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April 3, 2012 • Volume 9 / Number 7

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NEWS

Targeted Drug Shows Promise in Common Form of Lymphoma aacr

2012 American Association for Cancer Research annual meeting banner

Preliminary results from two early-phase clinical trials suggest that the investigational drug ibrutinib may benefit some patients with an aggressive type of non-Hodgkin lymphoma (NHL). In the trials, some patients with diffuse large B-cell lymphoma (DLBCL) who did not respond to standard therapies, or who had stopped responding to these treatments, experienced complete or substantial tumor shrinkage after treatment with ibrutinib. The treatment was well tolerated, with only minor side effects.

Dr. Louis Staudt of NCI’s Center for Cancer Research (CCR), who co-led both trials, presented the findings April 1 at the 2012 American Association for Cancer Research annual meeting in Chicago. Read more > >

COMMENTARY

Dr. Bert Vogelstein

A Conversation with Dr. Bert Vogelstein about Whole-Genome Sequencing to Predict Cancer Riskaacr

The director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University and an investigator with the Howard Hughes Medical Institute explains the potential and the limitations of whole-genome sequencing.

IN DEPTH

UPDATES

  • Legislative Update

    • Senate Appropriations Hearing Highlights NCI’s Provocative Questions Project
  • FDA Update

    • FDA Takes Action under the Tobacco Control Act of 2009
  • Notes

    • Cyber-Seminar will Explore Measuring the Health of a Community
    • Dr. John Potter to Deliver First Schatzkin Lecture in Nutritional Epidemiology

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 Shows Promise in Common Form of Lymphoma

2012 American Association for Cancer Research annual meeting banner

Preliminary results from two early-phase clinical trials suggest that the investigational drug ibrutinib may benefit some patients with an aggressive type of non-Hodgkin lymphoma (NHL). In the trials, some patients with diffuse large B-cell lymphoma (DLBCL) who did not respond to standard therapies, or who had stopped responding to these treatments, experienced complete or substantial tumor shrinkage after treatment with ibrutinib. The treatment was well tolerated, with only minor side effects.

Dr. Louis Staudt of NCI’s Center for Cancer Research (CCR), who co-led both trials, presented the findings April 1 at the 2012 American Association for Cancer Research annual meeting in Chicago. The impetus for the trials was a series of discoveries made by Dr. Staudt and his colleagues in CCR’s Metabolism Branch.

One of the trials, a phase I pilot study of 10 patients, enrolled only patients with activated B-cell-like (ABC) DLBCL. The ABC subtype is one of three molecular subtypes of DLBCL identified several years ago by Dr. Staudt’s lab. Patients with the ABC subtype, which accounts for about 40 percent of DLBCL diagnoses, have the poorest survival, they found.

Dr. Staudt’s lab also identified a signaling pathway—a communication network within cells—that is controlled by the B-cell receptor (BCR) and that, when overactive, enables tumor cells in the ABC subtype to survive and multiply. The receptor mutations Dr. Staudt’s lab identified in some patients with this subtype suggested the importance of this pathway in DLBCL. Finally, the researchers found that blocking a component of the BCR signaling pathway, called Bruton’s tyrosine kinase (BTK), causes ABC DLBCL cells to die.

Drs. Wyndham Wilson and Louis StaudtDrs. Wyndham Wilson (left) and Louis Staudt

“We had both functional evidence and genetic evidence that the BCR pathway was important in the ABC subtype,” Dr. Staudt said. “And that’s why we were excited about ibrutinib, because it’s a potent BTK inhibitor.”

Both trials were conducted in conjunction with California-based Pharmacyclics, which developed ibrutinib.

Two patients in the phase I trial had a complete response, one had a partial response, and a fourth patient who had not responded to any prior treatment had substantial tumor regression and a major improvement in his symptoms.

One patient with a complete response continues to take the oral therapy daily and has shown no signs of disease for 16 months, Dr. Staudt stated. And the patient whose disease stabilized had enough tumor shrinkage to qualify for an allogeneic bone marrow transplant and is now in complete remission.

Complete and partial responses also have been seen in the second trial. The phase II trial, which had enrolled 47 patients as of March 1, is not limited to patients with the ABC subtype, and patients with non-ABC subtypes have also responded to treatment with ibrutinib. (The researchers will share more complete findings from the trial at a later date.)

This preliminary finding likely means that tumor growth in some patients with non-ABC subtypes of DLBCL is driven at least in part by overactive BCR signaling, Dr. Staudt added.

“It’s hard to overstate the significance of seeing tumor shrinkage in patients who have never responded to any previous treatment,” known as primary refractory disease, said the trial’s principal investigator, Dr. Wyndham Wilson, also of CCR’s Metabolism Branch.

Primary refractory disease is the worst of the worst, so to see responses in these patients is really impressive.

—Dr. Wyndham Wilson

Initial treatments for DLBCL produce remissions in approximately 95 percent of patients. “Primary refractory disease is the worst of the worst,” Dr. Wilson said. “So to see responses in these patients is really impressive.”

The limited side effects of ibrutinib, most often mild nausea and fatigue, are another important finding from the studies.

“We have yet to have a case where we’ve stopped treatment or reduced the dose due to toxicity,” Dr. Wilson continued. “And that’s saying a lot, because many of these patients are fairly sick.”

Future research should include the development of tests to determine which patients have BCR-dependent lymphoma prior to treatment and whether the receptor is being affected during treatment, said Dr. Jonathan Licht of Northwestern University during the meeting’s opening plenary session.

Drs. Staudt and Wilson are continuing their work with ibrutinib. “We’re already discussing strategies for the next trials,” Dr. Wilson said. These are likely to include testing the drug in combination with chemotherapy in patients whose cancer has returned after remission or who did not respond to initial treatment, as well as testing the drug as a first-line treatment.

