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July 12, 2011 • Volume 8 / Number 14

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BREAKING NEWS

AACI and NCI Issue Report on Clinical Trials Reporting Program

The Association of American Cancer Institutes (AACI), in collaboration with NCI, announced the release of the AACI-NCI Clinical Trials Reporting Program (CTRP) Strategic Subcommittee Report.  

The report is the culmination of a 1-year effort to review the overall purpose of CTRP, data reporting requirements, and the CTRP implementation timeline. More information about CTRP, trial registration, patient accrual and outcomes reporting requirements, and the full report can be viewed online.

An archived videocast of the CTRP Subcommittee presentation to the NCI Clinical Trials and Translational Research Advisory Committee will be available in a few days at http://videocast.nih.gov.

NEWS

U.S. Colorectal Cancer Death Rates Continue to Drop, But Not Equally

Colorectal cancer death rates by state, 2003– 2007 ((Adapted and reprinted by permission from the American Association for Cancer Research: D Naishadham et al., State Disparities in Colorectal Cancer Mortality Patterns in the United States, Cancer Epidemiol, Biomarkers & Prev, 2011, 20(7); 1296-302) Findings from two new studies show that death rates from colorectal cancer in the United States continue to fall, a trend that began more than two decades ago. The mortality decline has been geographically uneven, however, with far greater decreases in the Northeast than in many other areas, particularly in a number of southeastern states. Read more > >


COMMENTARY

Dr. Sanya A. Springfield

NCI Cancer Disparities Research: Sharing Ideas, Forging Partnerships

The director of NCI's Center to Reduce Cancer Health Disparities welcomes colleagues to this year's Cancer Health Disparities Program Meetings Read more > >

  

IN DEPTH

UPDATES

  • FDA Update

    • Advisory Panel Upholds Recommendation to Withdraw Bevacizumab Approval for Breast Cancer
  • CMS Update

    • Medicare Will Cover Provenge Treatment for Prostate Cancer
  • Legislative Update

    • State Cancer Legislative Database Update Now Available
  • Notes

    • Lou Staudt and Shiv Grewal Named NIH Distinguished Investigators
    • NCI Cancer Classroom Webinar Series Wraps Up July 26
    • Proposals Sought to Use Biospecimens from SELECT and PCPT 

A MESSAGE TO READERS

Special Issue on Adolescents and Young Adults with Cancer

Don't miss our July 26 special issue, which will highlight issues that affect adolescent and young adults with cancer, as well as resources and ongoing programs that address these individuals.

Past special issues have focused on bioinformatics, cancer research training, and clinical trials enrollment.

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 071211.

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

Featured Article

U.S. Colorectal Cancer Death Rates Continue to Drop, But Not Equally

Findings from two new studies show that death rates from colorectal cancer in the United States continue to fall, a trend that began more than two decades ago. The mortality decline has been geographically uneven, however, with far greater decreases in the Northeast than in many other areas, particularly in a number of southeastern states.

Colorectal cancer death rates by state, 1990– 1994 (Adapted and reprinted by permission from the American Association for Cancer Research: D Naishadham et al., State Disparities in Colorectal Cancer Mortality Patterns in the United States, Cancer Epidemiol, Biomarkers & Prev, 2011, 20(7); 1296-302)

Colorectal cancer death rates by state, 2003– 2007 ((Adapted and reprinted by permission from the American Association for Cancer Research: D Naishadham et al., State Disparities in Colorectal Cancer Mortality Patterns in the United States, Cancer Epidemiol, Biomarkers & Prev, 2011, 20(7); 1296-302) (Adapted and reprinted by permission from the American Association for Cancer Research: D Naishadham et al., State Disparities in Colorectal Cancer Mortality Patterns in the United States, Cancer Epidemiol, Biomarkers & Prev, 2011, 20(7); 1296-302)

Although the studies are ecologic in nature and can't directly demonstrate a cause-and-effect relationship, authors of both studies agreed that substantial improvements in colorectal cancer screening rates have been the chief contributor to the national downward trend in mortality. Other factors, such as reductions in smoking prevalence and better treatments, have also played a role, they noted.

Socioeconomic disparities that have been proven to influence cancer screening rates and the treatment of diagnosed cancers likely help explain the geographic discrepancies in cancer mortality rates, several researchers said.

"That's a key point," said Dr. Ahmedin Jemal of the American Cancer Society, who led one of the studies. "Poverty affects not only access to screening and treatment but also prevalence of known risk factors for colorectal cancer, including smoking and obesity."

Disparities Drive Geographical Differences

In the first study, published online July 5 in Morbidity and Mortality Weekly Report, researchers from the Centers for Disease Control and Prevention (CDC) showed that the age-adjusted colorectal cancer death rate fell by 3 percent per year from 2003 through 2007, from 19 per 100,000 people to 16.7 per 100,000 people, yielding a difference of approximately 32,000 fewer deaths. The rate of new cases of colorectal cancer also declined during this period, the CDC reported, from 52.3 per 100,000 in 2003 to 45.5 per 100,000 in 2007.

Using data from the agency's Behavioral Risk Factor Surveillance System phone survey, the CDC study showed that, nationally, the percentage of people who were screened for colorectal cancer according to commonly accepted clinical guidelines rose from 52.3 percent in 2002 to 65.4 percent in 2010.

Mortality fell furthest "in states with some of the highest screening prevalence," wrote Dr. Lisa Richardson and her colleagues.

In the second study, Dr. Jemal and his colleagues, reporting in the July 7 Cancer Epidemiology, Biomarkers & Prevention (CEBP), identified significant geographic disparities in colorectal mortality rates. In the northeastern states of Massachusetts, Rhode Island, and New York (as well as Alaska) mortality fell more than 33 percent between 1990–1994 and 2003–2007. In many southern states, particularly along the Appalachian corridor, the decreases were much smaller; in Mississippi (as well as Wyoming), the rates were nearly unchanged between the early 1990s and mid-2000s.

Why Have Colorectal Cancer Mortality Rates Fallen?

