Results from several studies presented last week at a major research conference validate that a new test can predict the risk of breast cancer recurrence in a sizable group of patients; the studies also appear to identify which of those patients will benefit most from chemotherapy. The studies were heralded by researchers as an important moment in the move toward individualized cancer care. Central to the investigations is a test, Oncotype DX, that analyzes the expression of a 21-gene panel in biopsy samples from women with estrogen-dependent, lymph-node negative breast cancer, which accounts for more than 50,000 breast cancer cases in the United States each year.

The results, presented at the San Antonio Breast Cancer Symposium, "are some of the most striking I have seen in breast cancer," said Dr. Jo Anne Zujewski, a senior investigator in the NCI Cancer Therapy Evaluation Program, during a news conference.

Confirmation of earlier data on the ability of the assay - developed by Genomic Health Inc., which, along with NCI, funded some of the studies - to accurately predict recurrence risk was needed. What was lacking, some breast cancer researchers had argued,was data on whether the assay could forecast chemotherapy benefit, which would help guide treatment decisions.

An analysis of biopsy samples from patients in the tamoxifen plus chemotherapy arm of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-20 study using the assay, Oncotype DX, appears to answer that question. According to the lead investigator, Dr. Soonmyung Paik, patients with high "recurrence scores" on the assay (31 or higher on a 0 to 100 scale) had a significant benefit from chemotherapy (27.6 percent absolute increase in distant relapse-free-survival at 10 years). Patients with low recurrence scores (18 or lower), on the other hand, essentially received no benefit from chemotherapy. According to these results, about one-quarter of patients with node-negative, receptor-positive breast cancer are at high risk for recurrence and would benefit from chemotherapy in addition to tamoxifen, while about half of patients are at low risk and would not.

"I think the data indicated clearly that the benefit of chemotherapy is not uniform," said NSABP Chair Dr. Norman Wolmark.

The presentation of these data coincided with the New England Journal of Medicine's online publication last week of results from the first large-scale study using Oncotype DX on archival samples from NSABP. These data were initially presented last year and showed that the actual breast cancer recurrence rate was 6.8 percent at 10 years in patients with low recurrence scores, 14.3 percent in the intermediate score group, and 30 percent in the high score group.

The Oncotype DX assay is considered a breakthrough because it can be used on tumor specimens that are fixed and embedded in paraffin. This has been technically difficult to do because RNA is altered when stored in this fashion. Researchers at Genomic Health Inc., however, developed a method for performing genetic analyses that allows them to use the altered RNA, making testing of patient samples readily accessible to clinicians in all settings. Currently, Genomic Health's California-based headquarters is the only facility licensed to perform the test.

NCI will conduct a randomized, prospective clinical trial involving all the clinical trials groups that study breast cancer. The trial will use Oncotype DX to identify patients with recurrence scores in the intermediate range to determine whether they benefit from chemotherapy. "That's the group for whom we really don't know how well this test will perform," Dr. Zujewski said.

See news about NCI's FY 2005 budget 3

And 2004 was the perfect time to introduce the Bulletin. We saw significant advances that spanned the discovery-development-delivery continuum of cancer research. New findings in the area of cancer imaging, for example, suggest that we are moving toward a time when we can use advanced imaging technologies to monitor cancer at the molecular level, measuring treatment effects before they are clinically apparent, thus making more timely treatment decisions. New insights into the metastasis process were also gained this year, with researchers elucidating critical activity in the tumor microenvironment that enables metastasis to occur. With the launch in October of the NCI Integrative Cancer Biology Program, we will move more quickly toward unraveling the complex processes that underlie tumor growth and metastasis.

Some of the most highly praised studies published this year highlighted how genetic mutations influence the efficacy of new targeted agents - findings that should aid the movement toward more individualized care and development of other targeted agents. Combined with improvements in the use of more standard therapies, such findings presage a cancer care revolution.

With the launch of the cancer Bio-medical Informatics Grid (caBIG) and the NCI Alliance for Nanotechnology in Cancer, we hope to rapidly accelerate the cancer research technology revolution. I am confident these initiatives will transform how we conduct research, allowing scientists to perform their work more quickly and develop more effective diagnostic tests and therapies. Such technological advances clearly will affect our clinical trial system, a fact being considered by the NCI Clinical Trials Working Group formed this year. The group is rapidly moving toward providing recommendations for the NCI-supported clinical trials program to ensure that it yields more efficient, informative trials that quickly translate into new interventions.

