National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 22, 2011 • Volume 8 / Number 4


A diagram of the steps taken during a sentinel lymph node biopsy
Some Women May Not Need More Extensive Lymph Node Surgery for Breast Cancer

Clinical trials have shown that surgeons can remove less tissue from women who have early-stage, lymph node-negative breast cancer without harming their chances of the disease returning or their overall survival. Now, a study led by Dr. Armando Giuliano of the John Wayne Cancer Institute in Santa Monica, CA, adds to that knowledge by demonstrating that a surgical practice called axillary lymph node dissection isn’t necessary for some women with early-stage disease when cancer cells are found in the adjacent lymph nodes. Read more > >




  • HHS Update

    • President’s FY 2012 Budget Proposal Calls for Small Increase for NCI
  • FDA Update

    • FDA Approves First 3-D Device for Mammography
  • Update

    • TCGA Launches New Web Site
  • Notes

    • Radiation and Cancer Symposium to Honor DCEG’s Elaine Ron
    • SBIR Phase II Bridge Award Funding Available
    • President’s Cancer Panel Addresses Accelerating Scientific Innovation

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

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Featured Article

Some Women May Not Need More Extensive Lymph Node Surgery for Breast Cancer

A diagram of the steps taken during a sentinel lymph node biopsy In a sentinel lymph node biopsy of the breast, a radioactive substance and/or blue dye is injected near the tumor (first panel). The injected material is detected visually and/or with a probe that detects radioactivity (middle panel). The sentinel nodes (the first lymph nodes to take up the material) are removed and checked for cancer cells (last panel). [Enlarge]

Clinical trials have shown that surgeons can remove less tissue from women who have early-stage, lymph node-negative breast cancer without increasing their chances of the disease returning or affecting their overall survival. Now, a study led by Dr. Armando Giuliano of the John Wayne Cancer Institute in Santa Monica, CA, adds to that knowledge by demonstrating that a surgical practice called axillary lymph node dissection (ALND) isn’t necessary for some women with early-stage disease when cancer cells are found in the adjacent lymph nodes. The study was published February 9 in JAMA.

In this randomized phase III clinical trial, called ACOSOG Z0011, women with early-stage breast cancer who underwent sentinel lymph node biopsy  (SLNB)—the removal of one or two lymph nodes in the armpit to test for the presence of cancer cells—and whose sentinel nodes were positive for cancer, lived just as long as women who had SLNB followed by ALND—the removal of many lymph nodes from under the arm. Most of the women in the trial also received systemic therapy (hormone therapy, chemotherapy, or both) in addition to radiation therapy to the whole breast.

“These results support the use of SLNB alone in selected women with one or two positive sentinel lymph nodes, and could potentially spare thousands of women the side effects of a full axillary lymph node dissection,” commented Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI’s Division of Cancer Treatment and Diagnosis.

The findings are limited to a specific population of women, noted Dr. Eric Winer of Harvard Medical School, who also was not involved with the study. “Doctors…must be very cautious about applying these results to patients who would not have been eligible for this trial,” Dr. Winer said. Women who were not eligible included those with palpable axillary lymph nodes, women who had breast tumors larger than 5 cm in diameter, women with three or more positive sentinel lymph nodes, women who received chemotherapy or hormone therapy before surgery, and women who underwent mastectomy instead of breast-conserving surgery with radiation.

Radical mastectomy for breast cancer, pioneered in the 1880s, provided the first surgical treatment for this disease, but at great expense to quality of life: the deforming surgery removed large amounts of tissue, including the breast, the underlying chest muscles, and all of the lymph nodes under the arm, and left women with extensive life-long side effects, including pain and lymphedema.

Today, most women with early-stage breast cancer undergo breast-conserving surgery followed by radiation therapy in lieu of mastectomy, while women with more advanced disease can be treated with a modified radical mastectomy.

“Patients would like to avoid more radical surgery,” said Dr. Giuliano. “They’ve already seen with lumpectomy how less surgery can be as effective.”

Half of the women enrolled in this study were randomly assigned to SLNB followed by ALND and the other half to SLNB alone. Women in the ALND group had a median of 17 axillary lymph nodes removed, compared with a median of two in the SLNB-alone group. All women underwent breast-conserving surgery and received whole-breast radiation therapy. The use of adjuvant chemotherapy and hormone therapy was determined individually for each woman.

After a median of more than 6 years, the 5-year overall survival rate was 91.8 percent in the ALND group and 92.5 percent in the SLNB-alone group. Rates of disease recurrence were also virtually equal between the groups.

“What surgery and radiation do—what local therapy does—is provide local control of the cancer,” explained Dr. Giuliano. Local control means preventing the cancer from returning in the breast or nearby tissue. “Failure to have local control could impact survival, but we had such high local control rates [in both arms of this trial] that I think it’s unlikely that we will see a difference in survival over time.”

Importantly, almost all women in both arms of the trial received some kind of systemic treatment. “In an era when virtually all women receive some form of systemic therapy, this study would suggest that removing additional lymph nodes after sentinel node biopsy is not of further benefit,” said Dr. Winer. “We don’t know whether this result would have been seen in the absence of systemic therapy, but I think it’s a reasonable hypothesis that there could have been a difference,” he explained, since systemic therapies kill cancer cells throughout the body, including in the lymph nodes.

