it."

"Users of CellMiner need to realize that the COMPARE program on the DTP website still represents the gold standard for determining correlations using drug profiles," Dr. Bates noted. "CellMiner provides an easy-to-use format. But there are limitations in terms of the results it is able to generate. There is a larger body of data available on the DTP website, both for compounds and for molecular characterization data."

CellMiner's Prospects

CellMiner's developers plan to continue updating and enhancing the software. The next version will provide access to the whole-genome sequences for all protein-coding regions, or exons, of the genome across the NCI-60, Dr. Pommier indicated. The team is also making the open-source software available for others to use or modify as they wish to incorporate molecular profile data on other cell lines or human tumor samples.

Without specialized expertise, there's been a huge wall between people who want to ask these questions and the people who have access to the information. We're trying to take that wall down.

—William Reinhold

Cell lines from the NCI-60 panel, which are studied by cancer researchers worldwide, "have formed the basis for a lot of what scientists know about the physiology of cancer," Dr. Gottesman noted. But, as reported last November, research led by Dr. Jean-Pierre Gillet in Dr. Gottesman's lab has suggested that these and other cancer cell lines may have important limitations when used to identify genes associated with resistance to chemotherapy drugs in particular tumor types. The study showed that, in various cancer types, the expression of a specific set of genes associated with drug resistance was very different in cell lines from what it was in tumor samples representing the same cancer types.

The fact that some gene expression patterns in laboratory-grown cells such as the NCI-60 differ from those in the original tumor tissue is not surprising, researchers agree. However, Dr. Pommier said, "there is a vast array of genes in the NCI-60 that retain their expression pattern between the cell line and the tumor—that's what is coming out of the CellMiner analyses, because now it's easy to look at those genes."

Although researchers continue to debate the extent to which cancer cell lines represent the tumors from which they originated, "there's a lot we can still learn from the NCI-60," Dr. Gottesman said, "and having a tool that allows you to gain access to the huge amount of data that's been accumulated is a very useful thing."

Elia Ben-Ari

The CellMiner project was supported by NCI's Intramural Research Program.

A Closer Look

New Tools Enhance Molecular Portraits of Breast Cancers

Breast cancer cells with nuclei stained blue and the HER2 protein in red.The HER 2 protein (red) can trigger cell growth responses in breast cancer cells (nuclei stained blue).

Using a combination of analytical tools, investigators with The Cancer Genome Atlas (TCGA) Research Network have completed a molecular study of breast tumors from 825 women. The results, recently reported in Nature, confirm the existence of four major subtypes of breast cancer and add new details about the biological changes underlying these diseases.

The researchers used up to six different technologies to characterize subsets of the tumors. In addition to sequencing DNA and RNA, the investigators profiled patterns of DNA methylation and counted the number of copies of genes in tumors. This was also the first TCGA study to report protein expression patterns in tumor samples.

The integration of these results has given researchers a catalog of the genetic and epigenetic abnormalities in each subtype of breast cancer, underscoring the idea that these tumors are, in many respects, distinct diseases.

"This paper and five others [describing breast cancer genomes] published this year in Nature provide a new roadmap for translational and basic research on breast cancer," said co-lead investigator Dr. Matthew Ellis of the Washington University School of Medicine in St. Louis. Researchers could spend a decade following up on these results, he added. (See the sidebar for links to the study abstracts.)

Previous studies had hinted that one of the subtypes, basal-like breast cancer, was genetically similar to a form of ovarian cancer. The TCGA study confirmed this idea and suggested that treatments currently being tested for some ovarian cancers could be tested against these breast cancers.

"This finding really stood out," said Dr. Ellis. "And it led to discussions [among the study authors] about the most appropriate types of chemotherapy for patients with breast cancer." The other subtypes are known as luminal A, luminal B, and HER2-enriched breast cancers.

Making Use of Multiple Technologies

Speaking at a press briefing on cancer research last week, NCI Director Dr. Harold Varmus acknowledged that the four breast cancer subtypes have been known for years. What's new, he explained, is that, for each subtype, TCGA investigators used multiple technologies to describe the "landscape of genetic abnormalities" in greater detail than in the past.

"We haven't had a storehouse of so much valuable information about each of these categories of cancer, with the same tumors analyzed for a wide variety of properties," he said. "It's the repository that is so important."

Because the study included hundreds of tumors, the researchers were able to detect uncommon but recurring mutations. Some of these mutations indicated that the tumors might respond to existing drugs. "Repurposing drugs will be important for treating this disease," said Dr. Ellis.

Even if a particular mutation occurs in only 2 percent of patients, Dr. Ellis continued, breast cancer is common enough that researchers should be able to enroll enough women in clinical trials to test existing drugs that target these mutations.

