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November 17, 2009 • Volume 6 / Number 22

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NEWS

Updated guidelines suggest that women ages 50 to 74 who are at average risk for breast cancer undergo a routine screening mammogram every 2 years.Independent Task Force Updates Recommendations on Breast Cancer Screening

Yesterday, the United States Preventive Services Task Force updated recommendations on breast cancer screening, suggesting that women ages 50 to 74 who are at average risk for getting the disease undergo a routine screening mammogram every 2 years. The recommendations were published in the November 17 Annals of Internal Medicine. Read more > >

COMMENTARY

Dr. Eric J. (Rocky) Feuer

Guest Director's Update: Modeling for Research Success

by Dr. Eric J. (Rocky) Feuer

NCI's Cancer Intervention and Surveillance Modeling Network (CISNET) is a large coordinated program that uses complex, multi-cohort modeling to better understand at the population level the impact of both existing and emerging cancer control interventions—whether they are screening modalities or drug therapies or a multi-modal approach to smoking cessation—on trends in cancer incidence and mortality. Nine years since CISNET was launched, this innovative program is providing important insights on the prevention, diagnosis, and treatment of the four most common cancer types: prostate, lung, colorectal, and breast. Read more > >

A MESSAGE TO READERS

Special Issue on Training

Don’t miss our December 1 special issue on training, which will highlight important resources available through NCI’s intramural and extramural programs to help prepare the oncology workforce for the future.

NCI Cancer Bulletin special issues are some of the most popular among our readers. Past special issues have focused on personalized drug development, cancer imaging, and bioinformatics.

IN DEPTH

UPDATES

  • FDA Update

    • New Treatment for Rare Skin Cancer Approved by FDA

    Cancer.gov Update

    • NCI Web Site Consolidates Supportive and Palliative Care Information

    Notes

    • NCI's Radiation Biology Branch Chief Honored with ASTRO Fellowship
    • NIH to Host "Drug Repositioning" Conference Next Month
    • 2009 NCI Translational Science Meeting Held
    • President's Cancer Panel Explores Genetic Differences in Cancer Burden

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

Independent Task Force Updates Recommendations on Breast Cancer Screening

The U.S. Preventive Services Task Force logo

Yesterday, the United States Preventive Services Task Force (USPSTF) updated recommendations on breast cancer screening, suggesting that women ages 50 to 74 who are at average risk for getting the disease undergo a routine screening mammogram every 2 years. The recommendations were published in the November 17 Annals of Internal Medicine.

“When women are screened every other year instead of every year, you see a large reduction in the harms caused by false-positive screening results, and the reduction in breast cancer mortality remains high—between 70 and 99 percent of what you see with annual screening,” explained Dr. Diana Petitti, vice chair of the USPSTF committee that issued the recommendations. False-positive screening results can cause harms including unnecessary biopsies and emotional distress.

The USPSTF is a panel of independent primary care physicians from around the country that periodically reviews the evidence for preventive health services, including screening, medication, and counseling. The panel’s earlier recommendations for breast cancer screening, last updated in 2002, advised mammography with or without clinical breast exam every 1 to 2 years for women ages 40 and older.

Updated recommendations suggest that women ages 50 to 74 who are at average risk for breast cancer undergo a routine screening mammogram every 2 years. Updated recommendations suggest that women ages 50 to 74 who are at average risk for breast cancer undergo a routine screening mammogram every 2 years.

The new recommendations do not advise routine mammography for average-risk women ages 40 to 49. Instead, they advocate for “individualized informed decision making based on specific benefits and harms for women who consider screening before age 50 years,” noted Dr. Karla Kerlikowske of the San Francisco Veterans Affairs Medical Center in an accompanying editorial.

The updated 2009 recommendations also advise against teaching breast self-exam (BSE). The 2002 recommendations did not advise either for or against teaching BSE, but because no clinical trials to date have shown that widespread teaching of the technique reduces the number of deaths from breast cancer, the task force now recommends against systematic teaching of BSE.

However, explained Dr. Stephen Taplin, senior scientist in NCI’s Division of Cancer Control and Population Sciences’ Applied Research Program (ARP), a recommendation against routine teaching of BSE “certainly does not mean that women shouldn’t respond to lumps and bumps or other troublesome changes in their breasts that they discover on their own. Women should go to their health care provider when they have a concern.”

NCI and Breast Cancer Screening Research

Many questions about breast cancer screening remain unanswered, such as:

  • What are the relative benefits and harms of mammography for women ages 75 and older?
  • Why are interval breast cancers (tumors that are found in between scheduled screening examinations) often more aggressive and deadly?
  • Why do some breast cancers progress quickly while others do not, and can some individual tumors regress even without treatment?
  • Can gene or protein expression patterns of a tumor predict its aggressiveness?

NCI is currently funding many large-scale research projects addressing these questions, including:

The task force based the updated recommendations, in part, on two commissioned evidence reports that synthesized data that had accumulated since the USPSTF’s last revision 7 years ago. One of these was performed by the Oregon Evidence-based Practice Center (EPC) at Oregon Health and Science University and was intended to find and summarize all the high-quality, pertinent studies that could help answer the questions about optimizing breast cancer screening.

To this end, the EPC reviewed new studies and new data from published trials of screening mammography that had been reviewed by the task force in 2002, including the Age trial from the United Kingdom, the only clinical trial to specifically evaluate the effectiveness of screening mammography in women in their 40s. This set of data allowed the task force to more precisely estimate the reduction in deaths from breast cancer with mammography in this age group.