Rates of negative side effects from surgery were much higher in the ALND group, with 70 percent of women experiencing wound infection, delayed healing, or pain compared with 25 percent of women in the SLNB-alone group. Lymphedema was also reported by more women in the ALND group. (The researchers reported complete data on side effects seen during the trial in a previous paper.)

The results from ACOSOG Z0011, wrote Drs. Grant Walter Carlson and William Wood of the Winship Cancer Institute at Emory University in an accompanying JAMA editorial, are a “testament” to the overall improvements made in breast cancer treatment since the early 1970s, when the first large clinical trial testing less-invasive surgery for breast cancer began. At the time of that trial, only about 60 percent of women were living 5 years after diagnosis, compared with more than 90 percent of women in the current trial.

Women eligible for the study were recruited from 115 hospitals across the country, had an invasive breast tumor of 5 cm or less in size, no obviously swollen lymph nodes, and cancer cells in no more than two nearby nodes as detected by SLNB.

The researchers had planned to enroll 1,900 women in the trial. However, survival rates were so high in both study arms that the independent data and safety monitoring committee recommended closing enrollment after only 891 women had joined the study because the researchers were unlikely to observe enough deaths to ever discern a difference in overall survival between the groups, even after 20 years.

Dr. Winer urged some caution in declaring the results definitive, because the trial could not meet its planned accrual goals due to excellent overall survival. “But I don’t think we’re going to get better data than this,” he said. “Given these results, and given the reluctance of some surgeons and some patients to undergo axillary lymph node dissections based on these results, it would be almost impossible to mount another randomized trial in this same patient population.

“However, I do think there is room for clinical trials in somewhat different patient populations,” he continued, “since this study was only in women who underwent conservative surgery and radiation.”

For the thousands of women diagnosed with breast cancer each year whose disease fits the trial’s enrollment criteria, ALND may be a thing of the past for now. “Women with breast cancer should discuss all their options with their physician,” concluded Dr. Giuliano. “They may not need as radical an operation as they once believed.”

Sharon Reynolds

Cancer Research Highlights

Dutasteride May Slow the Growth of Early-Stage Prostate Cancer

For men who are undergoing active surveillance for early-stage prostate cancer, the drug dutasteride (Avodart) could help control the disease and prevent the need for more aggressive treatments. The finding, from a randomized, placebo-controlled trial, was presented during the 2011 Genitourinary Cancers Symposium, which was held February 17–19 in Orlando, FL. Dutasteride is already approved by the Food and Drug Administration (FDA) for the treatment of an enlarged prostate gland, or benign prostatic hyperplasia.

Active surveillance, previously called “watchful waiting,” refers to the practice of forgoing immediate treatment after a prostate cancer diagnosis in favor of regularly scheduled testing and clinical exams to closely monitor the disease. In the Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial, 302 men undergoing active surveillance were randomly assigned to receive either dutasteride, which belongs to the class of drugs known as 5-alpha reductase inhibitors, or placebo for 3 years. Biopsy specimens were collected at 18 and 36 months, or as warranted based on evidence of disease progression.

In the dutasteride group, 38 percent of the men experienced some progression of their cancer, compared with 49 percent of the men in the placebo group. This difference translated into a reduction in relative risk for cancer progression of 38.9 percent in the dutasteride group. In addition, taking dutasteride increased the chances that no cancer would be found during a participant’s final biopsy. Thirty-six percent of the men in the dutasteride group and 23 percent of the men in the placebo group had no cancer detected in their final biopsy specimens.

It would be “very reasonable” to give a 5-alpha reductase inhibitor to patients with “ultra low-risk” prostate cancer who elect for active surveillance, said the trial’s lead investigator, Dr. Neil Fleshner of the University Health Network in Toronto, during a press briefing. However, Dr. Fleshner cautioned, this would be considered an “off-label” use of dutasteride. In December, the FDA’s Oncologic Drugs Advisory Committee rejected GlaxoSmithKline's application to approve dutasteride for use in preventing prostate cancer, and Dr. Fleshner said that the company was unlikely to seek an additional approval for the drug.

“The results of REDEEM suggest that dutasteride has an antitumor effect against low-volume, low-risk prostate cancer,” said Dr. Howard Parnes of NCI’s Division of Cancer Prevention, who was not involved in the study. “I think that this class of drugs [5-alpha reductase inhibitors] deserves to be studied further in men undergoing active surveillance.”

The Genitourinary Cancers Symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Bisphosphonate Use May Reduce Colorectal Cancer Risk

Post menopausal women who used bisphosphonate drugs (primarily alendronate) for more than 1 year had a 59 percent lower risk of colorectal cancer, according to a study published online February 14 in the Journal of Clinical Oncology. The findings came from a population-based, case-control study of colorectal cancer in northern Israel.

Bisphosphonates are commonly prescribed to treat or prevent osteoporosis and are also used to treat bone metastases in patients with breast cancer. Laboratory studies have shown that these drugs can interfere with steps involved in cancer cell growth and spread, and thus may have anticancer properties in humans. Indeed, previous reports have shown fewer breast cancer cases in women taking bisphosphonates. However, these studies did not rule out whether the reduced breast cancer risk was due to the lower estrogen levels often found in women who have low bone density and who are thus more likely to use bisphosphonates. (Colorectal cancer is not known to be fueled by estrogen.)