Carmen Phillips

Cancer Research Highlights

Drawbacks of Adding MRI to Mammography Plus Ultrasound May Outweigh Benefits

Adding ultrasound or magnetic resonance imaging (MRI) to annual screening mammograms for women with an increased risk of breast cancer and dense breast tissue detects more new breast cancers than mammography alone but also results in more false-positive findings, according to results of a multicenter clinical trial. Findings from the ACRIN 6666 trial, which was co-sponsored by NCI’s Cancer Imaging Program and the Avon Foundation for Women, will be published April 4 in JAMA.

More than 2,800 women with dense breasts and at least one other risk factor for breast cancer, such as a personal history of breast cancer, consented to undergo three annual screens with mammography plus ultrasound. After three rounds of screening, 703 women underwent an MRI. Complete data were available for 612 of these women.

Researchers found that adding ultrasound to mammography increased breast cancer detection by an average of 3.7 cases per 1,000 women screened after the second and third rounds of annual screening. The majority of cancers detected only by ultrasound were node-negative invasive cancers. Until now, it had been unclear whether continuing annual ultrasound screening would detect more cancers.

Although the risk of false-positive results with annual screening ultrasound was lower in the second and third screens than in the first screen, the addition of ultrasound led to an increased rate of biopsies, with about 5 percent of women in the second and third screening rounds having a biopsy—only 7.4 percent of which revealed cancer.

Adding a single MRI further increased cancer detection to a rate of 14.7 cases per 1,000 women screened. Of the women screened with MRI, 7 percent had a biopsy only because of the MRI, of whom 19 percent were found to have cancer. The number of screens needed to detect one cancer was 127 for mammography, 234 for supplemental ultrasound, and 68 for supplemental MRI.

Although MRI was better at detecting cancer than mammography plus ultrasound, women found it less tolerable. The authors also noted that the rate of cancers found between screenings because of a palpable lump or other breast change was low and that all of these cancers were node negative at diagnosis. Thus, they said, “it is unclear that the added cost and reduced tolerability of screening MRI are justified in women at intermediate risk for breast cancer in lieu of supplemental screening with ultrasound.”

“Despite its higher sensitivity, the addition of screening MRI rather than ultrasound to mammography in broader populations of women at intermediate risk with dense breasts may not be appropriate, particularly when the current high false-positive rates, cost, and reduced tolerability of MRI are considered,” the authors concluded.

See also: “Mammography Plus Breast Ultrasound Yields Mixed Results

Ultrasound-Guided Breast-Conserving Surgery May Reduce Need for Further Surgeries

Using ultrasound to guide the surgical removal of tumors from women with palpable breast cancer is significantly better than the standard approach in ensuring that all cancerous tissue is removed while minimizing the removal of healthy tissue, a new study shows. The results, from a Dutch randomized, controlled clinical trial, were presented March 23 at the Eighth European Breast Cancer Conference, in Vienna, Austria.

If confirmed in other trials, the ultrasound-guided approach could become standard practice.

Breast-conserving surgery for palpable breast cancer is generally performed with guidance from [the] surgeon’s palpation only,” lead investigator Dr. Nicole Krekel of VU University Medical Center in Amsterdam said in a news release. Unfortunately, she noted, the standard approach “is associated with a high rate of margins that contain cancer cells, as well as the excision of excessively large volumes of tissue.” If a pathologist finds that tumor cells are still present at the site of surgery, additional surgery is usually needed to eliminate cancerous tissue and reduce the risk of local recurrence.

Dr. Krekel and her colleagues randomly assigned 124 patients with palpable early-stage breast cancer to either ultrasound-guided surgery or palpation-guided surgery. They found that only 3.3 percent of the margins in the ultrasound-guided surgery group contained cancer cells, compared with 16.4 percent in the palpation-guided surgery group. They also found that less healthy tissue was removed in the ultrasound-guided surgery group.

Using ultrasound enables surgeons to see all around the tumor during surgery and to position the incision on the breast optimally, Dr. Krekel explained.

“If we get the same results in the United States, and these results can be incorporated into community practice, it will spare many women unnecessary re-excision surgery,” said Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI’s Division of Cancer Treatment and Diagnosis.

See also: “Additional Surgery after Breast-Conserving Surgery Varies Widely

Also in the Journals: Methylation Levels in HPV DNA May Indicate Risk for Cervical Precancer

A new study suggests that human papillomavirus (HPV) DNA methylation levels could be used as a biomarker to predict which cervical HPV infections are most likely to progress to cervical precancer.

Using samples from some women in the Costa Rica HPV Vaccine Trial, Dr. Lisa Mirabello of NCI’s Division of Cancer Epidemiology and Genetics and her colleagues measured methylation levels at several sites of the genome of HPV 16, the HPV type that causes the majority of cervical cancers and precancers. Women with high methylation levels were at greater risk for persistent infection and cervical precancer than women who cleared the virus within 2 years.

The authors of the study, published March 23 in the Journal of the National Cancer Institute, are conducting follow-up studies to confirm their findings.

Anal HPV Infections and Precancerous Lesions Are Common in Men Who Have Sex with Men

A large percentage of men who have sex with men (MSM) have anal human papillomavirus (HPV) infections and anal precancerous lesions, according to a meta-analysis of data from more than 50 studies. The rate is even higher among those infected with the human immunodeficiency virus (HIV). The findings were published online March 23 in Lancet Oncology.

MSM are known to be at elevated risk for developing HPV-associated anal cancer, but because of a lack of data it has been unclear whether anal cancer screening would be beneficial in this subgroup. Dorothy A. Machalek of the University of New South Wales in Sydney, Australia, and her colleagues examined 53 studies published before November 2011 to determine the frequency of HPV infections, anal lesions, and anal cancers in HIV-negative and HIV-positive MSM.