About 20 percent of the patients with basal-like tumors might be candidates for drugs known as PARP inhibitors based on analyses of the genes BRCA1 and BRCA2 in their tumors, the researchers said. The group of basal-like tumors includes triple-negative breast cancers, which are difficult to treat and disproportionately affect younger women and African Americans.

The Translation Phase

Only three genes—TP53, PIK3CA, and GATA3—were mutated in more than 10 percent of the patients' tumors. Drugs that target changes resulting from defects in PIK3CA are in development and could be tested in selected patients with breast cancer. However, designing and implementing large clinical trials can take years, the researchers cautioned.

"People always want to know when this kind of research is going to affect clinical care," said Dr. Charles Perou of the Lineberger Comprehensive Cancer Center at the University of North Carolina, another study leader. "Now that we've made these discoveries, we're in the translation phase."

Many of the new discoveries can now be tested in the context of clinical trials. For instance, the study suggested there may be at least two groups of patients with HER2-positive tumors, and these groups may have different responses to treatment.

"We had a hint of this from past gene-expression studies," said Dr. Perou. But the integrated results of the TCGA analysis, which included proteomics, are "far more convincing and suggestive than results based on any one technology alone."

Dr. Perou co-authored one of the first studies to use genomics to distinguish subtypes of cancer. The study, published in 2000, used what was then a new tool—DNA microarrays—to profile the expression of 8,000 genes in breast tumors from 42 women.

More than a decade later, the technological advances in genomics have been "astonishing," noted Dr. Ellis. The missing component right now is information about proteins and the biochemistry of cancer cells, he observed.

"Over the next 10 years, we need to study proteins in the same way that we have just studied DNA and RNA over the last decade," said Dr. Ellis. Only then, he added, "will we develop a complete picture of the biochemistry of cancer cells."

Edward R. Winstead

Featured Clinical Trial

Comparing Radiation Therapy Regimens for Early-Stage Breast Cancer

Name of the Trial
Phase III Randomized Study of Accelerated Hypofractionated Whole-Breast Irradiation and Concurrent Boost versus Standard Whole-Breast Irradiation and Sequential Boost in Patients with Early-Stage Breast Cancer after Lumpectomy (RTOG-1005). See the protocol summary.

Dr. Frank Vicini Dr. Frank Vicini

Principal Investigator
Dr. Frank Vicini, Radiation Therapy Oncology Group

Why This Trial Is Important
Women treated with a lumpectomy for early-stage breast cancer often receive postsurgical, or adjuvant, radiation therapy to the breast that contained the cancer. Adjuvant whole-breast irradiation (WBI) has been proven to help prevent the recurrence of breast cancer and to reduce the likelihood of death from the disease. Although adjuvant WBI is considered a standard of care, many women in the United States who undergo lumpectomy for early-stage breast cancer do not receive radiation therapy following surgery.

One of the reasons women may forgo adjuvant WBI after breast cancer surgery is the length of time required to complete a standard course of radiation therapy. Typically, a woman would undergo radiation treatment to the whole breast 5 days a week for 5 weeks, followed by radiation focused on the area from which the tumor was removed (known as a sequential boost) for another 7 to 8 days. (The total duration of treatment is 6.5 weeks because radiation therapy is not given on weekends.)

For many women, the time, expense, and logistics of this extended treatment period may be unmanageable. Shortening the duration of post-surgical radiation therapy may allow more women to undergo this vital treatment.

"We want to see if we can deliver the entire course of radiation—meaning the whole breast irradiation and the boost—in 3 weeks using the more advanced radiation therapy technology now available," said Dr. Vicini.

A number of clinical trials have investigated the use of accelerated WBI using a method called hypofractionation, in which larger individual doses of radiation are given over a 3-week period. These trials have largely confirmed that hypofractionated WBI confers the same benefits as standard WBI. However, the patients in these studies were carefully selected to minimize factors that may affect the outcomes of treatment. Therefore, these patients may not represent the average woman with breast cancer.

This clinical trial is intended to determine whether a 3-week course of accelerated, hypofractionated WBI therapy is as safe and effective, both clinically and cosmetically, as a standard 6.5-week course of post-surgical radiation therapy. In this study, women with early-stage breast cancer will be randomly assigned to a standard 5-week course of WBI with a 7- to 8-day sequential boost course or 3 weeks of hypofractionated WBI with the boost irradiation given daily during the same 3-week period (that is, a concurrent boost).  

"There's already data showing that 3 weeks of radiation is as effective as 5 weeks, but that's in a more select group of patients," Dr. Vicini explained. "If hypofractionation with a concurrent boost proves as effective and safe as the standard 6.5-week course of radiation in this study, we will have applied [the therapy] to a group of patients that is more representative of the majority of women we see in the clinic. So, this study really has the potential to change the standard of care for the average woman with breast cancer."