Analyzing data from the Molecular Epidemiology of Colorectal Cancer study, Dr. Gad Rennert of Technion-Israel Institute of Technology in Haifa, Israel, and his colleagues compared 933 women diagnosed with colorectal cancer with 933 women who did not have the disease. The women in the two groups were matched by age, ethnicity, and area of residence. The researchers also adjusted for known colon cancer risk factors, including vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statin drugs, vitamin D, and postmenopausal hormones.

“This evidence does not provide a basis for using bisphosphonates for colorectal cancer prevention,” cautioned Dr. Asad Umar of NCI’s Division of Cancer Prevention. “Indications for these drugs may be limited due to their toxic side effects, including rare cases of osteonecrosis of the jaw, esophagitis and esophageal erosion, and a possible higher risk of bone fractures after prolonged use.” A controlled clinical trial would be needed to confirm the connection between bisphosphonate use and colorectal cancer risk, he concluded.

Common Genetic Deletion Found in Brain Cancers

Researchers have identified a gene that is deleted in approximately one out of four patients with glioblastoma, the most common form of brain cancer. In addition, the researchers found that patients whose tumors had lost one copy of the gene, called NFKBIA, tended to have unfavorable outcomes. The results appeared in the February 17 New England Journal of Medicine and on the journal’s Web site in December.

Abnormalities in NFKBIA have been linked to other cancers, including Hodgkin lymphoma and multiple myeloma, but this study is the first to implicate defects in the gene in glioblastoma. NFKBIA appears to be a tumor suppressor gene; it produces a protein that normally helps to block growth-promoting messages from two signaling pathways linked to cancer, the NF-kappa B and the epidermal growth factor receptor (EGFR) pathways.

Approximately one-third of glioblastoma tumors have alterations in the EGFR gene, which can cause cells to proliferate and become cancerous. To identify additional genetic alterations in glioblastoma, the researchers profiled the EGFR and NFKBIA genes in tumors from nearly 800 patients with glioblastoma.

Based on an analysis of the results and additional laboratory experiments, the researchers concluded that the loss of NFKBIA is another way that glioblastoma cells can activate the NF-kappa B and EGFR pathways. The results also suggest that a majority of patients with glioblastoma have alterations in either EGFR or NFKBIA; very few tumors had abnormalities in both genes.

“We have identified a gene that is known to play a role in cancer, and there are substantial efforts under way to target that NF-kappa B pathway,” said lead author Dr. Markus Bredel of Northwestern University’s Feinberg School of Medicine. “So there are high hopes that we’ll be able to target this alteration.” 

The researchers are developing a clinical test that could be used to detect the deletion in patients and potentially guide the selection of therapy in the future.

More DNA Rearrangements Found in Prostate Cancers

The first study to compare the genomic sequences of multiple prostate tumors has found recurring rearrangements of DNA that may contribute to the development of the disease. Using tumor samples from seven patients, the researchers confirmed the existence of previously identified genetic changes associated with prostate cancer and discovered other alterations that could lead to new treatments for the disease.

Drs. Levi Garraway of the Dana-Farber Cancer Institute and Mark Rubin of Weill Cornell Medical College and their colleagues reported the findings February 10 in Nature. The study was funded in part by NCI’s Early Detection Research Network.

Previous studies have shown that many prostate tumors have fused genes, changes that occur when DNA sequences from different parts of the genome are linked together inappropriately. In the current study, three of the seven patients had the fusion gene TMPRSS2-ERG, which occurs in approximately half of all prostate cancers, and according to a 2008 study, may contribute to the disease.

In addition, the researchers detected approximately 90 genomic rearrangements per tumor, although these were not all associated with prostate cancer. (A genomic study of breast tumors reported a similar prevalence of rearrangements, but the mechanisms by which they occur may differ in the two cancers, the researchers noted.)
An analysis of the chromosomal rearrangements “revealed a distinctive pattern of balanced breaking and rejoining not previously observed in solid tumors,” the study authors wrote. Some of the rearrangements appeared to disrupt multiple genes in parallel, and these changes could affect the regulation of genes associated with cancer, the authors suggested.

“This study underscores the importance of doing systematic whole-genome sequencing in cancer,” said the study’s first author, Dr. Michael Berger, who conducted the research while at the Broad Institute. “Some of these rearrangements would not have been detected by targeted sequencing approaches that focus on just part of the genome rather than the whole.”

Certain Physicians Are More Likely to Refer Patients to Clinical Trials

According to a survey-based study of more than 1,500 physicians treating patients with lung or colorectal cancer, medical oncologists were the most likely and surgeons the least likely to refer patients to, or enroll them in, clinical trials. The study, published online February 11 in the Journal of the National Cancer Institute, evaluated the characteristics of specialty physicians who refer patients to clinical trials, the types of trials in which they participate, and factors associated with physicians who report greater involvement in clinical trials.

Almost 88 percent of the medical oncologists who participated in the survey referred or enrolled one or more of their patients in the previous year, compared with 66 percent of radiation oncologists and only 35 percent of surgeons. Nearly half of the survey respondents were affiliated with NCI’s Community Clinical Oncology Program (CCOP) or an NCI-designated Cancer Center, yet one in three of these physicians reported no enrollments or referrals in that year.