New reports released this year also shed more light on the factors that influence cancer care disparities and the problems encountered by and the needs of cancer survivors. More importantly, through the NCI Center to Reduce Cancer Health Disparities and Office of Cancer Survivorship, we are addressing these issues. NCI, for example, is funding radiation oncology clinical trials at institutions that care for a large number of medically underserved patients. NCI is also firmly committed to preventing cancer and recently launched, with HHS, a national network of smoking cessation quitlines.

All of these efforts will lead us to an era of personalized oncology in which we prevent more people from developing cancer, detect the disease very early, and successfully eliminate or control their malignancy. I hope these representative examples give you a sense of the work being done in the cancer research community and of where we are going as an institute.

I'd like to extend my most sincere thanks to all of you who participate in helping advance cancer prevention, detection, diagnosis, and care. Your efforts are important and inspiring. Have a safe and happy holiday season and my warmest wishes for a new year filled with health, success, and joy.

Dr. Andrew C. von Eschenbach
Director, National Cancer Institute

"The tissue is the issue" say the experts, meaning that in order to conduct the discovery research fundamental to molecular medicine, it will be essential to have access to large numbers of high-quality, clinically annotated biospecimens. Around the globe, several countries are advancing toward large, networked systems to ensure that researchers have such access.

Advanced technologies such as genomics, proteomics, molecular imaging, and nanotechnology hold great promise for understanding disease at the molecular level. But experts note that progress in using these technologies to deliver new preventive, diagnostic, and therapeutic agents to cancer patients is hampered by a lack of cooperative infrastructure among institutions that collect, store, and distribute human biospecimens for research. "The need to align and optimize biospecimen resources in the United States is among the most critical scientific issues we face in the cancer research community," said Dr. Anna Barker, NCI deputy director for advanced technologies and strategic partnerships.

Human biospecimens - tissue, blood, urine, or other bodily materials - are critical for translating basic discoveries into new cancer interventions.

Biospecimens are collected for diagnostic procedures; however, material not used for patient diagnosis and care can be stored for research use with appropriate patient consent. Biospecimens are most valuable for research when they are annotated with detailed demographic, clinical, and longitudinal information that can be analyzed in combination with research results derived from analyses at the molecular level. Collections of biospecimens and associated data are called biobanks or biorepositories.

According to a report by the RAND Corporation, more than 300 million human biospecimens are currently stored in U.S. biorepositories. However, these biorepositories do not share common biospecimen standards and policies for quality control, data collection, ethical clearance, and access by the scientific community. "Given the variability in current procedures to collect, annotate, process, and store biospecimens, it is difficult for researchers to compare data derived from biospecimens collected at different institutions," said Dr. Julie Schneider, of NCI's Office of Technology and Industrial Relations. "Moreover, variations in informed consent processes hinder researchers' efforts to aggregate the large numbers of biospecimens typically required for high-throughput analyses."

NCI has been gathering input from its advisory boards on this complex issue. In addition, the future direction of biorepositories was discussed by representatives from the nonprofit, private, and government sectors, and by several international representatives at November's 2004 IBM Biobank Summit. Dr. Barker delivered the plenary lecture at the meeting, calling for participation, commitment, and leadership from the entire biomedical research community. "If we can solve this problem in a timely fashion," said Dr. Barker, "I think it will be a great advance for biomedical research and for the patients, who will be the ultimate beneficiaries."

The biospecimen networking concept is gathering momentum internationally, with several recently announced biobanking initiatives; NCI is planning to test several key biobanking principles within its integrated network of prostate cancer Specialized Programs of Research Excellence. In addition, NCI and the Foundation for NIH, which raises private sector funds for NIH biomedical research initiatives, are planning a demonstration project for a national effort that would collect, process, store, and distribute high-quality biospecimens from many cancer types.

"NCI has an opportunity to provide needed leadership in the area of biobanks and biospecimens and will continue to collaborate with all sectors and obtain grassroots input from the scientific community," said Dr. Barker.

Anastrozole Beats Tamoxifen as First-Line, Adjuvant Treatment

For postmenopausal women who develop hormone-receptor-positive, localized breast cancer, the standard adjuvant hormone treatment has been 5 years of tamoxifen. But new findings from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial have confirmed that the aromatase inhibitor Arimidex (anastrozole, developed by AstraZeneca, the sponsor of this study) provides these women with prolonged disease-free survival and a longer time to recurrence, as well as fewer treatment side effects. "Five years of anastrozole should now be considered as the preferred initial adjuvant endocrine treatment," the authors wrote in the December 8 Lancet.