Several years ago, research groups supported by NCI's Cancer Intervention and Surveillance Modeling Network, or CISNET, developed computer models that estimated the impact of different factors on colorectal cancer mortality rates in the United States.

They estimated that approximately half of the reduction in colorectal cancer mortality was due to increased screening, just over a third was due to reductions in risk factors such as smoking, and a smaller proportion, 12 percent, was due to improved treatment.

The overall colorectal cancer mortality rate decline is welcome news, said Dr. Electra Paskett of the Ohio State University Research Foundation Comprehensive Cancer Center, a leading researcher on cancer health disparities. The higher mortality rates in the Appalachian corridor, however, were not a surprise, she continued. Her research group at Ohio State has been studying the problem for some time and is investigating ways to improve screening rates there. (See the box at the bottom of the page.)

"Detecting colorectal cancer early and getting it treated—that's what affects mortality," she said.

When it comes to screening uptake, the role of socioeconomic disparities can't be ignored, Dr. Jemal and colleagues stressed. "Southern states have a larger proportion of the population that is poor and uninsured, among whom screening rates are lower," they wrote.

Lower socioeconomic status, lower education levels, and lack of health insurance affect whether people get screened and whether they receive the appropriate follow-up and treatment after diagnosis, Dr. Jemal said in an interview.

For example, a 2010 study by NCI researchers showed that, among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had been screened for colorectal cancer via sigmoidoscopy, black participants were substantially less likely to undergo a prescribed follow-up colonoscopy than white patients. Although study participants' socioeconomic status was not known, black participants had lower education levels—which often correlate with lower socioeconomic status—than white participants.

Dr. Paul Doria-Rose of NCI's Division of Cancer Control and Population Sciences (DCCPS) agreed with the study authors on the likely primary cause of the differences. "The disparities in colorectal cancer are well established at this point," he said. "I think the regional differences we're seeing reflect those disparities."

Improving Screening Rates

A number of research groups are studying ways to improve screening rates for various cancers, particularly in populations for which notable disparities have been identified in cancer incidence and mortality and for whom barriers, such as lack of access to care, exist.

A major step forward came with the passage of the Affordable Care Act, which, as of January 2011, mandates that Medicare beneficiaries and individuals with new health insurance plans or policies beginning on or after September 23, 2010, receive certain recommended preventive health screenings, including those for colorectal and breast cancer, for free.

In addition, DCCPS staff have just finished reviewing applications for an NCI-funded initiative called Population-Based Research Optimizing Screening through Personalized Regimens, or PROSPR, that aims to improve the screening process for all cancers for which there are established, effective tests.

The aim of the initiative is "to take a holistic approach to the entire screening process, see where the shortcomings are, and identify ways to improve them," Dr. Doria-Rose explained. "In many cases, we have screening tests that work. The biggest opportunities now are in getting more people to be appropriately screened."

Carmen Phillips

An Intervention Tailored to the Community

Working with several community-based coalitions in the Appalachian region of Ohio, Dr. Electra Paskett is leading a study aimed at reducing the high colorectal cancer death rates in that region by increasing screening.

Based on feedback from community leaders, the study's primary intervention uses a decidedly low-tech tool. "They said that fancy things like the Internet and smart phones don't work here," Dr. Paskett explained. "The best thing to use, they said, is billboards."

The billboards in some counties advertise the importance of getting screened, whereas billboards in the "control" counties encourage eating more fruits and vegetables. Phone surveys will be used to measure outcomes, such as awareness of the need for people 50 years of age and older to be screened and whether more people are being screened. Dr. Paskett and her research team are also working with community groups to help residents who are screened obtain appropriate follow-up care.

Interventions to improve screening awareness and uptake have to be tailored to target communities, Dr. Paskett stressed. "An approach that works in New York City may not work very well in rural Ohio," she said.

Cancer Research Highlights

EGFR-Targeted Drug Effective for Some Lung Cancer Patients

Patients with advanced non-small cell lung cancer (NSCLC) whose tumors have specific mutations in the EGFR gene lived longer without their disease progressing when treated with the drug erlotinib (Tarceva) than patients who received chemotherapy alone, according to results from a phase III trial presented last week at the 2011 World Conference on Lung Cancer in Amsterdam. 

Based on a recommendation from its independent data monitoring committee, the 174-patient EURTAC trial was halted in January after an interim analysis found that it had met its primary endpoint of improved progression-free survival.

Other trials have also shown that patients whose tumors have EGFR mutations have better outcomes when treated with an EGFR-targeted agent such as erlotinib or gefitinib (Iressa), which are both tyrosine kinase inhibitors. However, those trials included only Asian patients, and only one trial to date, called OPTIMAL, limited enrollment to participants whose tumors had EGFR mutations. The EURTAC trial was the first to enroll patients from Western countries (primarily Europe) with advanced NSCLC whose tumors had EGFR mutations, explained the lead investigator Dr. Radj Gervais of Centre François Baclesse in France.

Patients were randomly assigned to receive, as their initial treatment, either erlotinib or a chemotherapy regimen containing a platinum drug until their disease progressed. Patients treated with erlotinib lived a median of 9.7 months without their disease progressing compared with 5.2 months for patients treated with chemotherapy. There was also a very high response rate in the patients treated with erlotinib, Dr. Gervais reported, with 58 percent experiencing substantial tumor shrinkage compared with only 15 percent of patients who received chemotherapy.

Overall survival was slightly better in patients treated with erlotinib, but the improvement was not statistically significant. An overall survival improvement may never be seen, Dr. Gervais explained during a press briefing, because patients treated with chemotherapy as their first-line therapy were switched to erlotinib once their disease began to progress, which is in line with current clinical practice.

Because of this crossover to treatment with erlotinib, “showing a survival improvement will be a difficult task,” agreed Dr. Roy Herbst, a leading lung cancer researcher at the University of Texas M. D. Anderson Cancer Center, during the briefing.