“The role of physicians in recruiting patients to clinical trials is pivotal,” wrote Dr. Carrie Klabunde, an NCI epidemiologist who led the study within the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) in collaboration with her colleagues. These trends reflect opportunities to improve clinical trial recruitment.

Although surgeons had the lowest rate of patient referral or enrollment, they represented more than half of the group that was surveyed. Surgical oncologists and surgical subspecialists (thoracic and other types) were much more likely than general surgeons to refer or enroll patients. Female surgeons and those over age 60 were also more likely to refer or enroll patients.

When medical oncologists or radiation oncologists received monetary incentives, they referred or enrolled 20 percent more patients. Physicians who teach medical students or residents, or who are affiliated with a CCOP or an NCI-designated Cancer Center, were also substantially more likely to refer or enroll patients. In these groups, physicians who saw more than 19 patients per month or who attended weekly tumor board meetings were much more likely to refer or enroll patients.

“Realizing the full potential of clinical research in the 21st century will require…efforts to address the complex factors that shape cancer care in the United States,” wrote the authors. “More research is needed to better understand clinician attitudes toward clinical research and to examine specific features of practice infrastructure…that facilitate or hinder physician participation in clinical trials.”

Special Report

Targeted Therapies May Be Effective Against Rare Pancreatic Cancer

A histology slide of a pancreatic neuroendocrine tumor (Image courtesy of Dr. Ralph Hruban of Johns Hopkins University) Pancreatic neuroendocrine tumors (stained red in the histology slide above) are composed of back-to-back cells of uniform size and shape. And, unlike tumors that begin in the cells that line the pancreas (adenocarcinomas), pancreatic neuroendocrine tumors don’t have an excessive build up of stromal cells around them. (Image courtesy of Dr. Ralph Hruban of Johns Hopkins University)

Patients with advanced forms of a rare type of pancreatic cancer may have new, effective treatment options. According to results from two phase III clinical trials, the targeted therapies sunitinib (Sutent) and everolimus (Afinitor) increased the length of time patients with pancreatic neuroendocrine tumors (PNET) survived without the disease progressing. And, in the sunitinib trial, patients who received the drug also had better overall survival. The findings were published February 9 in the New England Journal of Medicine (NEJM).
Pancreatic neuroendocrine tumors account for less than 2 percent of new pancreatic cancer cases. Over the past 2 decades, no effective treatments for this cancer type have been identified, wrote Drs. Robert Jensen and Gianfranco Delle Fave in an accompanying editorial in NEJM, but the results from these trials “provide optimism” that this may no longer be the case.

Dr. Luis Diaz, of the Johns Hopkins University Kimmel Cancer Center, whose clinical work and research focuses on pancreatic and other gastrointestinal cancers, went even further, calling the results “pretty spectacular.” If the FDA approves these agents for patients with advanced PNET whose disease is progressing, he continued, they “should become the standard of care.”

The 171-patient trial that tested daily sunitinib—funded by the drug’s manufacturer, Pfizer—was stopped early by the study’s independent data and safety monitoring committee when an interim analysis showed a clear improvement in progression-free survival in patients receiving sunitinib and an increased risk of death and serious adverse events in the placebo group. Median progression-free survival was 11.4 months among patients who received sunitinib compared with 5.5 months among patients who received the placebo. Patients who received sunitinib also had a nearly 60 percent improvement in overall survival at the time of the analysis.

The everolimus trial, called RADIANT-3 and funded in part by the drug’s manufacturer, Novartis, enrolled 410 patients. Median progression-free survival in the trial was 11 months among patients who received everolimus daily compared with 4.6 months among patients who received a placebo. Follow-up in the everolimus trial was not long enough to judge whether overall survival improved; however, 73 percent of patients in the placebo arm eventually crossed over—which was allowed in the design of both trials—and received everolimus. As a result, an overall survival benefit in favor of everolimus may never materialize, wrote the trial’s lead author, Dr. James C. Yao from the University of Texas M. D. Anderson Cancer Center, and his colleagues.

In pancreatic adenocarcinoma, which accounts for the vast majority of pancreatic cancer cases, tumors arise from epithelial cells that line pancreatic ducts. With PNET, however, the disease arises from hormone-releasing cells in the pancreas, called islet cells.

Patients with PNET generally have better prognoses than patients with pancreatic adenocarcinoma. Even in patients who have advanced PNET, the disease can be quite stable for several years without treatment, Dr. Diaz explained. Once the disease begins to progress, however, commonly used treatments such as chemotherapy and streptozocin, which is the only FDA-approved drug for PNET, have limited efficacy and can be highly toxic, he said.

Sunitinib and everolimus have their own toxicities. In both trials, the drugs were associated with an increased risk of side effects, including serious events such as anemia and neutropenia, which in many patients prompted dose reductions or a temporary halt in treatment. However, the adverse events were manageable, the researchers reported, and were consistent with what has been seen with these drugs in the treatment of other cancers.

Both sunitinib and everolimus target proteins in intracellular signaling pathways that earlier studies have suggested can drive PNET progression and resistance to available treatments. For example, a study published in Science last month by researchers from Johns Hopkins, including Dr. Diaz, found mutations in genes in the mTOR signaling pathway, which is everolimus’ molecular target, in 14 percent of the PNET samples tested. Also, Dr. Yao and colleagues explained, patients with several genetic cancer syndromes in which the mTOR pathway is known to play an important role, including tuberous sclerosis and von Hippel-Lindau disease, often develop PNET.