After a median 68 months of follow-up, the data show that women who received anastrozole had a 26 percent risk reduction over tamoxifen in time to recurrence, and a 42 percent reduced incidence of contralateral breast cancer. The researchers noted that because their patients had a relatively good prognosis at the outset, it is too early to expect a difference in survival between the treatment arms, but with the additional finding that there were fewer participant withdrawals among those receiving anastrozole - perhaps due to the fact that patients receiving it had reduced incidence of endometrial cancer, blood clots, stroke, vaginal bleeding, hot flashes, and vaginal discharge - compared with those who received tamoxifen. "It is reasonable to switch patients currently on tamoxifen to an aromatase inhibitor," the authors wrote, and "the present data suggest that it is not appropriate to wait 5 years" before making the switch.

New Agent Proves Effective against Imatinib-Resistant CML

Patients with chronic myelogenous leukemia (CML) who had developed resistance to or were intolerant of imatinib (Gleevec) responded very well to a new investigational agent, BMS-354825, researchers reported last week at the American Society of Hematology (ASH) annual meeting. In the phase I study, partially supported by NCI, 86 percent of the 36 patients with imatinib-resistant, stable CML treated with the investigational drug BMS-354825 had a complete hematologic response, meaning that their white blood cell count returned to normal, for up to 9 months, with just a few patients experiencing minor side effects. Of the 29 chronic CML patients for whom the appropriate data were available, 28 percent had a major cytogenetic response, meaning the cancer-causing cells were eliminated. Positive results were also seen for study participants in the accelerated or blast phases of CML.

Although BMS-354825 and imatinib are targeted agents, the former is less selective. Both agents bind to the BCR-ABL tyrosine kinase, a mutated form of which initiates the overproliferation of white blood cells that eventually wreaks physiologic havoc. But BMS-354825 also inhibits another kinase that may be involved in imatinib resistance, SRC, and because it is less selective, can bind to other mutated forms of BCR-ABL that are at the root of imatinib resistance. In a study published in July in Science - led by Dr. Charles Sawyers from UCLA's Jonsson Comprehensive Cancer Center, one of the co-principal investigators of the study presented at ASH - BMS-354825 was effective against 14 of the 15 imatinib-resistant CML mutations tested (see July 27 NCI Cancer Bulletin ⁴).

Both Dr. Sawyers and co-principal investigator Dr. Moshe Talpaz of M.D. Anderson Cancer Center cautioned that these were preliminary results and that larger studies are needed to confirm the safety and effectiveness of this new agent. The drug's manufacturer, Bristol-Myers Squibb, announced during the ASH meeting that the company is moving rapidly to get the agent into phase II trials.

A Broken Promise to Our Children: The 1998 State Tobacco Settlement Six Years Later, finds that nearly every state is failing to provide adequate funding for tobacco control programs. The report, prepared by the Campaign for Tobacco-Free Kids, finds that in the current budget year only four states - Maine, Delaware, Mississippi, and Arkansas - are funding their tobacco prevention programs at or close to the levels recommended by the Centers for Disease Control and Prevention (CDC). While an additional 10 states fund tobacco prevention programs at about half the minimum the CDC recommends, the remaining 36 states and the District of Columbia provide less than half the CDC minimum, or provide no state funding whatsoever. All told, states spend $1 on tobacco prevention for every $23 spent by the tobacco industry to market tobacco products, despite receiving record levels of tobacco-generated revenue from the tobacco settlement and tobacco taxes. The Campaign for Tobacco-Free Kids is a coalition of more than 130 organizations committed to reducing tobacco use among both children and adults. Reflecting on the new report, Dr. John Seffrin, CEO of the American Cancer Society, stated, "This report shows a missed opportunity for states to save money and, more importantly, lives." The report can be viewed at http://www.tobaccofreekids.org/reports/settlements/.

Variations in state tobacco control funding and use of evidence-based interventions affect smoking prevalence and ultimately, smoking-caused disease. See the November 23 Director's Update in the NCI Cancer Bulletin ⁵ for more information on a study of state-specific prevalence of cigarette smoking among adults.

On December 7, NCI announced the selection of 15 organizations to operate its Cancer Information Service (CIS). The 5-year contract awards are anticipated to become effective Jan. 15, 2005, with a combined value projected to reach $20.9 million in the first year.

Located at medical centers across the country, these 15 regional offices will serve the United States, Puerto Rico, the U.S. Virgin Islands, and the U.S.-associated Pacific Territories. A complete list of awardees is available at http://www.cancer.gov/newscenter/pressreleases/CISAwardsRecompete2004.