As early as the end of the year, Astellas Pharma expects to submit an application to the FDA seeking approval for erlotinib as a first-line treatment in patients with NSCLC who have EGFR mutations. Roche funded the EURTAC trial.

Clinically Relevant Family Histories of Cancer Change Over Time

A person’s clinically relevant family history of certain cancers changes substantially between ages 30 and 50, particularly for colorectal and breast cancer, as more family members are diagnosed, a new study shows. The study highlights the importance of having an accurate, up-to-date family history.

The findings were reported July 12 in JAMA by investigators from the Cancer Genetics Network (CGN), a research resource that includes a national registry of people with a personal or family history of cancer. CGN is an NCI-funded project directed by Dr. Dianne Finkelstein of Massachusetts General Hospital and Harvard University.

“We wanted to find out how often changes in a person’s family history of cancer over time would affect the cancer screening schedule and tests recommended by standard guidelines,” said Dr. Sharon Plon of Baylor College of Medicine, the senior author on the paper.

The researchers examined family history data for colorectal, breast, and prostate cancer among 11,129 individuals enrolled in the CGN. Family history is an important predictor of risk for all three cancers. CGN investigators have followed registry participants for a decade with annual questionnaires on family history updates and other factors.

Using family history data that the participants provided when they entered the registry, investigators determined retrospectively the rate of change in each person’s family history from birth until the time of enrollment into CGN. They also examined the participants’ family history changes prospectively, from the time of their enrollment in the CGN to the time of their most recently completed questionnaire.

In particular, CGN investigators looked for changes in family history that would make someone a candidate for earlier or more intensive screening according to current American Cancer Society (ACS) guidelines. For individuals considered to be at high risk, ACS guidelines include earlier and more frequent screening for colorectal cancer and the addition of annual breast magnetic resonance imaging (MRI) for breast cancer.

The analyses showed that the participants’ clinically relevant family history changed substantially between the ages of 30 and 50, especially for colorectal and breast cancer. The proportion of individuals who should be recommended for high-risk screening for these two cancers increased 1.5 to 3-fold between ages 30 and 50.

“The results of this study could guide how often health care providers should ask their patients for an update in their family history,” said Dr. Finkelstein. “It is important to inform the physician of new diagnoses of cancer in family members at routine [annual] check-ups,” she added, noting that patients “should be aware of which of their close relatives have had cancer, the location or organ where the cancer started, and the age at which the relative was first diagnosed with cancer.”

Lung Tumor Study Reveals Variability of CT Scans

Doctors and researchers use imaging tools such as computed tomography (CT) to monitor the size of a patient’s tumor and to assess responses to new therapies during clinical trials. To evaluate the performance of CT for these purposes, researchers compared measurements of tumor size on scans of the same patient taken just minutes apart. On many repeat scans, the study found, radiologists identified changes in tumor size that, if real, would be considered clinically important.

In the report of their findings, published online July 5 in the Journal of Clinical Oncology (JCO), the researchers noted that decreases in tumor size of less than 10 percent may not be distinguishable from changes caused by inherent variability in the scanning process. Dr. Gregory Riely of Memorial Sloan-Kettering Cancer Center (MSKCC) led the study.

Radiologists have known that many nonbiological factors can create apparent changes in tumor size on repeat CT scans. This study, for the first time, has quantified the effect.

The researchers scanned 30 patients with non-small cell lung cancer twice within 15 minutes using the same CT machine. Three radiologists then read the images without knowing the interval between the scans. They reported changes of more than 2 mm in tumor diameter on many of the repeat scans.

Clinical trials have increasingly reported small changes in tumor size as evidence of drug activity, the study authors noted. They point out, however, that changes of this magnitude could be solely the result of variability in imaging. As such, these kinds of changes should not by themselves be a marker of efficacy in clinical trials, the authors said.

This unprecedented study of the performance characteristics of CT may have “important implications for the future of drug development,” noted Dr. Michael Maitland of the University of Chicago and his colleagues in an accompanying editorial.

Blocking Cdk1 Protein May Sensitize More Tumors to PARP Inhibitors

Investigators have found a potential way to compromise DNA repair in cancer cells that lack BRCA mutations, making them sensitive to treatment with PARP inhibitors. The results of the research, which was led by Dr. Geoffrey Shapiro of Dana-Farber Cancer Institute and Harvard Medical School, were published online June 26 in Nature Medicine.

Cancer cells that have BRCA mutations respond to treatment with PARP inhibitors because they have a defect in the DNA-repair pathway that becomes critical for cells when the DNA-repair pathway that involves PARP is disabled. The researchers hypothesized that blocking the activity of a protein called Cdk1 might create an effect similar to a BRCA mutation in cancer cells that lack such a mutation. Cdk1 controls the function of the normal BRCA1 protein in DNA repair and helps regulate the cell cycle.

To test their hypothesis, the researchers blocked Cdk1 function in several cancer-cell lines lacking BRCA mutations using either RNA interference or drugs designed to inhibit Cdk1 activity.

After blocking Cdk1 function and exposing the cells to gamma radiation, which damages DNA, they observed a 70 to 80 percent reduction in the formation of the DNA-repair machinery that can compensate for inhibition of the DNA-repair pathway that involves PARP.

When the researchers used RNA interference to block Cdk1 activity in two different cell lines lacking BRCA mutations, the cells were 100 to 200 times more sensitive to treatment with a PARP inhibitor than the same cell lines with normal Cdk1 levels. They saw similar results after blocking Cdk1 function with a drug.

In lung tumors lacking BRCA mutations that were grown in genetically engineered mice, the combination of a drug to block Cdk1 activity and a PARP inhibitor caused sustained tumor regression in 9 out of 13 mice that were treated for 3 weeks. Two of the mice remained alive 15 weeks after treatment without additional tumor growth. No damage to normal tissues or organs was observed with the drug combination.

The authors proposed that the combination of drugs should be tested in early-phase clinical trials. “Our hope is that doses of the Cdk1 inhibitor and the PARP inhibitor that we would study in clinical trials would be effective without harming normal tissues,” explained Dr. Shapiro.