The researchers estimated that nearly three-quarters of HIV-positive MSM are infected with high-risk HPV types, which can cause cancer. In contrast, 37 percent of HIV-negative MSM were infected with the same high-risk types.

Moderate and severe anal lesions were detected in 29.1 percent of HIV-positive and 21.5 percent of HIV-negative MSM. The overall incidence of anal cancer in these two groups was 46 per 100,000 HIV-positive MSM and 5 per 100,000 HIV-negative MSM.

Using these data, the researchers estimated that, each year, high-grade lesions progress to anal cancer in 1 of 600 HIV-positive MSM and in 1 of 4,000 HIV-negative MSM. These progression rates are much lower than those seen for high-grade cervical lesions, which progress to cervical cancer in 1 of 80 women with those lesions every year, suggesting that anal cancer screening in MSM may need to be approached differently than cervical cancer screening.

However, in an accompanying editorial, Dr. Nicolas Wentzensen of NCI’s Division of Cancer Epidemiology and Genetics pointed out that progression rates for cervical cancer and anal cancer may not be directly comparable. The researchers “were not able to differentiate between moderate and severe dysplasia,” said Dr. Wentzensen. “The progression models in the cervix are based only on severe dysplasia. If we also included moderate dysplasia in the cervix, we might find similarly lower progression rates.”

The researchers and editorialist agree that more research is needed before anal cancer screening is recommended as part of standard clinical care for MSM. “There needs to be a lot of standardization and better appreciation for how [screening] methods perform and how the treatment triggered by those findings affects men,” said Dr. Wentzensen. “That is very important data to obtain before implementing widespread screening.”

Olaparib Delays Progression of Ovarian Cancer after Initial Treatment

Long-term therapy with the targeted drug olaparib significantly improved progression-free survival among women with the most common type of ovarian cancer in a randomized, placebo-controlled phase II clinical trial. The interim findings were published online March 27 in the New England Journal of Medicine.

The trial included 265 women with relapsed, high-grade serous ovarian cancer who had responded to previous treatment with platinum-based chemotherapy. Patients were randomly assigned to receive either olaparib, a drug that blocks a DNA-repair protein called PARP, or a placebo.

Women who received olaparib experienced a median progression-free survival of 8.4 months, compared with 4.8 months for those who received the placebo. Patients in the olaparib group had a lower risk of disease progression after researchers took into account factors including BRCA gene mutation status, age, ancestry, and previous time to progression. Side effects were more common among women who received olaparib, but most of these were mild to moderate; few patients stopped therapy because of side effects.

The improvement in progression-free survival did not lead to improved overall survival. In an interim analysis, overall survival was virtually identical between the olaparib and placebo groups, at 29.7 months and 29.9 months, respectively.

Ovarian cancer usually responds to platinum-based combination chemotherapy, and if the disease returns, it may respond again to another platinum-based chemotherapy regimen. However, responses to subsequent courses of chemotherapy tend to be short-lived, explained the authors, who were led by Dr. Jonathan Ledermann of the University College London Cancer Institute.

This trial is one of several recent studies investigating whether maintenance therapy can help improve control of ovarian cancer. Researchers have found that maintenance therapy with either extended chemotherapy or the targeted agent bevacizumab may help delay cancer recurrence. Olaparib was recently found to induce tumor responses in women with recurrent, high-grade serous ovarian cancer or ovarian cancer associated with a BRCA1 or BRCA2 mutation. 

The results from the current study show that “maintenance treatment with olaparib [is] associated with a significant improvement in progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer,” the authors wrote. Furthermore, the authors noted that 21 percent of patients were still receiving the drug at the time of writing, which “indicates that the disease is controlled for a prolonged period in some patients,” they concluded.

“This is an important gain for ovarian cancer patients,” commented Dr. Elise Kohn of NCI’s Center for Cancer Research. “The doubling in time to progression with olaparib is an exciting observation and should be the stimulus for further olaparib-based studies.”

See also: “Drug that Inhibits DNA-Repair Enzyme Shrinks Some Breast and Ovarian Tumors

Transplant Recipients at Higher Risk of Aggressive Form of Lymphoma

Recipients of solid organ transplants are about 14 times more likely than the general population to develop diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin lymphoma (NHL). This finding and additional data from a comprehensive study of risk factors for this NHL subtype in transplant recipients were presented at the 2012 American Association for Cancer Research annual meeting.

Transplant recipients are known to be at increased risk for cancer, due in part to the immunosuppressive therapies they receive to prevent organ rejection. “NHL is one of the most common cancers diagnosed among transplant recipients, and there are many distinct histological types that are likely to have different causes,” explained the study’s senior investigator Dr. Lindsay Morton of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “Previous studies have looked at NHL, but have lacked the large number of patients or the detailed information needed to determine risk factors for NHL subtypes across all solid organ transplants.”

Dr. Todd Gibson of DCEG led the analysis using data from the Transplant Cancer Match Study, which links the Scientific Registry of Transplant Recipients with 14 population-based cancer registries. He and his colleagues identified 948 cases of DLBCL from among more than 175,000 transplant recipients. The risk of DLBCL was greater for younger transplant recipients, those who received a lung or pancreas transplant, and those who tested negative for the Epstein-Barr virus at the time of their transplant.

“Organ transplants are necessary and often life-saving treatments,” said Dr. Gibson. “But our work shows that these patients are at greatly increased risk for this particular subtype of lymphoma. We hope that our work can play a role in identifying the subgroup of people within the transplant population that is at greatest risk and can help inform efforts for surveillance and possibly prevention.”

Additional analyses are examining other risk factors for DLBCL in transplant recipients, including immunosuppressive medication use.