The EPC also analyzed data on more than 600,000 women ages 40 or older that had been collected by the Breast Cancer Surveillance Consortium. These data indicated that false-positive results on a mammogram are most common among women ages 40 to 49.

The second evidence report was prepared by NCI-funded members of the Cancer Intervention and Surveillance Modeling Network (CISNET). For this new study of mammography, six modeling teams examined the hypothetical outcomes of 20 different mammography screening strategies that differed in the ages when screening began and ended and in the number of years between scheduled screenings.

The models developed by these teams showed that screening every other year produced an average of 81 percent of the mortality reduction of yearly screening, but with nearly 50 percent fewer false-positive results. Screening women ages 50 to 69 every other year would provide a median reduction in breast cancer mortality of 16.5 percent compared with no screening. When compared with screening from ages 50 to 69, beginning screening every other year at age 40 produced a small additional reduction in mortality but increased the number of false-positive results by more than 50 percent.

“Everything about breast cancer screening is a trade-off, within the ages for which it has been shown to be beneficial,” explained Dr. Petitti. “All of these lines of evidence indicate that women ages 40 to 49 would have a small improvement in breast cancer mortality but also a large set of harms related to false-positive results.”

“It is important for women to understand that these results come from analyses of women who were drawn from the general U.S. population,” added Dr. Taplin, “and as such, they do not account for all variations in breast cancer risk and do not apply to women at very high risk for breast cancer.”

—Sharon Reynolds

Cancer Research Highlights

New Drug Blocks "Undruggable" Target in Cancer Cells

Researchers have created a new type of cancer drug that blocks a “master” protein considered to be untouchable by conventional agents. A team from Harvard University used the drug to suppress signals from a growth-promoting pathway, the Notch signaling pathway, that switches on inappropriately in some cancers. Cancer cells that depend on Notch signaling die when the pathway is blocked, Drs. Gregory L. Verdine, James Bradner, and their colleagues reported in the November 12 Nature.

The drug’s primary target is Notch1, a transcription factor that regulates genes involved in the growth and survival of cells. Transcription factors are mutated in various cancers, but these proteins have proved difficult to target directly because of their structures.

To solve this problem, the Harvard team, led in the lab by graduate student Raymond Moellering, designed a drug molecule (called SAHM1) that enters cells and interferes with a protein-protein interaction that is essential for the transmission of cell growth signals via the Notch pathway.

The researchers tested the drug using cells from patients with T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of the disease. The Notch1 gene is mutated in half of patients with T-ALL and produces an inappropriately active Notch1 protein. Activated Notch signaling has been seen in several other cancers, including lung, ovarian, and pancreatic cancer, and melanoma.

“We’ve drugged a so-called undruggable target,” said Dr. Verdine. “This study validates the notion that you can target a transcription factor by choosing a new class of molecules, namely stapled peptides.” The strategy may work for other transcription factors because the molecular logic of these proteins is similar to that of Notch1, he added.

In an accompanying editorial, Drs. Paramjit Arora and Aseem Ansari said that the group’s “remarkable results highlight the potential of molecules that mimic the secondary structures of proteins to target normally intractable protein-protein interactions.”

Treatment for Pancreatic Cancer May Target Tumor Microenvironment

Researchers have found some clues to suggest why combining nab-paclitaxel (Abraxane) with gemcitabine may be a more effective treatment for advanced pancreatic cancer than gemcitabine alone, the current standard of care.

This spring, updated results from an early stage clinical trial testing the combination therapy showed a promising response, particularly in patients whose tumors produced an abundance of the protein known as SPARC. Results from a mouse model study presented today at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference in Boston indicate that adding nab-paclitaxel to gemcitabine may improve response to treatment in part by altering the supportive tissue around the tumor, or stroma, allowing more gemcitabine to reach tumor cells.

The finding “shows that effective treatment does not necessarily require a fancy new molecular therapy, but just the smart combination of what is already available,” said the study’s lead investigator, Dr. Anirban Maitra from the Johns Hopkins University School of Medicine. Gemcitabine is the standard first-line treatment for pancreatic cancer, and nab-paclitaxel, a different form of paclitaxel (Taxol) that is bound to the protein albumin to improve its delivery, is approved for metastatic breast cancer.

To conduct the study, the research team tested the combination in pancreatic cancer mouse models generated at Johns Hopkins. Mice that received the combination were twice as likely to respond to the treatment as those that received gemcitabine alone, with an overall response rate (at least some tumor shrinkage) of 57 percent. They also found that mice given the combination therapy had significantly less of the “abundant fibrotic stroma” that typically surrounds pancreatic tumors and which was always seen in mice given only gemcitabine or no treatment at all. The concentration of gemcitabine in tumors from mice that received the combination therapy was 3.7-fold higher than in the animals given only gemcitabine.

Nab-paclitaxel was recently granted orphan drug status by the FDA (making it eligible for expedited FDA review and extended patent protection, among other things) for use in patients with pancreatic cancer and advanced melanoma. Enrollment is currently open for a phase III trial for pancreatic cancer that will compare gemcitabine plus nab-paclitaxel against gemcitabine alone.