Gene Mutations Linked to Altered Telomeres in Cancer Cells

Researchers have identified an association between mutations in two genes and highly abnormal telomeres in multiple forms of cancer, including the most common and aggressive form of malignant brain tumor, glioblastoma multiforme (GBM). Among hundreds of tumors tested, those with mutations in either of the two genes also had abnormal telomeres, researchers at the Sol Goldman Pancreatic Cancer Research Center and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins reported online June 30  in Science.

The researchers can now investigate whether the mutations contribute directly to changes in telomeres and cancer, which could have clinical implications. The work builds on a recent genetic analysis of pancreatic neuroendocrine tumors (PNET), a type of pancreatic cancer, by Hopkins researchers. This prior study found frequent mutations in one of two genes involved in the packaging of DNA—DAXX and ATRX.

The proteins encoded by these genes modify chromosome structure and are active at the telomeres. In the new study, the researchers hypothesize that the inactivation of these genes may make it possible for cancer cells to lengthen their telomeres, ensuring their survival. Normally, telomere DNA is progressively lost as a cell divides until the cell is no longer viable.

“The mutations in DAXX or ATRX seem to allow cancer cells to overcome the natural loss of telomere DNA and to keep dividing indefinitely,” said Dr. Alan Meeker, a molecular pathologist at the Kimmel Cancer Center and a lead author of the study. “This hypothesis needs to be tested through rigorous functional studies in the lab.”

When he and his colleagues analyzed more than 400 tumors, every sample that had mutations in the ATRX gene had abnormal telomeres. (They did not find any DAXX mutations in the non-PNET samples.) The association was relatively common in certain cancers, including central nervous system tumors, particularly GBM in children and adults.

“There was a perfect correlation between mutations in DAXX or ATRX and abnormal telomeres,” said Dr. Meeker. “This was really exciting. You rarely ever see a perfect correlation in biological research.” Understanding the mechanisms involved in generating the abnormal telomeres could reveal new therapeutic targets for cancer, he added.

Guest Commentary by Dr. Sanya A. Springfield

NCI Cancer Disparities Research: Sharing Ideas, Forging Partnerships

Dr. Sanya A. Springfield Dr. Sanya A. Springfield

As director of NCI's Center to Reduce Cancer Health Disparities (CRCHD), I am pleased to host and welcome the hundreds of high-level cancer researchers, practitioners, trainees, students, and community activists who are gathering in Bethesda, MD, this week (July 12–15) for the CRCHD Cancer Health Disparities Program Meetings 2011

We will share new scientific advances and help foster and expand creative and collaborative approaches to addressing cancer health disparities. The meetings are a time for our grantees to tune up and tune in with their colleagues and with NCI staff and scientists. It's also an opportunity for CRCHD staff to take the pulse of our numerous programs. 

These program meetings are especially important for our research trainees, who receive guidance on grant writing, the grant review process, and improving the public presentation of their research results. Over the course of 4 days, they will experience plenary sessions on new directions in disparities research, presentations of results from numerous studies, programmatic meetings, a mock grant review session, skill-building workshops, resource and tool sharing, networking opportunities, and poster competitions.

For the first time, we are partnering with Susan G. Komen for the Cure to bring together NCI-supported disparities researchers and community outreach groups from the National Capital Area to brainstorm and discuss issues of access, research participation, and biospecimen collection for breast cancer prevention and care among diverse populations.

In addition, the meeting will focus on the influence of issues such as comorbidities, global health, and obesity on cancer health disparities. An example is the discussion of the global health implications of rising cancer rates in Africa, where infectious outbreaks and chronic diseases that are associated with a higher risk for certain cancers are more common. These issues cross national borders and create the need for a global strategy to find comprehensive solutions.

The work CRCHD has historically been involved in—community-based research—is now being complemented with basic research, revealing a more complex picture of the roots of cancer disparities. For instance, one of the plenary sessions, "Basic and Translational Research for Cancer Health Disparities," will address the growing evidence that different population groups may have biological differences that are associated with various diseases and disorders. We at CRCHD hope that this new focus on basic research will culminate in better-targeted and more-refined community outreach and medical interventions.

The American Cancer Society's (ACS) recently released 2011 Cancer Facts & Figures underscores the importance of this week's gathering. The ACS reported that, as a result of continued declines in overall cancer death rates in the United States, about 898,000 deaths from cancer were avoided between 1990 and 2007. Nevertheless, a special section of the report on cancer disparities noted that cancer death rates have diverged among subgroups of the U.S. population.

In 1993, the death rate for the least-educated black and white men was more than twice that of the most-educated men in both groups. By 2007, the difference was nearly three-fold. The report goes on to note that 37 percent—or 60,370—of the premature cancer deaths that occurred in 2007 in people 25 to 64 years of age could have been prevented if all segments of the U.S. population had the same cancer death rates as those of the most-educated whites.

CRCHD staff and our grantees are attempting to change the face of cancer research by broadening the diversity of the cancer research workforce and focusing more research on underserved populations. (See "Inspired by Science: Cancer Research Internships for Minority Students" in this issue.)

We believe that an integrative and collaborative approach is necessary to reduce cancer disparities around the world. Coming together this week helps us foster new and creative strategies and solutions for addressing, and ultimately, eliminating health disparities.

Dr. Sanya A. Springfield
Director, NCI Center to Reduce Cancer Health Disparities

Spotlight

Technology
This article is part of a series of stories related to new technology in cancer research. You can read more articles in the series here. 

Whole-Genome Sequencing for Cancer Enters the Clinic

After completion of the Human Genome Project in 2003, NIH continued to fund three large-scale sequencing centers to explore applications of genetic sequencing to the study of human diseases: the Human Genome Sequencing Center at Baylor College of Medicine; the Broad Institute of Harvard and MIT; and the Genome Institute at Washington University in St. Louis. In this article, researchers at the Genome Institute at Washington University share their perspectives on the future of whole-genome sequencing in cancer medicine.