Some Melanoma Cells May Use the Body's Immune Response to Escape Destruction

Researchers have found evidence that some melanomas may use a protein induced by T cells—a type of immune cell that can attack cancer cells—to evade the immune system. The retrospective study involving tumor samples from 150 patients suggests that this protein, called B7-H1, suppresses T cells, ultimately preventing the immune system from destroying the cancer cells.

Treatments that block the B7-H1 pathway may, therefore, benefit patients with melanomas that express this protein, wrote Dr. Janis Taube of the Johns Hopkins Medical Institutions and her colleagues in a study published March 28 in Science Translational Medicine.

Almost 40 percent of the tumor samples expressed B7-H1, and expression of B7-H1 was strongly associated with the presence of tumor-infiltrating lymphocytes. Previous studies had shown that the immune-system protein interferon-gamma (IFN-gamma) induces B7-H1 expression in melanoma, and the Hopkins researchers found IFN-gamma in the B7-H1-positive tumors where the tumor cells came into contact with tumor-infiltrating lymphocytes.

The researchers then examined outcomes in patients with metastatic melanoma and found that overall survival was longer in patients with B7-H1-positive tumors than in those with B7-H1-negative tumors. This may be because B7-H1 expression indicates the presence of an active antitumor response that initially fends off cancer before it is turned off by the melanoma cells.

Monoclonal antibodies that target B7-H1, which may help restore the immune system’s recognition of melanoma cells, are being tested in clinical trials.

A Conversation With

A Conversation with Dr. Bert Vogelstein about Whole-Genome Sequencing to Predict Cancer Risk

Dr. Bert VogelsteinDr. Bert Vogelstein

Johns Hopkins researchers have used mathematical models based on clinical data from identical twins to test the ability of genomic testing to predict risk for 24 common diseases, including cancer. Dr. Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University and an investigator with the Howard Hughes Medical Institute, recently spoke with the NCI Cancer Bulletin about the research, which was published April 2 in Science Translational Medicine.

What was the goal of your study, and what did you learn?

Our goal was to provide a realistic interpretation of what the public can expect to obtain from whole-genome sequencing at some point in the future, in the best circumstances, assuming that the technology will be developed that enables us to fully interpret all of the sequencing information. One question we asked was: In this best possible case, what would whole-genome sequencing achieve for the average individual?

Our results suggest that more than half of people who undergo whole-genome sequencing could, in this best-case scenario, obtain results indicating that they have an increased genetic risk for one or more diseases.

However, most individuals will receive negative test results for most diseases, including most cancers, meaning that they have less than a 10 percent risk of developing those diseases. Therefore, whole-genome sequencing will generally not predict exactly what diseases they will get or what diseases they will die from.

What do your findings mean specifically for estimating cancer risk?

As one example, we estimate that as many as 2 percent of women who have a whole-genome sequencing test could get a positive result for ovarian cancer, which would mean that they have a more than 10 percent risk of developing ovarian cancer, several times higher than the risk of the average woman.

Whole-genome sequencing will not alleviate the need for effective cancer prevention and early detection measures.

On the other hand, 98 percent of women tested would get a negative whole-genome test result. This would not mean that they have no risk for developing ovarian cancer; it would simply mean that they have a level of risk similar to that of the general population and of most women who had not been tested. That’s because most ovarian cancers, and most cancers generally, are caused not by hereditary genetic alterations but by genetic alterations acquired after birth and caused by a combination of environmental influences and random events.

One of the implications of this study is that whole-genome sequencing will not alleviate the need for effective cancer prevention and early detection measures, which we already know can reduce cancer incidence and death. Equally important, we need more research to find better ways to prevent cancer or to detect it early.

What could people who have a positive result on a test, such as the one for ovarian cancer, do with that information?

[Patients] could get the best available surveillance, including ultrasound and gynecological exams to detect cancer as early as possible. And, hopefully, future research will result in more sophisticated and sensitive tests for detecting cancers early.

There are also environmental factors at play. Obesity is a risk factor for ovarian cancer, for example, and women at increased risk for this disease would certainly want to avoid that.

It’s been suggested that people would be better off spending their money on a gym membership than on genome sequencing. What do your results say about that line of thinking?

Our position is that the more knowledge individuals have, the better informed they will be, and the better the choices they will make. They may look at our data and decide that, for most diseases, whole-genome sequencing is not really going to be much help to them, but they know for a fact that getting more exercise will reduce their risk for several diseases, so they will choose to spend their money on the gym membership.

Another person may say, “My mother died of ovarian cancer, and if I’m at high risk, I want to know about it.” That person might want to buy both the gym membership and the genome-sequencing test. Someone else may say, “Knowing I have a slightly increased risk for some diseases is going to wreak havoc on my psyche, and it’s not worth it.”

I would not make that decision for anyone; like all health care decisions, it is extremely personal. I simply hope that our data will help medical professionals and others involved in health care inform their patients about what this technology can and can’t do.

What was your rationale for doing this study now?

This study evolved from our previous research. One of our goals is to try to understand the basis for familial cancers. In 2009, Alison Klein, Ralph Hruban, Sian Jones, and other members of our group reported on a family with familial pancreatic cancer not caused by a mutation in any of the genes known at that time to be involved in this disease.

Through genome-wide sequencing, we identified a heritable mutation in a gene called PALB2 in this family. This was the first time genome-wide sequencing had been used to identify the basis for a hereditary disease. Since then, a number of studies have identified the value of genome-wide sequencing for identifying the genetic basis of diseases in families.

So we began to wonder: If we could do this in families with a clear predisposition for cancer, could it be done for everybody? As whole-genome sequencing becomes less expensive, this becomes feasible. A few years ago it cost about $50,000 to sequence all of the approximately 20,000 genes in a human cell. Now it can be done for less than $5,000, and a few years from now the cost will be less than $1,000. We began to wonder about the public health implications and the value this might have for consumers.