In the Science study, patients with mutations in mTOR pathway genes—including PTEN, PI3K, and TSC2—had a worse prognosis than patients with other common mutations that they identified. In addition, Dr. Diaz noted, in several other cancer types, studies have shown that TSC2 mutations preferentially sensitize patients’ tumors to respond to mTOR inhibitors. Further studies are needed to correlate genetic alterations or mutations with response to the agents, he cautioned.

“But if you bundle our paper with the results from these two trials, they are synergistic and very complimentary with what we found,” Dr. Diaz said.

Additional biomarker studies may improve therapy choice and the selection of “rational combinations” of drugs in patients with both progressive and earlier disease, Dr. Yao said. Such biomarkers could include mutations in genes in the mTOR pathway for everolimus. They could also include findings from perfusion computed tomography (CT) scans, he continued. In a small study presented at the 2010 ASCO annual meeting, Dr. Yao explained, patients with NETs whose tumors had higher permeability on the CT scans—that is, greater flow of blood in and out of the tumor—had significantly better response to treatment with bevacizumab (which, like sunitinib, targets blood vessel formation) and everolimus than patients with low tumor permeability.

In the meantime, Drs. Jensen and Delle Fave wrote, in patients with advanced PNET there are still important questions left to answer. “Will patients have to continue taking these drugs for years since both drugs primarily stabilize, rather than cure, the disease?” they asked. “If patients no longer have a response to one drug, can they then be effectively treated with the other drug or with a combination of the two drugs?”

Several clinical trials testing everolimus in combination with other targeted therapies in patients with PNET are under way. Everolimus has been granted priority review by the FDA for the treatment of advanced PNET (as well as neuroendocrine tumors of the lung and gastrointestinal tract). Sunitinib is already approved in Europe to treat some patients with PNET, and according to a company spokesperson, Pfizer is working with the FDA to pursue a regulatory approval to use sunitinib in unresectable PNET.

Carmen Phillips

Profiles in Cancer Research

Dr. Robin Yabroff

Health Services and Economics Branch
NCI Division of Cancer Control and Population Sciences

Dr. Robin YabroffDr. Robin Yabroff

Dr. Robin Yabroff’s wire earrings sway as she talks enthusiastically about her favorite areas of research: projections of cancer trends into the future, patient-time costs, and comparing different methodologies. The draft of a survey is spread across her desk with edits and comments penciled neatly in the margins. This particular survey is designed to gather data about people who have or have had cancer and includes questions about their insurance coverage and employment status. Dr. Yabroff hopes the survey will help fill a gap in cancer patient data, particularly for those under the age of 65. 

Dr. Yabroff is a recognized leader in the field of health services research. As an epidemiologist in the Health Services and Economics Branch of NCI’s Division of Cancer Control and Population Sciences, she designs studies, develops surveys, and dissects data sets to understand how patients interact with the health care system, and how such interaction affects the quality of care they receive. She does this in collaboration with other researchers from different disciplines, and says that her daily interaction with colleagues is a critical aspect of the research.

“Working with the expertise of clinicians, statisticians, economists, and behavioral scientists improves the quality and potential impact of our research,” she said, “and helps us to develop research resources for other scientists to use.”

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Video produced and edited by Sarah Curry

Looking at the Big Picture

Like millions around the world, Dr. Yabroff has been touched by cancer in a personal way. In the early 1990s, her grandmother was diagnosed with breast cancer. A few years later, while working as a research associate at Georgetown University Medical Center’s Clinical Economics Research Unit, Dr. Yabroff had a choice: work on an infant mortality study or help craft a breast cancer study that examined how elderly women make decisions about their treatment.

Her grandmother’s recent struggle with treatment decisions, Dr. Yabroff said, made it “very natural” to take on the breast cancer study.   

In the late 1990s, the disease became personal again when her mother was diagnosed with ovarian cancer that progressed rapidly. And in 2005, Dr. Yabroff was herself diagnosed with breast cancer. These events molded her research as she was forced to sort through referrals and second opinions, treatment decisions, and questions about which expenses would be covered by her insurance plan.

Dr. Yabroff didn’t have clear career goals when she graduated from Indiana University with degrees in biology and psychology in 1987. She started out working in a research lab in an effort to find her niche. Later, she developed a curiosity about emerging biotech companies and the stock market, which led to an M.B.A and ultimately the study of health economics.

While at Georgetown’s Clinical Economics Research Unit, she worked as a research associate on several cancer cost-effectiveness studies. This research environment provided the perfect blend of clinical epidemiology and health economics, she said, and prompted her to pursue a Ph.D. in epidemiology at the Johns Hopkins Bloomberg School of Public Health.

It was during this time that her mother was diagnosed with ovarian cancer. The effect on the family was significant. Her mother had to stop working and her father took a leave of absence and subsequently retired. Dr. Yabroff, too, had to take time off from both work and graduate school, and her sister also took a leave of absence. The whole family had to adapt, she said. 