Survey Finds Pain Is Common Years after Breast Cancer Surgery

A nationwide study of women who had breast cancer surgery in Denmark found that 47 percent of participants reported chronic pain 2 to 3 years after breast cancer treatment. Of these, 13 percent indicated severe pain, 39 percent moderate pain, and 48 percent light pain. In addition, 58 percent of participants experienced sensory disturbances or discomfort.

These results, which appeared November 11 in the Journal of the American Medical Association, could help doctors identify patients at high risk of chronic pain and may lead to progress in chronic pain prevention and treatment, the researchers said.

Women with the highest risk of both chronic pain and sensory disturbances were those ages 18 to 39 years who had undergone breast-conserving surgery, the researchers found. Adjuvant radiotherapy, but not chemotherapy, was also associated with chronic pain. Axillary lymph node dissection was associated with a greater likelihood of pain compared with sentinel lymph node biopsy.

The study included 3,253 Danish women who underwent surgery for unilateral primary breast cancer in 2005 and 2006. The large sample size and standardized treatment approaches required by national protocols make this study the first of its kind.

 “We think that our results, based on a very large study in very well-defined nationwide treatment, help to understand what the most important risk factors are for chronic pain after breast cancer surgery,” said senior author Dr. Henrik Kehlet of the University of Copenhagen.

The co-author of an accompanying editorial, Dr. Loretta Loftus of the University of South Florida H. Lee Moffitt Cancer Center, agreed, saying the findings “alert us to patients more prone to pain so that we might identify them earlier on, even prior to surgery, to develop a multidisciplinary approach to treatment that helps patients avoid long-term suffering.”

Hormone Therapy Use Linked to Benign Breast Condition

Women diagnosed with atypical ductal hyperplasia (ADH) have a three- to fivefold increased risk of developing breast cancer. Researchers led by Dr. Tehillah S. Menes from the Elmhurst Hospital Center in New York have discovered a link between postmenopausal hormone replacement therapy (HRT) and increased risk of ADH, similar to the link seen between HRT and breast cancer risk. These results were published November 9 in Cancer Epidemiology, Biomarkers & Prevention.

The researchers looked at data from more than 2 million screening mammograms performed on women ages 40 and older between 1996 and 2005 that were collected by the NCI-funded Breast Cancer Surveillance Consortium. During that period, 1,064 women were diagnosed with ADH alone and 833 women were diagnosed with breast cancer with ADH (found in the same biopsy samples).

The rates of both ADH alone and breast cancer with ADH were significantly higher in women who were using HRT at the time of their diagnoses. The rates of ADH alone peaked in 1999 and then decreased over the study period, with a notable drop starting in 2002. The rates of breast cancer with ADH peaked in 2002 and then decreased slightly over the course of the study.
 
The use of postmenopausal HRT has declined in U.S. women since 2002, after results from the Women’s Health Initiative indicated an association between HRT use and breast cancer. Rates of ADH and cancer with ADH in this screened population have also decreased since 2002, and “This finding may be partially explained by the decrease in rates of use of postmenopausal [hormone therapy],” concluded the authors.

The cancers with ADH were more likely to be either ductal carcinoma in situ (non-invasive) or low-grade invasive cancers (which have a better prognosis compared to more advanced cancers) than cancers found without ADH during the same time period. This supports the theory that low-grade and high-grade breast cancers develop via separate pathways, explained Dr. Menes in a press release.

Targeted Treatment Shows Promise for Older Patients with Advanced Leukemia

Older people are at higher risk of complications during treatment for some types of leukemia. For this reason, patients over the age of 55 are often treated with lower-intensity regimens, but consequently, the risk of disease relapse remains high. Now researchers at Fred Hutchinson Cancer Research Center have shown that combining radioactive iodine (I131) with an antibody can focus radiation at disease sites while sparing healthy tissues in older patients. This increased treatment efficacy while maintaining levels of side effects similar to what is seen in younger patients with better prognoses. Their report appeared in the November 5 issue of Blood.

The phase I study was designed to determine the maximum tolerated dose of the radioactive antibody when used with a reduced-intensity regimen of chemotherapy, total body irradiation, and hematopoietic stem cell transplant in older patients with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) for whom all previous treatments had failed. Fifty-eight patients ages 50 to 74 participated.

The patients were first injected with trace amounts of the radioactive antibody, which targets the CD45 protein found on leukemia cells. Researchers then used a special camera to determine the location and concentration of the antibody throughout the patient’s body over the next 3 days. These studies showed that the antibody delivered multiple times more radiation to the bone marrow, lymph nodes, and spleen than to the liver, lungs, or kidneys.

Eight to 14 days later, patients received a therapeutic dose of the radioactive antibody, followed by 3 days of chemotherapy with the drug fludarabine, total body irradiation, and a transplant with blood-forming stem cells. The maximum tolerated dose of antibody radiation, received by 21 patients, was found to be 24 Gy to the liver.

All patients went into remission immediately after treatment, and all of them showed engraftment of the donated stem cells by 28 days after their transplant. The 1-year survival estimate for all patients in the trial was 41 percent (46 percent for those treated at the maximum tolerated dose). The rate of relapse was 40 percent, one that the authors indicated is still high, but similar to that seen in younger cohorts.

While acknowledging that their study was not designed to test efficacy, the authors were optimistic that the approach could be used to improve cure rates for older patients with AML or MDS who need to be treated with reduced intensity regimens. They noted that other radioactive compounds, as well as antibodies against other targets in the disease, should also be explored.