Launched in 1990 and formally completed in 2003, the Human Genome Project took 10 years to produce the first draft sequence of an entire human genome.

Today, a draft sequence of an entire human genome can be produced in about 10 days, according to Dr. Elaine Mardis, co-director and director of technology development at the Genome Institute.

In less than a decade, researchers have made a "total quantum leap" in technology, Dr. Mardis continued. This leap is bringing the concept of using whole-genome sequencing in everyday clinical decision making for cancer from science fiction-like speculation to reality, with the goals of providing treatment that is better tailored to individual patients and, eventually, improving their outcomes.

A Quantum Leap and Beyond

A DNA sequencing gel showing the frequency of the four genetic nucleotides (Image courtesy of John Schmidt) A DNA sequencing gel showing the frequency of the four genetic nucleotides (Image courtesy of John Schmidt)

The Human Genome Project used a process called Sanger sequencing, which is highly labor intensive. In Sanger sequencing, double-stranded DNA is separated into single strands, or templates, and mixed with short, single-stranded pieces of DNA called "primers" that bind to complementary sequences on the templates. An enzyme called DNA polymerase and radioactively labeled versions of the four nucleotides of the genetic code—thymine (T), cytosine (C), guanine (G), or adenine (A)—are then used to extend the length of each bound primer one nucleotide at a time based on the sequence of the template. This process produces numerous labeled extensions of the primers that differ in length by a single nucleotide.

Next, an independent process called gel electrophoresis is used to separate the labeled DNA products on the basis of size. Products ending in T, C, G, or A are loaded into separate lanes on a gel, and shorter molecules travel farther in the gel than longer ones. The final order of the products can be used to reconstruct, or read, the sequence of the DNA template. (See the image to the right.) The use of fluorescent dyes later in the Human Genome Project simplified the gel process slightly but did not substantially shorten the time required to complete the sequencing of an entire genome.

Beginning in 2005, however, technology emerged that eliminated the need for the gel stage of sequencing. In this new technology, as nucleotides are added to the DNA sequence growing from the primer, a chemical reaction takes place that releases a specific frequency of light for each of the four nucleotides of the genetic code. These pulses of light are recorded by a machine, providing an immediate readout of the sequence. This process is sometimes called "next-generation sequencing," but Dr. Mardis prefers the term "massively parallel sequencing," which highlights the capabilities of the new technology.

"In massively parallel sequencing, the sequencing reaction and the detection of the sequencing reaction happen in lock-step," she explained. "This allows you to not only completely eliminate the gel-based separation but examine each of hundreds of thousands or millions of reactions at the same time."

The leap in power provided by massively parallel sequencing can be difficult to grasp. Dr. Cherilynn Shadding of the Genome Institute likes to use a geographical comparison. She tells visitors that it would take 20 Central Parks full of Sanger sequencers to provide the same output as Washington University's two rooms of next-generation sequencing machines.

Dr. Elaine Mardis, co-director of the Genome Institute at Washington University in St. Louis, stands beside a next-generation DNA sequencing machine. (Photo courtesy of Washington University in St. Louis) Dr. Elaine Mardis, co-director of the Genome Institute at Washington University in St. Louis, stands beside a next-generation DNA sequencing machine. (Photo courtesy of Washington University in St. Louis)

From Proof-of-Concept to Real Clinical Questions

After the working draft sequence of the human genome was published in 2001, explained Dr. Richard Wilson, director of the Genome Institute, "we figured that we should be able to start applying the reference genome sequence and some of the technology that we had developed to look at regions of the genome that cause disease. We obviously had no shortage of diseases to pick from, but we tried to figure out where we could have the biggest impact, and we decided that was cancer."

In early collaborations with the Washington University School of Medicine and with Memorial Sloan-Kettering Cancer Center, Dr. Wilson and his colleagues launched pilot projects looking for mutations in candidate genes—but not the whole genome—in acute myeloid leukemia (AML) and non-small cell lung cancer. Although the lung cancer work provided some new information (including the fact that certain mutations in the EGFR gene make the cancer sensitive to the drugs erlotinib and gefitinib), "we didn't really discover anything new" when looking at familiar areas of the genome in AML, he recounted.

"In 2005, with some of these next-generation sequencing technologies coming out, we decided that the right way to look at cancer genetics was not just to make a list of our favorite genes and focus on those, but to sequence the whole genome, using both tumor and normal tissue from individual patients, and find all of the mutations," Dr. Wilson continued.

The Washington University researchers published findings from the first cancer genome to be sequenced––that of a patient with AML––in 2008. Follow-up from that study revealed that one of the new mutations discovered, in a gene called DNMT3A, may help identify patients with AML who are at high risk of recurrence. In 2009, the team sequenced its second whole genome from a patient with AML, and, in 2010, the first genome from a woman with inflammatory breast cancer was sequenced.

The cost per whole-genome sequence has dropped rapidly over the past 3 years. The 2008 AML study cost just over $1.5 million. Over half a million of that was devoted just to developing the bioinformatics required to compare the tumor with normal genomes, "because that had never been done before," said Dr. Mardis. Today, she said, the same sequencing costs only $10,000.

This reduction in cost combined with continuing improvements in speed have let researchers move from proof-of-concept studies to larger projects, asking questions about the impact of rare genetic mutations on response to treatment and outcomes. In their Cancer Genome Initiative, the Washington University researchers have sequenced the complete tumor and normal genomes of 150 patients.

The results from 50 of these patients, presented this year at the American Association for Cancer Research annual meeting, compared genetic alterations in women whose tumors responded to treatment with an aromatase inhibitor with those in women whose tumors were resistant to this treatment. The results are being analyzed for genetic clues that might identify resistance before treatment begins.

Another project, in collaboration with St. Jude Children's Research Hospital, is sequencing the genomes of at least 600 children with cancer in hopes of finding new genetic targets for therapy.