What are the biggest caveats to note about this study?

The main caveat is that we’re not talking about what’s possible now but about what might be possible at some time in the future. Any perceived value of this approach [to learning about genetic risk] should be tempered by the realization that we’re not there yet.

Much of your cancer data was obtained from Scandinavian twin registries. Would the results have been different if you had looked at people of other ethnicities?

From other studies, and given what we know about cancer, I don’t think the generalities would be different. You can’t change the genes people are born with. You can change their environment, but with cancer, random influences play a large role. In different populations, you would find slightly different results, but we believe that the general conclusions would stand.

What are the implications for public health?

The best possible finding for a study like ours would be that a large part of the screened population [that test positive] might be at high risk for cancer and, conversely, that those who didn’t test positive would have a very low risk. In that scenario, we might have been able to recommend that prevention and surveillance measures be concentrated on individuals at increased risk.

But this study and earlier studies show that individuals at high genetic risk account for only a minority of those who will die of cancer, so the public health implications of whole-genome sequencing are not as strong as we might have wished for.

—Interviewed by Eleanor Mayfield

Special Report

U.S. Cancer Deaths Continue Steady Decline

According to the latest data on nationwide death rates from cancer, overall mortality from cancer declined from 1999 to 2008, maintaining a trend seen since the early 1990s. Mortality fell for most cancer types, including the four most common types of cancer in the United States (lung, colorectal, breast, and prostate), although the rate of decline varied by cancer type and across racial and ethnic groups. The complete Annual Report to the Nation on the Status of Cancr, 1975–2008 appeared March 28 in Cancer.

Graph showing male and female cancer death rates, 1975-2008

NCI, the American Cancer Society, the Centers for Disease Control and Prevention (CDC), and the North American Association of Central Cancer Registries (NAACCR) collaborated on the report. Cancer incidence data came from NCI’s Surveillance, Epidemiology, and End Results (SEER) database and from the CDC, with analyses of pooled data by NAACCR. Mortality data came from the CDC’s National Center for Health Statistics.

The declines in cancer death rates (mortality) averaged 1.7 percent per year for men and 1.3 percent per year for women from 1999 through 2008.

Among men, the overall rate of new cancer cases (incidence) fell by an average of 0.6 percent annually from 1999 to 2008. Among women, incidence dropped by an average of 0.5 percent annually from 1999 to 2006 but held steady from 2006 to 2008.

Cancer incidence in children ages 0 to 14 rose from 1999 to 2008 (by 0.5 percent a year), continuing a trend seen in previous Annual Reports to the Nation. However, advances in treatment contributed to a steady decline in mortality rates for children with cancer in the last 5 years (an average of 2.8 percent per year).

“Steady progress, as measured by declines in cancer death rates for many cancers, is good because we have an aging, growing population,” said Dr. Brenda K. Edwards, NCI’s senior advisor for surveillance. “While the number of people diagnosed with cancer or who die of the disease may be increasing, the decline in cancer death rates for more than a decade is the best indicator of progress due to prevention, screening, diagnosis, and treatment,” she added.

Not All Good News

There were some notable exceptions to the overall decreases in incidence and mortality. From 1999 to 2008, death rates rose for pancreatic cancer in men and women, for liver cancer and melanoma in men, and for endometrial cancer in women. The cervical cancer death rate, which had been falling for decades, showed no further decrease over the last 5 years.

And, although incidence rates fell overall for men and women from 1999 to 2008, the decline was not distributed evenly across racial and ethnic groups. Cancer incidence rates did not decrease significantly among American Indian/Alaska Native men and women combined or among black, Asian and Pacific Islander, and American Indian/Alaska Native women. 

Although incidence rates in black men did decline, this group still had the highest cancer incidence rate of any racial and ethnic group, 15 percent higher than that of white men and nearly double that of Asian and Pacific Islander men.

Major Modifiable Risk Factors

Chart showing all cancer death rates by time period and race/ethnicity

Each Annual Report to the Nation includes a special feature that focuses on a topic of importance to the cancer research community and the public. This year's report featured an analysis on the contribution of excess weight (overweight and obesity) and insufficient physical activity to the nation’s cancer burden.

More than 60 percent of the U.S. adult population is estimated to be overweight or obese, and a similar percentage of adults do not get the recommended amount of physical activity. The rates of insufficient physical activity are even worse for children; for example, up to 90 percent of high school girls do not engage in recommended levels of physical activity.

Excess weight “is a major modifiable risk factor for cancer and other diseases—probably second only to tobacco use in terms of its impact on cancer incidence and mortality,” said Dr. Edwards. “The risk may be modest but it’s so pervasive that we felt this was the time to look at [cancer] incidence in this context.” Physical inactivity not only contributes to excess weight but is itself a risk factor for several cancer types.

The report was not designed to quantitatively link the trends in excess weight and lack of physical activity to the national trends for cancer, explained Dr. Rachel Ballard-Barbash, associate director of the Applied Research Program in NCI’s Division of Cancer Control and Population Sciences. Many other studies have shown convincing links between excess weight and several cancer types, including endometrial, postmenopausal breast, colorectal, kidney, esophageal, and pancreatic cancer.

The point of the special feature, she noted, “is to highlight specific types of cancer that are related to [excess weight and lack of sufficient physical activity], show how these behaviors relate to these cancers in terms of their relative risks, and briefly describe some of the mechanisms by which they relate.” The special feature also highlights national- and state-level prevention strategies in policy and environmental change that are intended to help people achieve recommended changes in their diets and physical activity levels.