Potential Strategy for Treating Diffuse Large B-cell Lymphoma Found

Two research teams working independently have identified a potential strategy for treating a form of diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adults. Each group found that blocking a protein called MALT1 resulted in the death of cells from patients with the activated B-cell-like (ABC) type. These patients have poor prognoses, and the findings could point to new treatment strategies, the researchers said.

MALT1 is an enzyme that breaks down proteins in cells (a protease). Previous studies have shown that the enzyme helps to activate a signaling pathway that drives the growth of ABC DLBCL cells, called the nuclear factor-kappa B (NF-κB) pathway. The new findings suggest that inhibiting MALT1 switches the pathway off, and as a consequence the ABC DLBCL cells die.

“This discovery is the beginning of new research aimed at inhibiting the NF-κB pathway in tumors,” said Dr. Louis Staudt from NCI’s Center for Cancer Research, who co-led one of the studies with Dr. Margot Thome of the University of Lausanne, Switzerland. Their results appeared online November 6 in the Proceedings of the National Academy of Sciences.

Dr. Jürgen Ruland of the Technical University of Munich led the other study, published last month in the Journal of Experimental Medicine. Both groups conducted similar experiments with the same types of cells and inhibitors. While these inhibitors are unlikely to be used in the clinic, the fact that both groups achieved the same result strongly suggests that MALT1 could have a role in future strategies for treating this lymphoma, Dr. Staudt said.

Guest Director's Update

Modeling for Research Success

Dr. Eric J. (Rocky) Feuer Dr. Eric J. (Rocky) Feuer

Kentucky has the highest smoking rate in the country. Nearly 29 percent of adults in the Bluegrass State smoke. But what could happen if it significantly strengthened its tobacco control policies? Could that number be appreciably reduced?

According to one complex computer model developed by NCI-funded researchers, the SimSmoke model, markedly enhanced tobacco-control efforts in Kentucky could reduce smoking prevalence there to 14 percent over the next 17 years, saving 17,000 lives in the process. That’s a powerful message for the people of Kentucky, particularly its health care professionals and policymakers. And it also demonstrates the utility of modeling as an important tool in biomedical research.

NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET) is a large, coordinated program that uses complex multi-cohort modeling to better understand, at the population level, the impact existing and emerging cancer control interventions—whether they are screening modalities, drug therapies, or a multimodal approach to smoking cessation—have on trends in cancer incidence and mortality. Nine years after CISNET was launched, this innovative program is providing important insights on the prevention, diagnosis, and treatment of the four most common cancer types: prostate, lung, colorectal, and breast.

Importantly, the “outputs” that can be generated by these models go beyond mortality, though that is the most important consideration with any cancer intervention. Outcomes such as overdiagnosis, quality-adjusted life years, and the direct costs associated with different interventions or intervention approaches (such as different screening intervals) can also be generated.

The role of modeling—and, consequently, a program like CISNET—has taken on greater importance as cancer interventions become more complex, technology continues to change at a torrid pace, and we gain further insight on the long-term consequences and outcomes of existing interventions.

Modeling also fills an important information gap, because we’ll never have evidence from randomized clinical trials for every possible care situation, even those that represent fairly common care scenarios. Modeling research attempts to step into this breach, using surveillance data from programs like SEER as well as usage trends of the interventions being studied, clinical trial results (which remain the gold standard for assessing the efficacy and risks of any intervention), findings from epidemiologic studies, and laboratory research on the biologic and molecular characteristics of precancerous lesions and tumors.

Last year CISNET was commissioned by the U.S. Preventive Services Task Force (USPSTF) to conduct a decision analysis to assess the life-years gained with different screening approaches for colorectal cancer—much like what was done for the updated mammography recommendations issued yesterday. Two “microsimulation models” were used to assess the impact of screening with fecal occult blood testing, sigmoidoscopy, and colonoscopy beginning and ending at different ages and conducted over different time intervals (e.g., every 5 years, 10 years, etc.). The USPSTF used the results, along with an intensive literature review performed by other researchers, to help update its screening recommendations for colorectal cancer.

As this modeling study for colorectal screening demonstrated, using such data and what might be called highly educated assumptions, modeling can do what no other type of study can do: track a population over its entire life course. And when you then have multiple researchers using their own individual models that take into consideration different parameters, something that is often done with CISNET studies, it strengthens the credibility and robustness of the results.

Looking forward, there are some exciting opportunities for CISNET on the horizon. We have had discussions, for example, about a potential collaboration with NCI’s Integrative Cancer Biology Program, which supports complex computer models of processes like tumor development at the molecular and cellular level. Another study will use modeling to assess some of the discrepant results between the recently published large U.S. and European clinical trials of PSA screening for prostate cancer.

CISNET is part of NCI’s Surveillance Research Program within the Division of Cancer Control and Population Sciences. Programs like CISNET demonstrate that surveillance research is not just a way to demarcate cancer trends. Rather, it is a feedback mechanism for the entire cancer research community. With CISNET, we use modeling to digest surveillance and other data and translate it in ways that otherwise cannot be done. It is an important process that allows us to optimize our research enterprise and obtain the biggest possible declines in cancer mortality in the most effective manner.