The contracts involve three program areas: the CIS Partnership Program, CIS Contact Centers, and the CIS Research Program.

CIS Partnership Program
CIS works with national, state, and regional organizations to develop and disseminate cancer information and education programs to reach people without easy access to them, such as minority and medically underserved populations.

NCI will award 15 contracts to operate a regionalized CIS Partnership Program. Working together, CIS and its partners will reach those most in need of cancer information and services.

CIS Contact Centers
CIS is the federal government's source for the latest, most accurate cancer information for the public, patients and their families, and health professionals. In addition, CIS offers smoking cessation counseling. Each year, CIS receives nearly 300,000 calls through its toll-free telephone service, which has been in operation for nearly 30 years and offers information in English and Spanish.

Four of the 15 organizations will operate CIS Contact Centers to provide information to the public by telephone and through LiveHelp, the instant messaging service accessible through NCI's Web site, www.cancer.gov.

CIS Research Program
The CIS Research Program studies ways to promote healthy behaviors and communicate cancer information effectively. It helps both the CIS Contact Centers and Partnership Program better understand, apply, and disseminate effective communication approaches to educate the public about cancer and contribute to the nation's cancer control efforts.

All 15 organizations will participate in the CIS Research Program and will engage in cancer control, behavioral, and health communications research that supports NCI's priorities and programs. Four of the organizations were selected as coordinators of the Research Program.

"Advances in technology have enabled us to reduce the number of Contact Centers from 14 offices in 2004 to 4 offices in 2005," said Mary Anne Bright, CIS director. "This new configuration of 15 regional Partnership Program offices with 4 Contact Centers maximizes NCI's potential for preserving and enhancing trusted, long-standing regional partnerships."

Additional information about CIS can be found at http://cis.nci.nih.gov.

Community Participation in Research
PAR-05-026
Letter of Intent Receipt Dates: Apr. 17, 2005; Apr. 17, 2006; Apr. 17, 2007
Application Receipt Dates: May 17, 2005; May 17, 2006; May 17, 2007

For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2464. Inquiries: Dr. Sabra Woolley - woolleys@mail.nih.gov.

Innovative Technologies for Molecular Analysis of Cancer
This is a reissue of RFA-CA-05-002.
Letter of Intent Receipt Dates: Jan. 17, May 17, Sept. 18, 2005
Application Receipt Dates: Feb. 17, June 17, Oct. 18, 2005

For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2480. Inquiries: Dr. Gregory J. Downing - downingg@mail.nih.gov.

Application of Emerging Technologies for Cancer Research
This is a reissue of RFA-CA-05-003.
Letter of Intent Receipt Dates: Jan. 17, May 17, Sept. 18, 2005
Application Receipt Dates: Feb. 17, June 17, Oct. 18, 2005

For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2481. Inquiries: Dr. Gregory J. Downing - downingg@mail.nih.gov.

Innovations in Cancer Sample Preparation
This is a reissue of RFA-CA-05-004.
Letter of Intent Receipt Dates: Jan. 17, May 17, Sept. 18, 2005
Application Receipt Dates: Feb. 17, June 17, Oct. 18, 2005

For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2482. Inquiries: Dr. Gregory J. Downing - downingg@mail.nih.gov.

Name of the Trial
Randomized Study of Traumeel S for the Prevention and Treatment of Mucositis in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation (COG-ACCL0331). See the protocol summary at http://cancer.gov/clinicaltrials/COG-ACCL0331.

Principal Investigators
Dr. Susan Sencer and Dr. Indira Sahdev of the Children's Oncology Group.

Why Is This Trial Important?
Chemotherapy drugs for cancer may produce a number of side effects. These side effects can prevent or delay further treatment and may lead to serious complications, including infection and death. Therefore, researchers are eager to find effective ways to prevent or lessen side effects from chemotherapy.

Mucositis (sores and ulcers in the lining of the mouth) is a common side effect of chemotherapy. This trial is testing a homeopathic preparation, called Traumeel S, as a treatment for mucositis in young patients undergoing chemotherapy in preparation for stem cell transplantation. High-dose chemotherapy and stem cell transplantation are frequently used in treating pediatric patients with leukemia or solid tumors. Traumeel S is a homeopathic remedy containing certain minerals and extracts from 12 different types of plants.