The Future Is Now

Drs. Timothy Ley (left) and Richard Wilson are leaders in the field of cancer genome sequencing. (Photo courtesy of Robert Boston, Washington University in St. Louis) Drs. Timothy Ley (left) and Richard Wilson are leaders in the field of cancer genome sequencing. (Photo courtesy of Robert Boston, Washington University in St. Louis)

These studies will provide questions for testing in future clinical trials. An even more futuristic aspect of whole-genome sequencing for cancer is its potential to influence treatment decisions for individual patients—not decades in the future but today.

This May, the Washington University researchers published a case report of the use of whole-genome sequencing to guide the care of a woman with a rare subtype of AML that responds well to a specific targeted therapy, sparing her from more aggressive stem-cell transplantation. The disease subtype could only be identified definitively in her case through whole-genome sequencing.

The analysis, explained Dr. Mardis, proved that whole-genome sequencing can provide important information for clinical decision making at the same cost and in the same time frame as traditional pathologic and cytogenetic techniques that are used to diagnose AML.

"Cytogenetics and limited molecular tests are used now to provide prognostic information for AML patients, but the current tests don't allow us to precisely classify risk for all patients. Further, a complete panel of current tests can cost up to $10,000 per patient, and that cost will go up as new prognostic genes are discovered," said Dr. Timothy Ley, associate director of the Genome Institute.

To improve treatment planning, Dr. Ley and his colleagues are planning to sequence the whole genome of every patient with intermediate-risk AML seen at the Siteman Cancer Center, beginning at the end of this year. These patients are difficult to assign to either chemotherapy or more aggressive stem-cell transplantation based on traditional diagnostic techniques alone.

"More than 200 AML patients have now had their exomes [the portion of the genome that contains protein-coding genes] or whole genomes sequenced, and we will know a lot more about what mutations matter for outcomes by the end of the year," explained Dr. Ley. "All the patients we sequence will be followed to understand whether the decisions we make based on the sequencing data translate into improved survival."

A major issue in looking at the whole genome for cancer is that so many of the mutations discovered so far are not shared among many patients with a single type of cancer or lie in areas of the genome whose function is unknown.

Dr. Wilson thinks the genetic diversity of cancer uncovered so far "actually keeps us going as researchers rather than gets us down. It reminds us that this is not an easy disease that we've decided to work with," he commented. "If it was easy to understand, we wouldn't need whole-genome sequencing."

Sharon Reynolds

Featured Clinical Trial

Preventing Smoldering Multiple Myeloma from Progressing

Name of the Trial
Phase II Trial of IPH2101 (Anti-KIR) in Smoldering Multiple Myeloma (SMM) (NCI-11-C-0024). See the protocol summary.

Dr. Ola Landgren Dr. Ola Landgren

Principal Investigator
Dr. Ola Landgren, NCI Center for Cancer Research

Why This Trial Is Important  
Multiple myeloma is an often-deadly cancer in which abnormal plasma cells accumulate in the bone marrow. Despite recent advances in treatment, the disease remains incurable. Consequently, doctors are eager to find ways to prevent it in people at high risk.

Multiple myeloma is characterized by a marker in the blood (and/or urine) called monoclonal protein (also called M protein), bone lesions, anemia, kidney failure, hypercalcemia, or a combination of these symptoms. The detection of M protein in the blood without evidence of bone lesions or organ damage indicates the presence of one of two precancerous conditions that carry differing risks of progression to multiple myeloma. One of these conditions, called monoclonal gammopathy of undetermined significance (MGUS) has, on average, a low risk of progressing to multiple myeloma. In contrast, patients with smoldering myeloma have, on average, a much higher risk of developing multiple myeloma.  

Typically, doctors manage patients with MGUS or smoldering myeloma using an active surveillance strategy that involves varying degrees of monitoring based on the presence of certain risk factors. There are no standard treatment options for people with these conditions. However, experts in multiple myeloma research are beginning to approach the conditions differently, with more aggressive monitoring of those with high-risk MGUS and smoldering myeloma.

Based on current knowledge, the average time of progression from high-risk smoldering myeloma to multiple myeloma is less than 2 years. Researchers have begun to investigate whether treating people with smoldering myeloma with novel strategies can help delay or prevent some of them from developing multiple myeloma.

Treatment of smoldering myeloma with therapies that are used to treat multiple myeloma is complicated by the fact that current treatments for multiple myeloma carry risks of severe side effects that may outweigh the potential benefits. Nevertheless, some clinical trials are being conducted to compare the use of common myeloma drugs, such as lenalidomide, with surveillance alone. Although early results suggest this approach may be beneficial, it's too early to tell if treatment is truly preventing progression or only delaying it. Researchers at NCI are pursuing a different approach that they hope will help those with smoldering myeloma while bypassing some of the side effects commonly associated with aggressive therapy.

In this trial, people diagnosed with smoldering myeloma will be treated with an experimental biological agent called IPH2101 that helps immune cells called natural killer cells (NK cells) attack and destroy myeloma cells. NK cells normally have the ability to destroy myeloma cells, but myeloma cells can trigger receptors on the surface of NK cells, called KIR receptors, that deactivate the immune response of NK cells against myeloma cells. IPH2101 is a monoclonal antibody that attaches to and blocks KIR receptors, so myeloma cells cannot use this mechanism to turn off an NK-cell attack.

"Our recent investigations show that virtually all patients who develop frank multiple myeloma go through a period of asymptomatic disease (MGUS and smoldering myeloma); so, if we can catch it then, I believe that may give us the best chance to cure some of them," said Dr. Landgren.

"Our tests in people participating in the study show that [IPH2101] binds to the NK cells at an extremely high rate," so it should prevent the tumor cells from deactivating the NK cells very effectively, Dr. Landgren explained. "So far, we've seen no serious side effects in participants receiving the drug. At NCI, we are developing several novel treatment studies for patients diagnosed with smoldering myeloma or multiple myeloma."

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. Also see the NCI's Multiple Myeloma Clinical Research Section Web site.