Dr. Eric J. (Rocky) Feuer
Chief, Statistical Research & Applications Branch
NCI Division of Cancer Control and Population Sciences

A Closer Look

Exploring the Reasons Women Choose Mastectomies

Percent use of breast-conserving surgery (BCS) by state. Darker shading in New England, the Mid-Atlantic States, Florida, and the West Coast represents higher frequency of use. The mountain states and deep south have lower use of BCS, with Mississippi having the lowest use in the nation. Not shown are Alaska (55 percent) and Hawaii (67 percent). Percent use of breast-conserving surgery (BCS) by state. Darker shading in New England, the Mid-Atlantic States, Florida, and the West Coast represents higher frequency of use. The mountain states and deep south have lower use of BCS, with Mississippi having the lowest use in the nation. Not shown are Alaska (55 percent) and Hawaii (67 percent). [Enlarge]

Since the 1980s, advances in surgical techniques, radiotherapy, and hormone and chemotherapy treatments have altered the decision-making landscape for women newly diagnosed with early stage breast cancer. Breast-conserving surgery (BCS) followed by radiation has become the preferred course of treatment for many women, based on studies showing it to be as effective as modified radical mastectomy at reducing recurrence and mortality from the disease while preserving breast tissue.

During that time, mastectomy rates “have precipitously declined from virtually 100 percent,” said Dr. Steven J. Katz, of the University of Michigan Health System in Ann Arbor, to around 30 percent, where they appear to have stabilized. But new data indicate that mastectomies may now be on the rise. When patients who are judged to be good candidates for BCS choose mastectomy instead, health care providers want to know why.

“Most surgeons favor the less invasive BCS,” said Dr. Katz, and some health care providers contend that mastectomy rates as high as this “are proof of overtreatment, possibly even mistreatment.” The controversy raises questions about how newly diagnosed breast cancer patients are making their decisions.

“A direct way to reduce concerns about overtreatment is to ensure that women make their decision based on accurate knowledge about mastectomy’s risks and benefits,” said Dr. Sarah T. Hawley, research professor in internal medicine at the University of Michigan.

With major invasive surgery like mastectomy, there is substantial recovery time, and complications such as bleeding or infection are more likely to occur than with BCS. Even though many women elect to have breast reconstruction and are satisfied with the results, “mastectomy is irreversible and can have psychological effects, such as a change in body image and the loss of normal breast functions,” said Dr. Hawley.

Several studies have been published this year that address the factors that might influence women’s choice.

Are Surgeons Influencing the Decisions?
 
Mastectomy rates vary widely around the country, and studies have shown that “the patients of higher-volume surgeons or surgeons working in cancer centers and teaching hospitals are less likely to receive mastectomies,” said Dr. Katz.

Despite the widespread belief by most surgeons that BCS is the preferred treatment, a study led by Dr. Monica Morrow and colleagues in the October 14 Journal of the American Medical Association (JAMA) sheds light on the influence of some surgeons for patients considering mastectomy. This study also helps to address whether mastectomy is being overused. Dr. Morrow is chief of the breast service at Memorial Sloan-Kettering Cancer Center.

Surveys were received from 1,984 women diagnosed with early stage breast cancer (including ductal carcinoma in situ) who were included in the Surveillance, Epidemiology, and End Results (SEER) registries in Detroit and Los Angeles. The researchers oversampled Latina (502) and African American (529) women to better discern differences in race/ethnicity.

Approximately two-thirds of the women in the study underwent BCS only and one-third underwent a mastectomy. Among the women who had a mastectomy, 13 percent based their decision on their doctor’s recommendation, nearly 9 percent chose mastectomy for themselves when their surgeon did not recommend one procedure over the other, and the remaining 9 percent were referred for mastectomy after their initial BCS was unsuccessful.

So, are surgeons influencing women to have mastectomy when there are no categorical clinical reasons for it? “Not in this study,” noted Dr. Katz, who was part of the research team. “Only 6.2 percent reported that their surgeon recommended a mastectomy when they were candidates for both surgery options.” Furthermore, patients who sought a second surgeon’s opinion rarely received a different recommendation. “It is clear,’ said Dr. Morrow, “that surgeons were not the major cause of mastectomy in patients, unless there were medical reasons that precluded BCS.   

“Ultimately the surgeons’ recommendations were sound,” continued Dr. Morrow, who doesn’t believe that more detailed preoperative imaging using techniques such as MRI will help surgeons make better recommendations for or against BCS. In fact, a study presented at the 2008 American Society of Clinical Oncology annual meeting and published in the September 1 Journal of Clinical Oncology suggested that preoperative MRI may do more harm than good by contributing to overdiagnosis and overtreatment, and may result in higher mastectomy rates.

Understanding Treatment Decisions

During the period when BCS evolved to become a viable, comparable, and––ultimately––recommended treatment over mastectomy, little empirical research was done on how women were actually making the decision, said Dr. Katz. Such studies can be tricky to do, he explained, but more have been done in the last decade. This approach has been spearheaded by a new NCI-supported research initiative devoted to studying treatment decision making and quality of care, the Cancer Surveillance and Outcomes Research Team (CanSORT).

To look more closely at what factors might influence a woman to choose mastectomy, Dr. Hawley used the same survey approach described above in another study published October 7 in the Journal of the National Cancer Institute (JNCI), once again oversampling Latinas and African Americans in SEER registries in Detroit and Los Angeles in 2005. What did patients think about their surgeons’ influence? When patients felt that they themselves were the primary decision maker, 27 percent chose mastectomy, a rate that dropped to 16.8 percent when the decision was considered to be a shared one and 5.3 percent when the patient identified the surgeon as the primary decision maker.