Dr. Yabroff remembered accompanying her mother to the hospital for 24-hour chemotherapy treatments and helping her deal with insurance hurdles and referrals. “It was like a full-time job helping her navigate her care,” she recalled.

Luckily, her mother had good health insurance coverage. “Even in the best-case scenario, cancer treatment is really tough to manage,” she said. “So, what happens when patients and their families don’t have some of those advantages?”

The experience led her to pursue research in end-of-life care, as well as topics such as the impact of cancer on employment and productivity (that of patients and caregivers) and disparities in health care delivery. While at Georgetown University Medical Center’s Lombardi Cancer Center, she served as co-investigator on a study of caregiver burden at the end-of-life and several studies estimating the cost effectiveness of interventions to improve breast cancer outcomes.

The Burden of Time

More recently, Dr. Yabroff worked with colleagues to examine how much time cancer patients spend receiving care and the costs associated with that time. This effort emerged as one of her favorite studies, she said, because there has been little research done looking at patient time, and also because she personally spent an enormous amount of time getting treatment for her mother and then getting treatment herself.

The study, published in 2007, used linked data from NCI’s Surveillance, Epidemiology, and End Results (SEER) Program and Medicare to examine how often different services were used, such as hospitalizations and emergency room visits, and then applied time estimates to those services (including travel time). They also used several methods for valuing patient time.

“We estimated that the patient time burden associated with cancer care was considerable,” she said, citing the example of ovarian cancer patients who spent an estimated 410.6 hours during the initial phase of care after diagnosis compared with 42.4 hours for similar individuals without cancer. And the average time cost associated with ovarian cancer in the initial phase of care was $5,605, Dr. Yabroff and her colleagues found. But their estimates were probably low because they only included services Medicare pays for and did not include family and caregiver time.

In her latest collaborative study, Dr. Yabroff and her colleagues examined cancer incidence and survival data from SEER, U.S. population projections, and cost estimates based on linked SEER and Medicare data to develop cost projections for cancer care through the year 2020. That study predicted how many people would be in each phase of care (beginning, continuing, or end-of-life) and used cost estimates specific to each phase of care to project the overall costs associated with cancer.

Lessons Learned and Critical Questions

Last year, Dr. Yabroff received three NIH Merit Awards for contributions to her field. This year marks her fifth year being cancer free. The focus of her research continuously shifts, but her curiosity about how people receive medical care, including prevention, screening, and treatment for cancer, remains constant.

“When you see disparities in health outcomes,” she said, “you start thinking, are there ways health care delivery could be improved? Much of it is related to how people use health care.” Disparities in cancer survival, for example, can change based on how people use screening and treatment in different ways, she explained.

And after nearly 20 years of health services research, Dr. Yabroff has learned that there are many questions that influence this relationship.

“Do you have health insurance, and if so, is it employer-based? Do you have a usual source of care? Does your doctor recommend screening? If you are diagnosed with cancer, are you able to get a second opinion for treatment recommendations? I like to consider these kinds of questions,” she said. “We have a complicated health care system in the United States.”

How people use this complicated system, particularly as oncology evolves, is something Dr. Yabroff looks forward to documenting in the future, particularly with advances such as targeted cancer therapies. How will these therapies be recommended and used by oncologists? What groups of patients will receive these treatments? And what will be the costs associated with their use?

“I just hope that our research ultimately helps people receive the highest quality of care. Not just in terms of how patients and families interact with their clinicians, but in how they deal with employers and health insurers,” Dr. Yabroff said. “Because I know what effect those interactions can have on cancer treatment, quality of life, and how well people survive this disease.”
Sarah Curry

Featured Clinical Trial

Treating Multiply Relapsed or Refractory Hairy Cell Leukemia

Name of the Trial
Randomized Phase II Trial of Rituximab with Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia (NCI-10-C-0025). See the protocol summary.

Dr. Robert Kreitman Dr. Robert Kreitman

Principal Investigator
Dr. Robert Kreitman, NCI Center for Cancer Research

Why This Trial Is Important
Hairy cell leukemia is an uncommon cancer of the blood in which the body produces a large number of abnormal B lymphocytes (a type of white blood cell). These abnormal cells appear “hairy” when viewed under a microscope and give the disease its name. Hairy cell leukemia is usually treated with a chemotherapy drug called cladribine when signs or symptoms of the disease develop, such as low blood cell counts, recurrent infections, or a swollen spleen.

Pentostatin, another chemotherapy drug in the same class as cladribine, is also effective against this cancer. However, most patients and doctors prefer cladribine because the typical course of treatment lasts 5–7 days as opposed to 3–6 months or longer with pentostatin. 

Cladribine and pentostatin have different mechanisms of action, but they both produce high rates of complete remission and have similar toxicity. Although responses to cladribine and pentostatin can last years or even decades, these drugs do not appear to cure most patients. Consequently, many patients relapse, need more treatment, and eventually develop resistant, or refractory, disease. Therefore, doctors are interested in finding new treatments or new combinations of existing treatments for patients with hairy cell leukemia who have relapsed or not responded to previous therapies.