"An earlier study of Traumeel S conducted in Israel showed a significant reduction in mucositis among young patients undergoing stem cell transplantation," said Dr. Sencer. "With this trial, we hope to confirm those findings and therefore determine whether Traumeel S is an effective treatment for chemotherapy-related mucositis.

"There is a great deal of interest in complementary and alternative medicines among the public and studies have shown that our patients are using them," added Dr. Sencer. "We feel we have a responsibility to test these methods as rigorously as we would test any other intervention."

Who Can Join This Trial?
Researchers seek to enroll 180 patients aged 3 to 25 who are undergoing myeloablative stem cell transplants. See the list of eligibility criteria at http://cancer.gov/clinicaltrials/COG-ACCL0331.

Where Is This Trial Taking Place?
The study is part of the NCI's Community Clinical Oncology Program and is being conducted at sites in the United States and elsewhere. See the list of study sites at http://cancer.gov/clinicaltrials/COG-ACCL0331.

Contact Information
For more information, see the list of study contacts at http://cancer.gov/clinicaltrials/COG-ACCL0331 or call the NCI Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The call is toll free and confidential.

The research teams will use transgenic mouse models of human cancers to study current proteomic technologies, compare results, and provide reference data sets and biological resources for widespread research use. This will enable comparability of results among laboratories currently using different proteomic technologies. The common data sets and resources will also make it easier to develop and test the next generation of biomarker discovery technologies. This framework will provide direction for the development of specific strategies to target biomarkers that signal the earliest stages of cancer in humans.

This 2-year effort will result in the first reliable and broad-based technological platform for the discovery and clinical validation of protein biomarkers for cancer. Information will be closely integrated and distributed through caBIG, an open-source, open-access, information network linking teams of cancer and biomedical researchers.

"Proteomics holds enormous potential for the early detection of cancer, but researchers must have standard reagents and reproducible technologies to accelerate the discovery and development of these biomarkers into clinical use," said NCI Deputy Director Dr. Anna Barker. "We believe that this unique network - with its teams of experts - will speed up the development of effective proteomic technologies for the benefit of cancer patients and their families."

One of the proteomics research teams is headed by Dr. Samir Hanash of the University of Michigan. Other researchers on the team are from Harvard-Partners Center for Genetics and Genomics, Massachusetts Institute of Technology, Dana-Farber Cancer Institute, Van Andel Research Institute, and Memorial Sloan-Kettering Cancer Center.

Drs. Martin McIntosh and Amanda Paulovich of Fred Hutchinson Cancer Research Center are leading the other proteomics research team, whose members include researchers from the Institute for Systems Biology, Pacific Northwest National Laboratory, and Plasma Proteome Institute.

Draft NIH Public Access Policy Elicits Comments
NIH is proposing a public access policy to create a stable, permanent archive of peer-reviewed, NIH-funded research publications. The archive will enable NIH to more efficiently track and manage its research portfolio, monitor its scientific productivity, and ultimately help set research priorities; and to make the published results of NIH-funded research readily accessible to scientists, health care providers, and the public. NIH intends that the proposed policy will preserve the critical role of journals and publishers in peer review, editing, and scientific quality control processes.

The draft policy requests, but does not require, that NIH-funded investigators submit electronically to NIH the final, peer-reviewed author's copy of their scientific manuscripts. The copy would be embargoed from release by NIH for 6 months after the publisher's date of publication. The copy would be publicly available in the National Library of Medicine's PubMed Central.

NIH developed the proposed policy and published it in the NIH Guide to Grants and Contracts and the Federal Register for public comment this fall. NIH received more than 6,000 comments and is in the process of reviewing them; a final policy is expected in the coming weeks. More specific information can be found at http://www.nih.gov/about/publicaccess/index.htm.

Input Needed on Future of Clinical Trials
The Clinical Trials Working Group (CTWG), seeks input via its interactive Web site to obtain feedback about revising the cancer clinical trials system. The Web site, http://ncicbforums.nci.nih.gov/ictQuestions/
login_form, asks users to log in by choosing from a menu a description that best identifies the group they represent. Users are also required to enter a password (CTWGstakeholder) prior to providing their thoughts. The password is also given on the log-in page. All responses will be confidential. The Web site is open for feedback through January 15, 2005.

President Nominates Leavitt to Lead HHS
President Bush yesterday nominated Michael O. Leavitt to replace outgoing Secretary of the Department of Health and Human Services Tommy G. Thompson. Mr. Leavitt, formerly governor of Utah, is currently Administrator of the Environmental Protection Agency. Confirmation hearings will begin when Congress reconvenes in January.