In the JAMA study, the researchers concluded that patient preferences—including concerns about recurrence or radiation effects—probably play an important role in the choice of surgery, since a quarter of all mastectomies were elected by patients whose first surgeon did not specifically recommend one approach over the other. “It’s particularly important to evaluate how these patients formulate their preferences for the surgery options,” said Dr. Hawley, a co-author. (See the box below.)

The JNCI study may be the first to evaluate the role of the patient’s family and friends in the choice of surgery. When someone else was present for the discussion about treatment, women more often received mastectomy. Less acculturated Latinas placed the most importance on others’ opinions, and a substantial proportion of women took their spouse’s opinion into account when making the decision. Women who said that their spouse was very important in decision making were less likely to receive an initial mastectomy than women who indicated that their spouse was not or marginally important in their decision making. “This highlights the important role that others may play in shaping treatment discussions and, ultimately, decisions,” said Dr. Hawley.

Beliefs, Perceptions, and Evidence

At face value, said Dr. Katz, “a patient’s preference for mastectomy might seem irrational, but there are a number of issues involved. We know that patients’ concerns about cancer recurrence can greatly influence their surgical treatment decisions and drive preferences for mastectomy. Policymakers and some physicians might underestimate such powerful cognitive and emotional factors that favor the more aggressive treatment.”

“A high quality decision can be defined as one that is fully informed, and consistent with the decision maker’s underlying values,” Dr. Hawley explained. This suggests that the process of decision making might be more important than the actual decision made, said Dr. Katz.

Researchers who study outcomes have found that patients can be more influenced in their treatment decision by how they understand, interpret, and value the factors they are facing than by the data that clinicians often use to buttress their recommendations. Such knowledge about patient preferences and their decision-making process is the foundation for improved risk communication and counseling.

––Addison Greenwood

Tracking Patients through the Process

Researchers at the University of Michigan looked prospectively at patients choosing between breast-conserving surgery (BCS) and mastectomy, and found interesting trends in their results. The women had a mastectomy rate of 39 percent, but only a quarter (10 percent) were candidates for BCS who nonetheless chose mastectomy. The other 29 percent includes patients whose surgery failed to achieve negative margins (3 percent), those with absolute clinical indications against BCS (15 percent), and more than 11 percent whose tumors could not be adequately shrunk by chemotherapy before undergoing surgery. The results were published earlier this year in The Breast Journal.

Featured Clinical Trial

Combination Therapy for Patients with Myelodysplastic Syndromes

Name of the Trial
Phase III Randomized Study of Lenalidomide with Versus without Epoetin Alfa in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes and Symptomatic Anemia (ECOG-E2905).  See the protocol summary.

Dr. Alan List Dr. Alan List

Principal Investigator
Dr. Alan List, Eastern Cooperative Oncology Group

Why This Trial Is Important
Myelodysplastic syndromes (MDS) are a group of diseases in which the bone marrow does not make enough healthy blood cells. About one-third of MDS patients go on to develop leukemia. Decreased blood cell counts (cytopenias) are a hallmark of MDS, with anemia (low red blood cells) being the most common type of cytopenia.  

MDS patients with symptomatic anemia may require blood transfusions to maintain safe red blood cell levels. Doctors often treat these patients with erythropoietin to help stimulate red blood cell production, but this treatment succeeds in only about 20 percent of patients. Currently there is no generally effective standard therapy for MDS patients who fail to respond to erythropoietin.

Some MDS patients with anemia who have not responded to erythropoietin do benefit from the drug lenalidomide (Revlimid). Specifically, patients with a gene deletion on chromosome 5q (5q31.1) are more likely to respond to lenalidomide therapy. Additionally, a recent pilot study suggests that lenalidomide may help sensitize patients without the 5q deletion to erythropoietin, leading to improved red blood cell production in those who had previously not responded to erythropoietin therapy.

In this trial, patients with MDS and symptomatic anemia who have a low or low-intermediate (also referred to as intermediate-1) risk of progression to leukemia will be treated with lenalidomide, and some will also receive a form of erythropoietin called epoetin alfa (Procrit). Patients with the 5q deletion will be assigned to the lenalidomide-only arm of the trial, while those without the deletion will be randomly assigned to receive either lenalidomide only or lenalidomide in combination with epoetin alfa. Patients in the lenalidomide-only arm may “cross over” to the combination therapy if they do not achieve a response or if they relapse after their initial treatment.

“This study should answer the question of whether or not combining erythropoietin with lenalidomide can help ameliorate anemia and reduce or eliminate the need for transfusions in a greater number of patients with MDS,” said Dr. List. “If the combination is successful, this will be one of the first combination therapies ever employed for this disease.

“We are also hoping to answer a number of biological questions related to MDS, including whether there are biomarkers that can help us predict which patients will likely respond to combination therapy,” he added.

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.

Also In the News

Study of Selenium to Prevent Second Lung Cancer Stopped

A phase III chemoprevention study of selenium in people with early stage non-small cell lung cancer (NSCLC) has been stopped because the intervention appears ineffective. The study, called E5597, was sponsored by NCI and conducted by the Eastern Cooperative Oncology Group. Researchers were investigating whether selenium would prevent the development of second primary lung cancers in patients with surgically removed, early stage NSCLC.