A biological agent called rituximab binds to and kills cells that express an antigen called CD20 (CD20-positive cells). Moreover, rituximab has been used successfully to treat some patients with hairy cell leukemia who have relapsed or not responded to previous chemotherapy. Although the hairy cells that remain after cladribine or pentostatin treatment are essentially always CD20 positive, only a minority of patients respond to rituximab therapy alone. However, combinations of rituximab and either cladribine or pentostatin seem to be highly effective in nearly all patients. Dr. Kreitman is currently directing a randomized clinical trial of rituximab with cladribine in newly diagnosed (untreated) patients and patients who have had only one prior course of cladribine, but no prospective trial has yet evaluated rituximab with pentostatin in patients with hairy cell leukemia. 

Yet another drug, called bendamustine, has been shown to be effective against other cancers involving B lymphocytes, such as some B-cell non-Hodgkin lymphomas and chronic lymphocytic leukemia. Bendamustine’s mechanism of action is different from those of cladribine and pentostatin, and it is known to act synergistically with rituximab in lymphoma cells. NCI researchers think that combining bendamustine and rituximab may prove effective in treating patients with multiply relapsed or refractory hairy cell leukemia. 

In this trial, patients with hairy cell leukemia who have not responded to initial chemotherapy followed by second-line treatment with rituximab, or who have relapsed following two courses of chemotherapy, will be randomly assigned to receive rituximab combined with either pentostatin or bendamustine. Either way, patients will be able to “crossover” to the other regimen if the first one does not work. Doctors will assess the objective response rates of each regimen and try to determine whether one regimen is superior. 

“Most of the calls we get at NCI are from multiply relapsed hairy cell patients,” said Dr. Kreitman. “The majority of these patients will have received only cladribine, but because pentostatin works differently, some patients with disease that is refractory to cladribine may be sensitive to pentostatin. So it makes sense to use rituximab along with pentostatin as a comparator to bendamustine and rituximab for patients with multiply relapsed or refractory disease.”

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

An archive of "Featured Clinical Trial" columns is available at

HHS Update

President’s FY 2012 Budget Proposal Calls for Small Increase for NCI

The Obama administration’s federal budget proposal for fiscal year (FY) 2012 increases the NIH budget by approximately 4 percent, to $31.8 billion, and includes a small increase for NCI. Under the proposal, NCI’s budget would be $5.196 billion, up from the $5.098 billion that NCI obligated in FY 2010. Because Congress failed to approve a federal budget for FY 2011 during its last session, all federal agencies are currently operating at FY 2010 levels under what is known as a continuing resolution.

In a press briefing to unveil the administration’s budget proposal for the Department of Health and Human Services (HHS)—which includes NIH, the Food and Drug Administration, and the Centers for Disease Control and Prevention, among other federal health agencies—HHS Secretary Kathleen Sebelius said the budget positions the country well for making future advances in biomedical research and health care. But the proposal will by no means please everyone, she acknowledged. (View the video archive of the press briefing online.)

“Years of deficits have put us in a position where we need to make some tough choices,” Secretary Sebelius said. “We looked closely at every program in the Department” to find areas where waste could be cut and programs could be redesigned “to put a new focus on results.” In some instances, she continued, the proposal cuts programs that would have been maintained “in better fiscal times.”

The increased funding for NIH will continue to open up new frontiers of research in areas such as cell-based therapies and genomics, offering new and more effective treatments for diseases such as cancer and autism, Secretary Sebelius predicted. The proposal will “allow our scientists to pursue these discoveries while keeping America at the forefront of biomedical research,” she said.

The budget proposal includes funding for the National Center for Advancing Translational Sciences, although precise budgetary figures for the new center are not yet available. The President’s proposal also includes $100 million for the Cures Acceleration Network, a program intended to focus on developing new therapies for diseases and conditions that are not being addressed by the private sector, explained NIH Director Dr. Francis Collins during the briefing. Congress has already authorized the Network’s establishment, but has not yet authorized funds to support it.

During a recent town hall meeting with NCI staff, NCI Director Dr. Harold Varmus laid out the Institute’s funding priorities for FY 2011, which included maintaining the same number of new research grants, continued support for genomics initiatives, and implementing planned changes to NCI’s clinical trials program.

Congress will now take up the administration’s budget proposal as it sets spending levels for FY 2012. (View NCI’s funding priorities for FY 2012 online.) Republican leaders have called for setting government spending at 2008 levels, which could entail significant reductions for NIH. However, before those issues are settled, Congress must finish its work on appropriations for the current fiscal year. The continuing resolution under which the federal government is now operating expires on March 4.

Carmen Phillips

FDA Update

FDA Approves First 3-D Device for Mammography

The Food and Drug Administration (FDA) has approved the first 3-dimensional (3-D) mammography device for both screening and diagnosing breast cancer. The device is called the Selenia Dimensions digital breast tomosynthesis system, or Dimensions 3-D, and is manufactured by Hologic, Inc., based in Bedford, MA.

The approval, as explained in an FDA news release, was based on results from two studies in which radiologists were able to improve their ability to distinguish cancers from noncancers by 7 percent using the 3-D system compared with conventional mammography systems.

A 2-D mammogram image on the left shows a possible lesion, but the tomosynthesis images reveal no lesion in the breast. In the 2-dimensional (2-D) image on the left, there is a potential lesion in the subareolar region of the breast. In the tomosynthesis images on the right, it is easy to see that there is no lesion present. One can pick out individual structures on the separate slices, which summate to form the potential lesion seen on the 2-D projection image. (Image courtesy of Hologic, Inc.)