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

Community Update

Inspired by Science: Cancer Research Internships for Minority Students

Noah Espinoza Noah Espinoza found an internship at the Fred Hutchinson Cancer Research Center through NCI's Minority Institution Cancer Center Partnership.

Noah Espinoza, who grew up in a small ranching community in New Mexico, was excited when he was selected in 2008 to participate in the prestigious Cancer Research Internship Program for Undergraduate Students at the Fred Hutchinson Cancer Research Center in Seattle, WA. He had heard about the program during his senior year at New Mexico State University (NMSU), when Fred Hutchinson scientist Dr. Beti Thompson visited one of Espinoza's classes to talk about the internship opportunity.

"One of the things that motivated me to apply was that [the internship] would allow me to take the next step of getting hands-on experience in health care research," said Espinoza, who graduated from NMSU in May 2008 with a bachelor's degree in Community Health prior to heading for Seattle. "The program at NMSU was mostly focused on training me to become a lay health worker and educator, but I didn't feel like I had any 'real world' experience with research, and that's why I was so excited to be going to 'The Hutch.'"

Espinoza found his internship through the Minority Institution Cancer Center Partnership program (now called Partnerships to Reduce Cancer Health Disparities) developed and funded by NCI's Center to Reduce Cancer Health Disparities (CRCHD). NMSU and the Hutchinson Cancer Center have partnered through the NCI program since 2002 to expand the number of underrepresented students who are trained in cancer research.

Dr. Thompson, who is on the Cancer Prevention faculty at Fred Hutchinson, has led the partnership since its inception. "It is a wonderful program because NMSU has the student population of Hispanics and Native Americans that Hutchinson is interested in working with in our efforts to reduce cancer health disparities in those populations," she explained. "In return, our cancer center has helped NMSU increase [its] cancer research infrastructure and provided advanced training opportunities for [its] students." The goal is to encourage more NMSU students to pursue graduate education in cancer research.

First Impressions

Each summer, between six and ten NMSU undergraduates are accepted through a rigorous selection process into the Cancer Research Internship Program, which involves 9 intense weeks of mentored research activities, seminars, social activities, and a final poster session. Dr. Thompson recalled being impressed with Espinoza when he arrived at the University of Washington.

Dr. Beti Thompson Dr. Beti Thompson, Noah Espinoza's mentor at the Fred Hutchinson Cancer Center

"Noah is very passionate about what he does, including research," she said. "He takes great care in looking up scientific literature, making sure he knows what he's talking about, and just really digging deep into any topic that he's interested in."

"I was really amazed by the supportiveness of everybody at the Hutch, especially Dr. Thompson," commented Espinoza. "She has lots of research projects going on, so there was plenty of work for me and the other interns."

After he finished his internship research project doing data entry and analysis for the smoking cessation program "Quit and Win," Dr. Thompson invited Espinoza to do similar work on her program of home health parties aimed at increasing cancer screening rates among Hispanic farm workers in Washington State. In that program, trained lay health workers visit a Hispanic family and their friends to talk about the importance of colorectal cancer screening.

"It's like a Tupperware party, only what we're selling is cancer prevention," explained Dr. Thompson.

Involvement in that project "was the turning point for me," Espinoza recalled, "because, with data analysis, you're discovering meaningful things and getting an understanding of what's working in order to improve people's health. That was one of the main reasons why I decided to apply for graduate school­; because I want to be able to do more of that sort of research."

Upward and Onward

Dr. Thompson and her colleagues subsequently wrote recommendations that helped Espinoza get into the University of Washington Master of Public Health in Epidemiology program. She also helped him write and apply for a 2-year grant to do research on physical activity for his graduate thesis.

"I'm hoping I can continue my career here at the Hutch," Espinoza said. "I see myself working with rural or underserved populations, trying to address the issues of health, cancer prevention, and quality of life in those populations."

"Noah embodies the goals of our partnership with NMSU," Dr. Thompson noted. "He is the kind of person who we want to get into the pipeline because he's going to be a fantastic mentor later on for Hispanic students and other students of underrepresented populations who are trying to get ahead in the research field. His enthusiasm is very contagious."

Bill Robinson

Watch a video of Noah Espinoza produced by the Fred Hutchinson Cancer Research Center online.

More information on training opportunities for students and researchers can be found online.

FDA Update

Advisory Panel Upholds Recommendation to Withdraw Bevacizumab Approval for Breast Cancer

A panel of experts advising the Food and Drug Administration (FDA) recommended unanimously that the agency withdraw its accelerated approval of bevacizumab (Avastin) for treating metastatic breast cancer. FDA Commissioner Dr. Margaret A. Hamburg will make a final decision on whether to implement the panel’s recommendation after a period of public comment. (Electronic or written comments must be submitted to Regulations.gov by July 28.)

Members of the Oncologic Drugs Advisory Committee (ODAC) of the FDA’s Center for Drug Evaluation and Research recommended withdrawing the approval on June 29. In a series of three votes, panel members agreed with the FDA that bevacizumab should no longer be approved for use with chemotherapy as a first-line treatment for HER2-negative metastatic breast cancer.

The FDA granted accelerated approval for this indication in February 2008 based on the results of a single phase III clinical trial. However, such approvals are contingent on the results of additional, confirmatory trials. Last July, after reviewing the results of two additional clinical trials, ODAC voted 12 to 1 to recommend against the use of bevacizumab for metastatic breast cancer. (See: FDA Advisory Committee Recommends against Bevacizumab for Metastatic Breast Cancer.)

Genentech, a division of Roche and the manufacturer of bevacizumab, was granted an appeal hearing. Representatives of the company, as well as patients and breast cancer advocates, spoke during the 2-day meeting held in Silver Spring, MD.

In the first of three 6–0 votes, the advisory panel agreed with FDA officials that the ongoing trials have not demonstrated a clinical benefit with bevacizumab for participants in the trials. The panel also agreed that the available evidence did not show that bevacizumab was safe in this setting—that is, the risks outweighed the benefits for breast cancer patients. (Cancer patients who receive bevacizumab in combination with chemotherapy may be at an increased risk of serious side effects that may lead to death.)