The study’s independent data and safety monitoring board recently reviewed the data and found that selenium supplementation was unlikely to produce the hoped-for 40 percent annual reduction in incidence of new lung cancers in participants. Study investigators have not found that selenium supplements caused severe side effects or worsened disease; however, they will continue to monitor the health of those who were enrolled in the trial.

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

Community Update

U.S.-China Cancer Research Collaborations to Be Expanded

NCI Director Dr. John E. Niederhuber and Meeting Chair Dr. Qimin Zhan, vice president of the Chinese Academy of Medical Sciences NCI Director Dr. John E. Niederhuber and Meeting Chair Dr. Qimin Zhan, vice president of the Chinese Academy of Medical Sciences

More than 100 cancer experts from the United States and China gathered in Beijing on November 9 and 10 to celebrate the 30th anniversary of the signing of the 1979 Health Protocol between the two countries and to discuss new opportunities for future scientific cooperation.

Participants, including a number representing NCI, reviewed the history and scientific accomplishments of joint U.S.-China cancer research studies over the past 30 years, summarized the state of the science for several advanced technologies driving personalized cancer medicine, and identified emerging opportunities for future cooperation in areas including molecular epidemiology, genomics, proteomics, and nanotechnology.

Chinese meeting co-chair Professor Qimin Zhan, vice president of the Chinese Academy of Medical Sciences, noted, “I look forward to new collaborations. As a result of these discussions at the meeting, we will find new points, some common ground, and common interests for future projects. I’m confident of that.”

NCI Director Dr. John E. Niederhuber, who welcomed the attendees during the opening session, was joined by other NCI leaders and scientists in the wide-ranging discussions.

“There are several unique opportunities to work with Chinese scientists to develop personalized cancer medicine,” said NCI Deputy Director Dr. Anna Barker, the U.S. co-chair of the meeting. “As a key participant in the Human Genome and International Haplotype Map projects, and with major recent achievements in proteomics and nanotechnology, China is poised to be a major player in this field.

“Large numbers of Chinese scientists trained in the United States are returning to leadership positions in China’s biomedical research sector," Dr. Barker noted, including Professor Zhan, who trained for 7 years in NCI laboratories earlier in his scientific career. These interactions have helped to further strengthen the countries’ relationships, facilitating communication and mutual understanding, said Dr. Barker.

At a recent meeting of the National Cancer Advisory Board, Dr. Barker reviewed the background and potential for leveraging the U.S.-China history of successful cancer cooperative research programs. Currently, NCI supports more than 50 China-related projects in areas such as basic research, epidemiology, occupational/environmental health, and tobacco control. She noted that developing research partnerships in China allows access to populations not observed in the United States who were exposed to chemical and/or infectious agents that increase cancer risk, and it provides opportunities to use Western scientific approaches to evaluate traditional Chinese medicine techniques.

In addition, China’s investment in science and technology nearly tripled between 2000 and 2005, to an estimated 1.1 percent of its GDP, and continues to increase. “There is a tremendous opportunity for NCI to expand collaboration during this growth phase,” Dr. Barker commented.

Dr. Zhan agreed, noting that China’s Minister of Health Dr. Zhu Chen, who addressed the meeting’s dinner banquet on November 9, “is very supportive of cancer research and all medical research collaborations between our two countries.”

NCI recently launched a new Office of China Cancer Research Programs in Beijing, which is led by Dr. Julie Schneider. “Over the past year or so, I’ve been laying the groundwork to create this new program,” she commented. “Following the 30th anniversary meeting, we will complete a strategic plan for expanding NCI partnerships in China, which will be an important first step for this new NCI program.”

Dr. Zhan is excited about NCI’s new office in Beijing. “NCI can play a more and more important role in China,” he predicted. “Considering that NCI is in the leading position for cancer research in the United States and in the world, I believe NCI can provide a lot of help to us.”

Additional U.S.-China conferences are being planned, including a symposium on nanobiology and nanomedicine in the spring and a possible workshop next autumn to review the state of cancer treatment clinical trials in China.

—Bill Robinson

FDA Update

New Treatment for Rare Skin Cancer Approved by FDA

The FDA has approved the drug romidepsin (Istodax) for the treatment of cutaneous T-cell lymphoma (CTCL), a rare cancer with about 1,500 new cases diagnosed each year. The approval covers the use of romidepsin in patients whose disease has recurred or worsened following chemotherapy.

In two phase II clinical trials involving 96 and 71 patients, respectively, approximately 35 percent of patients experienced some tumor shrinkage with romidepsin, lasting a median of 15 months in the larger trial and 11 months in the smaller trial. Six percent of patients had their tumors disappear altogether.

“CTCL is a devastating cancer in which many patients suffer from disfiguring tumors, horribly itchy and infected skin, and, in advanced stages, lesions in other organs,” said Dr. Youn Kim, director of the Multidisciplinary Cutaneous Lymphoma Group at Stanford Cancer Center, in a news release from Gloucester Pharmaceuticals, which manufactures romidepsin. “Current systemic therapies have proved inadequate,” she continued, so the drug will address “a significant unmet need.”

Romidepsin is only the second agent in a class of drugs known as histone deacetylase inhibitors to be approved by the FDA. These drugs are thought to work in part by activating genes that suppress tumor growth.

Although the compound was initially identified and pursued by another pharmaceutical company, much of the preclinical development and the first human trials involving romidepsin were conducted by Drs. Susan Bates and Richard Piekarz of NCI.