With conventional 2-dimensional (2-D) mammograms, overlapping tissue in the breast can hide potentially malignant lesions and can cause benign areas to appear suspicious. The Dimensions 3-D system uses both 2-D and 3-D images, producing “a stack of thin high-resolution image slices intended to provide clear rendition of structures in the breast and their spatial relationship with the surrounding breast tissue,” explained a Hologic news release.

The FDA approval was based on a retrospective study presented to the FDA’s Medical Devices Advisory Committee (MDAC) in September 2010. Compared with a 2-D system for breast cancer screening, the use of the Dimensions 3-D system reduced the recall rate from 51.5 percent to 12.9 percent. In this analysis, a Breast Imaging Reporting and Data System (BI-RADS) score of 0 was used as the basis for calculating recall rates. A BI-RADS score of 0 means that a mammography study is not yet complete and further evaluation, perhaps additional mammography views or an ultrasound, is required to make a final assessment.

The MDAC unanimously voted in favor of approval. Because it uses both 2-D and 3-D images, the Dimensions 3-D system doubles the radiation dose that patients receive, the FDA noted. There is “uncertainty” around cancer risk estimates associated with radiation exposure; however, the cancer risk associated with radiation from the new system is 1.5 percent higher than the baseline risk, which is defined as no radiation exposure from mammography, and is less than 1 percent higher than the risk associated with 2-D mammography, according to the agency.

Under federal regulations, the FDA noted, all health care professionals must obtain 8 hours of training with a new mammography technology before they can perform procedures on patients. Update

TCGA Launches New Web Site

Screenshot of The Cancer Genome Atlas Web site

The Cancer Genome Atlas (TCGA) project has launched an updated Web site that offers several new content areas and interactive features to help members of the public understand how TCGA works and what they can expect from discoveries that are made through the project.

The site includes case studies that describe how the research community is using TCGA data to make or validate new discoveries, with a video series of TCGA investigators explaining the genetic basis of cancer and the many areas of TCGA research. 

The site also includes written profiles of the researchers who work with TCGA, along with perspectives from members of the research community, research briefs on studies that used TCGA data, and regular updates from TCGA leadership. An interactive graphic on the site illustrates how TCGA works.

Readers can sign up for updates  to receive routine notices about the latest news on TCGA. 


Radiation and Cancer Symposium to Honor DCEG’s Elaine Ron

Dr. Elaine Ron Dr. Elaine Ron

On March 9, NCI will sponsor a symposium on research strategies in radiation and cancer. The event will honor the groundbreaking research of the late Dr. Elaine Ron, former branch chief and senior investigator of the Radiation Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics (DCEG).

Experts in the field of radiation and cancer epidemiology will discuss strategies for studying thyroid and other cancers caused by radiation exposure, as well as the carcinogenic effects of medical, environmental, occupational, and accidental radiation exposures. Speakers will identify promising new cancer research directions and strategies in radiation epidemiology, and the symposium will include a talk about international research opportunities by Dr. Christopher Wild, director of the International Agency for Research on Cancer.

For more information and to register for free, visit the symposium Web site.


SBIR Phase II Bridge Award Funding Available

NCI’s Small Business Innovation Research (SBIR) Program has announced $10 million in funding for up to 10 new awards in FY 2011. The awards are available to small businesses seeking additional funding to support the next stage of development for previously funded NIH-wide SBIR Phase II Bridge Award projects in the areas of cancer therapeutics, imaging technologies, interventional devices, diagnostics, and prognostics.

NCI created the Bridge Award to help small businesses obtain necessary funding to accelerate the commercialization of promising cancer technologies and ultimately improve cancer prevention, detection, and treatment for patients. The Bridge Award funding opportunity is specifically designed to accomplish these goals by incentivizing partnerships between NIH’s SBIR Phase II awardees and third-party investors and/or strategic partners.

Information about how to apply for these awards is available online. Applications are due April 7.


President’s Cancer Panel Addresses Accelerating Scientific Innovation

The President’s Cancer Panel held the fourth and final meeting of its 2010–2011 series, The Future of Cancer Research: Accelerating Scientific Innovation, on February 1 in Atlanta. The meeting included expert testimony and discussion regarding opportunities to facilitate progress within the National Cancer Program (NCP), including opportunities made possible by new models for funding research.

Meeting participants from public and private organizations discussed grant review and funding models designed to support innovative projects. For example, they discussed utilizing an anonymous review process in which reviewers do not know the identity of the applicant, prohibiting the submission of preliminary data with an application, and using a “champion-based” review in which reviewers select one application for funding and make recommendations about other submissions. These approaches differ substantially from traditional review models and are intended to be more streamlined and to encourage applications from early-career investigators.

Speakers also stressed the importance of involving consumers and advocates in the grant-review process to encourage the funding of projects that have a direct, practical impact on the community.

Meeting participants highlighted the need for a national strategy to guide and coordinate the NCP, including analysis of current activities across all sectors to ensure that efforts are not being duplicated and that critical areas are being addressed. They also discussed how to improve coordination and data sharing across sectors of the cancer research community, including the dissemination of negative results and other findings that are not commonly published in mainstream journals.
The Panel will summarize the discussion and recommendations from this meeting, along with the other meetings in the series, in its 2010–2011 annual report to the President of the United States.