As the nation’s weight has risen, so has the incidence of some, although not all, types of cancer related to excess weight and lack of sufficient physical activity. From 1999 to 2008, incidence rates of kidney cancer and of adenocarcinoma of the esophagus each rose about 3 percent per year for men and women, while incidence of pancreatic cancer rose 1.2 percent per year among men and women.

NCI Cancer Bulletin special issue on obesity and cancer research

In addition, incidence rates of endometrial cancer rose significantly among black, Asian and Pacific Islander, and Hispanic women. Incidence of postmenopausal breast cancer stabilized from 2005 to 2008, after a period of decline.

“Although all of these cancers are influenced by multiple factors, the high prevalence of excess weight and insufficient physical activity likely contributed to these observed increases and to the lack of decline in breast cancer,” the authors wrote. “Continued progress in reducing cancer incidence and mortality rates will be difficult without success in promoting healthy weight and physical activity, particularly among youth.”

Excess weight and lack of physical activity also influence cancer survivorship, explained Dr. Ballard-Barbash, as both can negatively affect outcomes after a cancer diagnosis, further increasing the need for these risk factors to be addressed on a personal and societal level.

Sharon Reynolds

Spotlight

Drugs Target Epigenetic Changes to Reprogram Cancer Cells

Research results presented at the 2012 American Association for Cancer Research (AACR) annual meeting offer new insights into an emerging treatment approach for cancer, known as epigenetic therapy. Rather than killing cancer cells by damaging their DNA or disrupting vital communication pathways, epigenetic therapy attempts to change the behavior of cancer cells by blocking chemical changes to DNA, including a process called methylation that turns genes on or off.

A DNA molecule that is methylated on both strands on the center cytosine. (Image by Christoph Bock, Max Planck Institute for Informatics)When chemical tags called methyl groups attach to a DNA molecule, genes can be turned on or off. DNA methylation plays an important role in gene regulation in cancer. (Image by Christoph Bock, Max Planck Institute for Informatics)

The concept behind epigenetic treatment is to “reprogram” the network of chemical changes that affect the DNA of cancer cells, explained Dr. Jean-Pierre Issa of the Temple University School of Medicine in Philadelphia. This reprogramming can alter the activity of critical genes in cancer cells that drive their growth and survival. The treatments, Dr. Issa said, “can effectively reset DNA methylation.”

Dr. Issa led the first trial in humans to test an investigational epigenetic drug called SGI-110, which is a modified form of a methylation-blocking drug called decitabine (Dacogen). SGI-110 is more stable than decitabine, which may allow for prolonged exposure to the drug. Decitabine is approved by the Food and Drug Administration (FDA) to treat myelodysplastic syndrome (MDS), a precursor to leukemia.

Dr. Issa’s lab and researchers at Astex Pharmaceuticals collaborated to develop SGI-110, with funding from the Stand Up To Cancer initiative.

Sixty-six patients with MDS or acute myelogenous leukemia (AML) were enrolled in the trial, which tested a series of doses in two treatment schedules of SGI-110. Two patients with AML whose disease had returned after previous treatments had complete responses, and one had a partial response, Dr. Issa reported at the meeting. The patients who had complete responses had the greatest decrease in methylation and the highest levels of the drug in their circulatory system.

Treatment was generally well tolerated, with only moderate side effects. The lack of side effects makes sense, Dr. Issa explained, because “cancer cells are much more reliant on DNA methylation for survival than normal cells.”

One of the dosing regimens inhibited DNA methylation more effectively than the other, he noted, so future trials will use that dosing regimen.

Giving Cancer Cells a New Memory

Dr. Stephen Baylin of the Johns Hopkins University Kimmel Cancer Center presented findings at the AACR annual meeting from a laboratory study of decitabine and another methylation blocker, azacitidine (Vidaza). (The findings were also published March 20 in Cancer Cell.) Azacitidine is also FDA approved for the treatment of MDS.

Dr. Baylin’s team found that low doses of the drugs had antitumor effects in cell lines and in mouse models of different cancer types—including leukemia and breast and colon cancer. Post-treatment analyses of treated cells showed decreased DNA methylation and the reactivation of genes that can affect tumor growth and cell death.

The concept behind epigenetic treatment is to "reprogram" the network of chemical changes that affect the DNA of cancer cells.

The study—which Dr. Cynthia Zahnow co-led and NCI, Stand Up To Cancer, and other groups helped fund—was not necessarily designed to assess the anticancer affects of the drugs, explained Dr. Baylin, but to better understand the epigenetic effects of low-dose treatment.

The cells were treated with the drugs for only 3 days, he noted. Next, the cells were “rested for 1 to 2 weeks, and then we put them into the mice to see what the cells ‘remembered’” in terms of gene activity that influenced their behavior. Tumor growth was substantially inhibited in mice that received the treated cells compared with mice that received untreated cells, implying that the demethylating drugs had produced a “memory” antitumor response.

The drugs, Dr. Baylin continued, also appear to alter gene activity in stem cell-like cancer cells—cells that are capable of self-renewal and that studies have suggested are inherently resistant to most current therapies.

Azacitidine and decitabine were tested extensively in the 1970s and 1980s but were too toxic for patients at the high doses needed to rapidly kill cancer cells. The FDA approved much lower doses of the drugs to treat MDS, however. Low doses of the drugs have also shown efficacy in some patients with AML. Although neither drug is FDA approved for AML, some doctors are using them off-label to treat the disease, Dr. Issa said.

Dr. Baylin believes that these new findings suggest that low-dose azacitidine and decitabine may be of benefit in multiple cancers. He also presented updated results from an early-phase trial (initially reported last year) of low-dose azacitidine combined with entinostat, another epigenetic drug, for patients with advanced lung cancer. Several patients have had strong tumor responses, he reported, some of which continued even after treatment was stopped.