Finally, the panel recommended against the continued approval of the drug for metastatic breast cancer while the sponsor, Genentech, conducts another study intended to verify the drug’s clinical benefit.

Bevacizumab is approved for treating other cancers, including advanced colorectal, lung, kidney, and brain cancers. Until the FDA commissioner makes a decision, bevacizumab remains an approved drug for use with paclitaxel in women with HER2-negative metastatic breast cancer. 

Further reading: Questions and Answers about Avastin

CMS

Medicare Will Cover Provenge Treatment for Prostate Cancer

The Centers for Medicare and Medicaid Services (CMS) announced it will cover the cost of sipuleucel-T (Provenge), an autologous cellular immunotherapy for prostate cancer, for Medicare beneficiaries. In a National Coverage Determination (NCD) memo released June 30, CMS stated that there is sufficient evidence that the therapy is effective for its FDA-approved use: the treatment of men with metastatic prostate cancer who have few or no symptoms of the disease.

Sipuleucel-T was approved by the FDA in April 2010 based on the results of a phase III clinical trial called IMPACT. The trial showed that the treatment, which uses a modified form of a patient’s own white blood cells, improved the median overall survival of men with metastatic, hormone-refractory prostate cancer by 4.1 months compared with the median survival of men who received a placebo treatment. Sipuleucel-T also showed little evidence of serious side effects.

CMS initiated a National Coverage Analysis last year, agency officials explained, because of questions about whether all of Medicare’s regional carriers would cover the therapy. In the absence of an NCD, local Medicare contractors had discretion to decide whether to cover the therapy. Treatment with sipuleucel-T consists of three vaccinations over a 4- to 6-week period at a total cost of $93,000.

In November 2010, a Medicare advisory panel offered support for sipuleucel-T coverage. Three other treatments are approved for metastatic, hormone-refractory prostate cancer: the chemotherapy drug docetaxel, which has significant toxic effects that deter many men from taking it; cabazitaxel (Jevtana), which was approved by the FDA last year for men with advanced disease who do not respond to docetaxel; and abiraterone (Zytiga), which was approved earlier this year for the same indication.

Legislative Update

State Cancer Legislative Database Update Now Available

The latest edition of the SCLD Update has been posted on NCI's State Cancer Legislative Database (SCLD) Web site. This issue contains an overview of all new cancer-related measures enacted by state legislatures during the first quarter of 2011.

The issue also features a fact sheet on state laws requiring third-party coverage for cervical cancer screening. Currently, 27 states and the District of Columbia have enacted laws requiring third-party insurers to provide coverage for annual screening. (In Maryland, the law applies only to HPV testing.) 

These laws differ in their coverage of specific screening tests and often stipulate age and frequency requirements, either in the text of the law itself or by requiring coverage to conform to the screening guidelines of a particular national organization.

A U.S. map indicating those states with laws requiring third-party coverage for cervical cancer screening enacted as of March 31, 2011

Notes

Lou Staudt and Shiv Grewal Named NIH Distinguished Investigators

Drs. Lou Staudt and Shiv Grewal Drs. Lou Staudt and Shiv Grewal

NIH Director Dr. Francis Collins named Drs. Louis M. Staudt and Shiv Grewal NIH Distinguished Investigators. This title is conferred upon preeminent researchers whose career accomplishments are considered exceptional. Fewer than 3 percent of NIH researchers bear the title, which requires peer and NIH director review and approval. 

Dr. Staudt, deputy chief of the Metabolism Branch in NCI's Center for Cancer Research (CCR), has led a major effort to create a diagnostic microarray that provides molecular diagnostic and prognostic information to patients with lymphoid malignancies. Dr. Staudt's research team also uses functional genomics, chemical genetics, and large-scale RNA interference, or RNAi, to identify new molecular targets for the treatment of lymphoid malignancies.

Dr. Grewal, head of the Chromosome Biology Section in CCR's Laboratory of Biochemistry and Molecular Biology, studies epigenetic control of gene expression and development. This work led him and his research team to discover a connection between natural RNAi and heterochromatin formation. In 2002, this discovery was selected as a "Breakthrough of the Year" by Science magazine.

NCI Cancer Classroom Webinar Series Wraps Up July 26

NCI's free, four-part webinar series, Cancer Classroom, concludes July 26 from 2:00 p.m. to 3:30 p.m. ET. The session, Clinical Trials 102, completes an overview of the clinical trials process, including recruitment and accrual challenges and available NCI resources.

The goal of the series has been to provide the educational guidance, tools, and resources necessary for early-career public health professionals or those new to the field of oncology to address cancer as a public health issue. Although the workshops are free, preregistration is required. To register or learn more, visit the NCI Cancer Classroom Series Web site.

If you missed the first three sessions, view them online:

Proposals Sought to Use Biospecimens from SELECT and PCPT

SWOG, formerly known as the Southwest Oncology Group, is making resources from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Prostate Cancer Prevention Trial (PCPT), available to the wider research community for the development of novel translational research projects.

Together, SELECT and PCPT randomly assigned more than 53,000 men without prostate cancer to intervention or placebo, generating substantial clinical data related to the risk of developing prostate cancer, as well as corresponding biorepositories for molecular, epidemiologic, and other studies.

Proposals in four major categories will be considered:  prostate cancer, cancers other than prostate, ancillary studies to SELECT and PCPT, and other health outcomes. Each proposal should include a concise plan of the research to be conducted during the proposed project period.

A proposal involving humans or animals may be approved, but funds will not be committed until appropriate institutional review board approval is received. Lists of previously approved studies and information about biorepositories and data elements are available at the SELECT and PCPT links above.

Researchers interested in using samples from SELECT or PCPT must submit a letter of intent to SWOG by 5:00 p.m. ET on September 1, 2011.  Full applications are due by 5:00 p.m. ET on October 29, 2011.

SWOG will review proposals in January 2012 and send notifications in April 2012.