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

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

Legislative Update

President Signs 6-Month Spending Bill

Last month Congress passed a short-term measure to allow government spending to continue for the first half of fiscal year 2013. President Barack Obama signed the bill into law on September 28, before the start of the fiscal year on October 1. The measure, commonly referred to as a continuing resolution, allows federal agencies, including NCI, to continue operating at approximately fiscal year 2012 funding levels through March 2013.

For more information about congressional appropriations that affect NCI, please visit the Office of Budget and Finance’s website

Congressional Caucus Hosts Childhood Cancer Summit

Dr. Javed Khan speaks at the Childhood Cancer Summit. (Image courtesy of the Congressional Childhood Cancer Caucus)NCI's Dr. Javed Khan speaks at the Childhood Cancer Summit. (Image courtesy of the Congressional Childhood Cancer Caucus)

The Congressional Childhood Cancer Caucus held its third annual summit on September 20. For the first time, invited representatives from NCI and the Food and Drug Administration (FDA) spoke about federal efforts to support childhood cancer research. The event, which takes place each September in observance of Childhood Cancer Awareness Month, was hosted by Representatives Michael McCaul (R-TX) and Chris Van Hollen (D-MD), co-chairs of the caucus.

Both Van Hollen and McCaul emphasized the caucus' bipartisan support for childhood cancer research and cited recent laws enacted to advance pediatric medical research and encourage drug development for pediatric cancers in particular. These laws—the Best Pharmaceuticals for Children Act (BPCA), the Pediatric Research Equity Act (PREA), and the Creating Hope Act—were part of the FDA Safety and Innovation Act, a bill to reauthorize funding of the FDA, which President Obama signed into law in July.

Dr. Javed Khan, a senior investigator from NCI's Pediatric Oncology Branch (POB), spoke with members of Congress and their staff members, as well as cancer survivors and others from the childhood cancer advocacy community, about the challenges and opportunities in the pediatric oncology field.

Dr. Khan described his cancer genomics research, including his work with NCI's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, an effort to identify and validate therapeutic targets for several childhood cancers. He leads a research team in analyzing the genomes of pediatric solid tumors to identify molecular targets for neuroblastoma and rhabdomyosarcoma.

He also shared examples of other research under way at NCI, efforts by the NCI-supported Children's Oncology Group (COG), and partnerships between the intramural and extramural research communities and industry.

Research on other cancers can lead to progress in pediatric cancer research, Dr. Khan stressed. He offered a number of examples, including a recent COG trial of the drug crizotinib (Xalkori), originally developed to treat non-small cell lung cancer with genetic alterations in the ALK gene. NCI-supported researchers recently reported promising results from a phase I clinical trial of crizotinib to treat children with neuroblastoma, anaplastic large cell lymphoma, and a rare type of sarcoma, called inflammatory myofibroblastic tumor. All three diseases have been associated with abnormalities in the ALK gene.

Dr. Khan was joined by Dr. Gregory Reaman, associate director for Oncology Sciences at the FDA, a pediatric oncologist and former chair of COG. Dr. Reaman discussed the FDA's implementation of BPCA, PREA, and the Creating Hope Act. He mentioned that the FDA will host a public meeting focused on stakeholder engagement and that the agency hopes to schedule a second day to address pediatric oncology.

Other speakers at the summit included Brianna Commerford, a high school student from New Jersey and a 6-year survivor of stage IV Hodgkin lymphoma. Commerford worked closely with members of the caucus and the childhood cancer advocacy community to build support for the Creating Hope Act.

Dr. Khan's participation in the summit followed a visit by congressional staff to NCI in early September. Staff from several congressional offices, including those of McCaul, Van Hollen, and Senators Jack Reed (D-RI) and Pat Roberts (R-KS), met with Dr. Crystal Mackall, chief of the POB; Dr. Alan Wayne, head of the POB Hematologic Diseases Section; and Dr. Malcolm Smith, associate branch chief for Pediatric Oncology in NCI's Division of Cancer Treatment and Diagnosis.

For more information about NCI's legislative activities, visit the NCI Office of Government and Congressional Relations website.

Further reading: "Genome Study Points to Treatments for High-Risk Form of Childhood Leukemia"

Holly Aprea Gibbons

FDA Update

FDA Approves Ultrasound Imaging System for Dense Breast Tissue

The Food and Drug Administration (FDA) recently approved the first ultrasound device for use with standard mammography in women with dense breast tissue: the somo-v Automated Breast Ultrasound System (ABUS).