A number of patients in the trial, many of whom had already received multiple prior therapies, “are going on to subsequent therapies,” Dr. Baylin said, “and we have started to see some very robust responses.”

For example, four patients with advanced lung cancer who participated in the azacitidine/entinostat trial at Johns Hopkins went on to receive one of two investigational immunotherapy drugs called anti-PD1 and anti-PD-L1. Both drugs target molecules involved in blocking immune responses to tumors. Dr. Suzanne Topalian of the Johns Hopkins University Kimmel Cancer Center reported at an AACR plenary session that 3 of the 4 patients have had objective tumor responses. 

A Maturing Field of Research

Although epigenetically directed therapy shows promise, there are still many unknowns, stressed Dr. Kornelia Polyak of the Dana-Farber Cancer Institute. Even though the clinical trial and the study found evidence of DNA demethylation, “it could be much more complex than that,” Dr. Polyak said.

The drugs may be having other effects, she continued. Epigenetic therapies may affect the structure of chromatin, the complex of DNA and proteins that forms chromosomes, which could cause side effects over a long period. In patients with advanced cancer, who have few treatment options, this may not be a significant concern, she noted. “But as we push these agents forward into earlier disease, it’s something we’ll need to look at very carefully,” Dr. Polyak said.

But from a clinical standpoint, she continued, demethylating agents are attractive “because even short-term treatment can have long-term effects. We’ve already seen that in MDS.”

“The field is maturing nicely,” Dr. Issa said. But more work is needed. “The [demethylating] drugs we have don’t cure patients, and we’re seeing resistance to these drugs develop.”

Dr. Baylin and Dr. Issa’s groups are studying DNA demethylating drugs in other cancer types and in combination with other therapies. “One of the biggest things we’re seeing is that these drugs are priming patients for better responses to subsequent therapies,” Dr. Baylin said.

Carmen Phillips

Featured Clinical Trial

Virus Therapy for Extensive-Stage Small Cell Lung Cancer

Name of the Trial
Phase II Randomized Study of Seneca Valley Virus-001 (NTX-010) after Platinum-Based Chemotherapy in Patients with Extensive-Stage Small Cell Lung Cancer (NCCTG-N0923). See the protocol summary.

Dr. Julian MolinaDr. Julian Molina

Principal Investigator
Dr. Julian Molina, North Central Cancer Treatment Group

Why This Trial Is Important
Lung cancer is the leading cause of cancer death in the United States. Although about 85 percent of lung cancer cases are non-small cell lung cancer, more than 30,000 people are diagnosed with small cell lung cancer each year in the United States. Small cell lung cancer is the most aggressive type of lung cancer, with 5-year survival rates ranging between 5 percent and 15 percent. The most important prognostic factor is the extent of disease, that is, whether it is limited stage or extensive stage. Unfortunately, about two-thirds of patients have extensive-stage disease at diagnosis.

Combination chemotherapy, in which a platinum drug is paired with one or two other drugs (often etoposide), is the cornerstone of treatment for patients with extensive-stage small cell lung cancer. Although many patients initially respond to treatment, the disease almost always returns. Consequently, the likelihood of long-term survival for these patients is exceptionally low. New treatment approaches are needed to improve long-term survival of patients with small cell lung cancer.

Seneca Valley virus-001 (also called NTX-010) is an oncolytic virus that was originally discovered as a contaminant in cell cultures. In preclinical experiments, the virus was found to readily infect, replicate in, and kill cancer cells with neuroendocrine features (including small cell carcinomas) but was not toxic to normal cells.

These studies led to a phase I dose-escalation trial in patients with small cell carcinomas and carcinoid tumors. The six patients in the study with small cell cancers (five of whom had small cell lung cancer) were all treated at the lowest dose. Nevertheless, the researchers found evidence of viral infection in three of the six patients with small cell cancer, including one who experienced stable disease for 10 months and was still alive more than 3 years after treatment.

In this clinical trial, patients with extensive-stage small cell lung cancer who have received platinum-based chemotherapy will be randomly assigned to receive Seneca Valley virus-001 intravenously or an intravenous placebo. Patients with previously untreated disease are eligible for the trial, but they must undergo four to six cycles of a platinum-based chemotherapy regimen and then be assessed for response. Patients with stable disease or a response will be randomly assigned to treatment or placebo. Patients participating in the study may also undergo two rounds of prophylactic cranial irradiation. The primary objective is to compare progression-free survival between the two groups. The investigators will also compare overall survival and assess adverse events, response rates, and quality of life.

“Our study is aimed at patients who have received first-line chemotherapy for extensive-stage small cell lung cancer; we’re randomizing them on a one-to-one basis to receive either the virus at the highest dose tested in the phase I study or a placebo,” said Dr. Molina. “It’s important that we compare the virus treatment to what you normally do for patients in this situation, which is nothing.”

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

Senate Appropriations Hearing Highlights NCI's Provocative Questions Project

Senate appropriators commended NCI for the Provocative Questions Project (PQ) at a March 28 hearing before the Senate Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies (Labor-HHS) considering the fiscal year 2013 NIH budget. NCI Director Dr. Harold Varmus joined NIH Director Dr. Francis Collins and several other NIH institute and center directors at the hearing.

The hearing showcased bipartisan support for NIH and the nation’s biomedical research enterprise while also recognizing current budget constraints. Senator Richard Shelby (R-AL) commented on the need for “out-of-the-box thinking” to address those constraints and recognized PQ as an important example, saying, “This project shows that there are innovative ways to energize the research community, even when budgets are constrained.”

Dr. Varmus explained, “[PQ] is an initiative that solicited over 750 applications to study these deeper questions and empowered the scientific community to help us define what needs to be answered in the future.”