Early animal model studies showed that the drug caused significant cardiotoxicity, explained Dr. John Wright from NCI’s Cancer Therapy Evaluation Program. “The NCI Developmental Therapeutics Program identified in animals an administration strategy that minimized cardiac toxicity and also completed additional toxicology, pharmacology, and formulation studies that paved the way for the first human clinical trials, which were led by NCI,” he said.

Romidepsin is being studied in clinical trials for other indications, including peripheral T-cell lymphoma.

Cancer.gov Update

NCI Web Site Consolidates Supportive and Palliative Care Information

Visitors to NCI’s Web site will now find it easier to get extensive information on supportive care and palliative care. NCI’s Office of Communications and Education combined two sections of the site into one, called Coping with Cancer: Supportive and Palliative Care, with improved, streamlined organization. A single menu page highlights and links to key resources in the section. The design of the page was refined through iterative testing with patients and caregivers.

Featured topics include managing the physical and emotional effects of cancer and treatment, finding health care services, financial and legal concerns, and information for caregivers, friends, and family. Information for cancer survivors and links to clinical trials testing new supportive and palliative care interventions are also available.

Notes

NCI's Radiation Biology Branch Chief Honored with ASTRO Fellowship

Dr. James B. Mitchell Dr. James B. Mitchell
Dr. James B. Mitchell, chief of the Radiation Biology Branch in NCI’s Center for Cancer Research (CCR), was named to the 2009 class of American Society for Radiation Oncology (ASTRO) Fellows. Dr. Mitchell is one of 12 distinguished ASTRO members who received this award at a ceremony during the society’s 51st annual meeting held earlier this month in Chicago. The fellows were recognized for their leadership within ASTRO and for making significant contributions to radiation oncology, specifically in the areas of research, patient care, education, and leadership or service.

Dr. Mitchell joined CCR in 1979 and has served as a branch chief since 1993. His research focuses on modification of the radiation response, with particular attention to protecting patients against oxidative stress.



NIH to Host Drug Repositioning Conference Next Month

On December 4, NCI will co-sponsor a meeting titled, “CTSA Pharmaceutical Assets Portal: Matching Academia and Industry for Drug Positioning,” with the National Center for Research Resources and the NIH Clinical Center.

The half-day conference will convene leaders from the pharmaceutical industry, government, and research, to explore how drugs that were originally designed for one purpose can be used for another—an effort to counter the increasing trend in research and development costs that can slow drug discovery in the private sector. The Clinical and Translational Science Award (CTSA) Pharmaceutical Assets Portal is a tool that is designed to help match researchers’ knowledge of targets and diseases with the repositioning needs of the pharmaceutical industry.

The conference will take place from 9:00 a.m. to noon at the Lipsett Amphitheater in Building 10 on the NIH campus. Online registration is requested by November 25. The event will be videocast at http://videocast.nih.gov. For more information, contact Monica Barnette at 301-650-8660.

2009 NCI Translational Science Meeting Held

2009 NCI Translational Science Meeting logo

At the 2009 NCI Translational Science Meeting held earlier this month, more than 800 extramural and intramural researchers, patient advocates, and NCI staff convened to discuss accelerating early translational cancer research. This marks the second such meeting devoted to NCI’s goal of using innovative methods to rapidly and efficiently move the most promising new scientific discoveries from the laboratory into development and early phase clinical testing. The objectives of this year’s meeting were twofold: to enhance collaborations and interactions among all NCI-supported translational science investigators and to assist NCI in identifying opportunities worthy of support through the new Translational Research Acceleration Initiative (TRAI).

The "2009 NCI Translates" meeting consisted of 21 poster sessions, each focused on an area of interest related to a specific Translational Research Working Group (TRWG) Developmental Pathway. In addition to facilitating interaction among researchers with similar interests, each poster session was followed by a discussion about how the presented research relates to the TRWG Developmental Pathways and what factors may impede progress down the pathway. Additional panel sessions were held so that participants could discuss barriers and solutions relevant across all of the pathways.

Spearheading the TRAI effort is Dr. Lynn Matrisian, Ingram Distinguished Professor and chair of cancer biology at Vanderbilt University and currently special assistant to the NCI director. Dr. Matrisian was a co-chair of the TRWG, which developed the report upon which the TRAI framework is built.  For more information, visit the Coordinating Center for Clinical Trials.

President's Cancer Panel logo

President's Cancer Panel Explores Genetic Differences in Cancer Burden

The President’s Cancer Panel held the second meeting of its 2009–2010 series, “America’s Demographic and Cultural Transformation: Implications for the Cancer Enterprise,” on October 27 in Los Angeles. The panel heard testimony on differences in cancer burden among racial and ethnic populations due to genetic background and differences in tumor biology. Speakers reported racial and ethnic differences in cancer incidence, presentation, and prognosis that cannot be entirely accounted for by variations in socioeconomic, cultural, and behavioral factors. With these genetic differences in cancer development, it has become apparent that current research data based largely on non-Hispanic white populations are not always appropriate for the diverse current and projected populations within the United States. Speakers recommended improved research methods with increased recruitment of minority groups and objective determination of genetic ancestry through new technologies.

The panel will consider speaker recommendations when writing its 2009–2010 report to the President. Additional testimony on the effects of the changing U.S. population on cancer care and research will be heard at two future meetings:

December 9, 2009 - Wilmington, DE
February 2, 2010 - Miami, FL