The somo-v ABUS will be available for women who have no symptoms of breast cancer, have had a mammogram that did not detect cancer, and have not had a procedure that could alter the breast's appearance in an ultrasound image, such as surgery or biopsy.

Dense breasts have a high amount of connective and glandular tissue compared with less-dense breasts, which have more fatty tissue. An estimated 40 percent of women undergoing screening mammography have dense breasts. These women have a higher risk of developing breast cancer, and, when cancer is detected, it is often at a more advanced stage and more difficult to treat than cancers found at a less advanced stage.

Mammograms of dense breasts can be difficult to interpret because connective and glandular tissue—as well as most tumors—appear as white areas on mammograms. As a result, dense breast tissue may obscure small tumors, potentially delaying the detection of breast cancer. 

The somo-v ABUS directs high-frequency sound waves at the breast, and multiple images of the entire breast are captured for review in about 1 minute. The system’s software generates three-dimensional images of breast tissue for evaluation.  

The FDA based its approval, in part, on a clinical study in which board-certified radiologists reviewed mammograms alone or with somo-v ABUS images for 200 women with dense breasts who had mammograms that appeared to be free of cancer. Biopsies were performed on masses detected with the somo-v ABUS to determine whether they were cancerous. The results showed a statistically significant increase in breast cancer detection when ABUS images were reviewed together with mammograms, compared to mammograms alone.

As part of the approval, the FDA is requiring the manufacturer to train physicians and technicians to use ABUS and to provide a manual that clearly defines quality-control measures.

New Treatment for Advanced Colorectal Cancer Approved

The Food and Drug Administration (FDA) has approved the drug regorafenib (Stivarga) to treat patients with colorectal cancer that has progressed after treatment and spread to other parts of the body. Regorafenib blocks several enzymes that promote cancer cell growth.

The safety and effectiveness of regorafenib were evaluated in a single clinical study of 760 patients with previously treated metastatic colorectal cancer. Patients treated with regorafenib plus best supportive care (BSC) lived a median of 6.4 months, whereas patients treated with placebo plus BSC lived a median of 5 months. In addition, patients treated with regorafenib experienced a delay in tumor growth (progression-free survival) for a median of 2 months compared with a median of 1.7 months in patients in the placebo group.

Regorafenib is being approved with a boxed warning alerting patients and health care professionals that severe and fatal liver toxicity occurred in some patients treated with the drug during clinical studies. The most common side effects include weakness or fatigue, loss of appetite, hand-foot syndrome, diarrhea, mouth sores, weight loss, infection, high blood pressure, and changes in voice volume or quality.

The drug was reviewed under the FDA’s priority review program, which provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists.

Notes

NCI Director Discusses "What Impedes Cancer Research"

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On September 25, NCI Director Dr. Harold Varmus spoke at the National Press Club about the barriers that hinder the nation's ability to make faster progress against cancer.

In a talk titled "What Impedes Cancer Research?" Dr. Varmus explained how the nearly $90 billion dollars that NCI has spent on research in the last 40 years has changed the understanding of cancer and its prevention, diagnosis, and treatment. But, while this effort has had many benefits—most importantly a decline in cancer death rates—cancer remains a leading cause of death in the United States and the world.

Dr. Varmus discussed the barriers to greater and faster progress against cancer, such as the complex biology of tumors and the difficulties of developing new ways to prevent, diagnose, and treat cancers.

What You Need to Know About Cancer Booklets Updated

What You Keed to Know booklet covers

Three booklets in NCI's What You Need to Know (WYNTK) series have been updated:

  • What You Need To Know About Breast Cancer (html, pdf)
  • What You Need To Know About Lung Cancer (html, pdf)
  • What You Need To Know About Prostate Cancer  (html, pdf)

Booklets in the WYNTK series are for people who have been recently diagnosed with cancer and want to learn about stages, treatment options, sources of support, and follow-up care. The booklets offer lists of questions about treatment options that people can take to their next medical appointment.

These three publications are available online in HTML, PDF, and eBook formats, and are also available in print.

The Boletín, NCI's Spanish-Language Newsletter, Turns Three

Boletín del Instituto Nacional del Cáncer screenshot

NCI's monthly Spanish-language newsletter, the Boletín del Instituto Nacional del Cáncer, celebrated its third anniversary last month. The Boletín, a free online publication that includes selected articles from the NCI Cancer Bulletin, features stories about the causes, prevention, diagnosis, and treatment of cancer.

Available on NCI's Spanish-language website, the Boletín publishes between 16 and 18 stories per issue and has more than 2,500 subscribers in the United States and abroad.

The Boletín staff welcomes your feedback. Please share your suggestions as well as topics you'd like to see discussed in future issues. You can also connect with us on Facebook, view informational videos on YouTube, and follow us on Twitter.