Subcommittee Chair Senator Tom Harkin (D-IA) asked Dr. Varmus to outline NCI’s strategies for continued progress during difficult fiscal times. Dr. Varmus identified a number of steps that NCI is taking. “We have been looking very carefully, for example, at grants that get lower priority scores that meet high-priority topics to make sure those get funded. We’ve been reorganizing our Clinical Trials Cooperative Groups to be sure they operate effectively and are answering deep scientific questions,” he said.

Senator Mark Pryor (D-AR), a clear cell sarcoma survivor, asked Dr. Varmus to speak about NCI’s pancreatic cancer research portfolio and efforts to prioritize this research. Dr. Varmus emphasized that pancreatic cancer research is a priority for the institute, saying, “We have a much larger number of investigators working on the disease, and we have scientific opportunities that are very dramatic. …As a result, over the course of the last decade, the amount of money NCI spends on this disease—despite a flattening of our budget—has gone up about 300 percent.”

Dr. Varmus further described the NCI priority-review process for cancers that have seen less progress in treatment, citing as examples pancreatic, lung, and ovarian cancers, as well as glioblastoma. He also recognized the role of advocacy organizations in encouraging an increased focus on pancreatic cancer, particularly by providing incentives to NCI-supported investigators to pursue this challenging area of research.

The complete witness list, webcast, and testimony are available on the subcommittee’s website.

Dr. Varmus also appeared with Dr. Collins at the March 20 hearing before the House Appropriations Labor-HHS Subcommittee, which focused on NIH’s National Center for Advancing Translational Sciences. The House hearing was not webcast, but the witness list and testimony are available on the committee’s website.

For more information on NCI appropriations, cancer-specific legislation, recently enacted public laws, and other legislative resources, visit the NCI Office of Government and Congressional Relations website.

FDA Update

FDA Takes Action under the Tobacco Control Act of 2009

On March 29, the Food and Drug Administration (FDA) released two draft guidance documents intended to provide the public with accurate information about the chemicals in tobacco products and to help prevent misleading marketing by the tobacco industry. The documents are part of the FDA’s implementation of the Family Smoking Prevention and Tobacco Control Act of 2009.

“We are committed to stopping…practices that may cause people to start or continue using tobacco products that could lead to preventable disease and death,” said FDA Commissioner Dr. Margaret Hamburg in a press release.

The first document provides guidance on how tobacco companies will comply with the requirement to report the amount of harmful and potentially harmful constituents (HPHCs) found in their products. There are more than 7,000 chemicals in tobacco and tobacco smoke. The guidance document establishes a list of 93 HPHCs in tobacco and tobacco smoke and identifies 20 representative HPHCs for which testing methods are well established and widely available.  The FDA intends to focus reporting enforcement on these 20 HPHCs during 2012 and to make information about the HPHCs in specific tobacco products available to the public in a consumer-friendly format by April 2013.

The Tobacco Control Act establishes rigorous scientific criteria that must be met before the FDA can allow a tobacco company to market a product with a claim of “reduced harm.” With this in mind, the second draft guidance document describes the scientific studies and analyses an applicant should submit to the FDA to demonstrate that its product will, or is expected to, significantly reduce harm or exposure to individuals and benefit the health of the population as whole. The “modified risk tobacco product” draft guidance is open for public comment until June 4, 2012.

Notes

Cyber-Seminar Will Explore Measuring the Health of a Community

Dr. Kurt Stange, Terry Allan, and Dr. Paul JarrisDr. Kurt Stange, Terry Allan, and Dr. Paul Jarris

The April 10 Research to Reality (R2R) cyber-seminar will explore tools and resources, such as the County Health Rankings, that can be used to measure the health of a community. Participants will examine ways to measure a community’s health that can stimulate multi-stakeholder engagement and serve as a focus for efforts to improve community health and health equity.

Dr. Kurt Stange of Case Western Reserve University will highlight models used to measure the health of a community and discuss how knowledge generated and followed over time can empower multi-stakeholder groups to work together to improve health, its determinants, and health equity. 

Terry Allan of the Cuyahoga County Board of Health and Dr. Paul Jarris of the Association of State and Territorial Health Officials will share their experiences working across sectors to measure community health at the local and national levels. Participants will be invited to share their experiences and lessons learned and to discuss how other communities can use this approach to improve health and equity.

For more information and to register for this event, visit the R2R website, where you can watch presentations and join discussions. All R2R cyber-seminars are archived on the website approximately 1 week after the presentation. For more information on the cyber-seminar series, please e-mail ResearchtoReality@mail.nih.gov.

Dr. John Potter to Deliver First Schatzkin Lecture in Nutritional Epidemiology

Dr. John PotterDr. John Potter

The inaugural Arthur Schatzkin Distinguished Lecture in Nutritional Epidemiology will be held at 3:00 p.m. on April 16 in Lipsett Amphitheater on the NIH main campus in Bethesda, MD. NCI established this annual lecture to honor the memory of Dr. Arthur Schatzkin, a visionary scientist, mentor, and leader in the field of nutrition and cancer.

Dr. Schatzkin joined NCI in 1984 and served as chief of the Nutritional Epidemiology Branch from 1995 to 2011. He was committed to understanding the role of nutrition in cancer etiology and prevention and was instrumental in addressing major methodological issues of research in nutritional epidemiology. Dr. Schatzkin passed away in January 2011. 

This year's lecturer is Dr. John Potter, member and senior advisor of the Division of Public Health Sciences at Fred Hutchinson Cancer Research Center and professor of epidemiology at the University of Washington. Dr. Potter's research focuses on the role of diet and physical activity in the development of cancer, with a particular emphasis on the epidemiology, biology, early detection, and prevention of colon cancer. The title of his talk is "Nutrition, Environment, Development, and Cancer: Casting a Wider Net."