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National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 13, 2009 • Volume 6 / Number 1

Breaking News

ASCO Urges KRAS Gene Testing for Colorectal Cancer

The American Society of Clinical Oncology (ASCO) recommended today that patients with metastatic colorectal cancer who are candidates for anti-EFGR therapy have their tumors tested for KRAS gene mutations. In a “provisional clinical opinion,” ASCO recommends that patients with mutated forms of the KRAS gene should not receive the drugs cetuximab 1 (Erbitux) and panitumumab 2 (Vectibix), based on recent studies indicating this treatment is only effective in patients with normal forms of the gene.


A studio photo of chemotherapy drugs in a dripping IV bottle 3

FU-Based Chemotherapy Cures Some Patients with Colon Cancer 3

Researchers from the Adjuvant Colon Cancer Endpoints (ACCENT) Group used individual patient data from 18 phase III trials of adjuvant fluorouracil-based chemotherapy for colon cancer to show that the regimens provide their survival benefit primarily by reducing the high risk of recurrence within the first 2 years after surgery.  Read more > > 3


Director's Update: Resource Digs Deep into NCI's Research Funding 9

NCI recently launched a newly enhanced Funded Research portal on its Web site. For a decade or more visitors to could search the cancer research portfolio, but the enhanced portal now provides consolidated information from varying NCI locations on one site, including funding and other data on NCI's intramural research program. The result is a significant increase in public access to this broader range of data. Read more > > 9

In Depth


  • FDA Update 17

    • New Prostate Cancer Drug Approved
    • Gardasil Indication for Men Reviewed
    • A Warning for Bone Density Drug
  • CMS Update 18

    • CMS Proposes Expanding Medicare Coverage of PET Scans in Cancer Patients
  • Notes 19

    • NCI Scientists Receive 2008 HHS Awards
    • NCI Holds Annual Intramural Scientific
    • New Issue of CCR Connections Released

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.

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Featured Article

FU-Based Chemotherapy Cures Some Patients with Colon Cancer

A studio photo of chemotherapy drugs in a dripping IV bottle Chemotherapy drugs in a dripping
IV bottle

For several decades, chemotherapy regimens based on the drug fluorouracil 20 (FU) have been part of the treatment for high-risk stage II or stage III colon cancer. Many clinical trials have shown that these regimens improve overall survival, but how they affect the risk of recurrence over time has not been clear.

In a study 21 published online January 5 in the Journal of Clinical Oncology, researchers from the Adjuvant Colon Cancer Endpoints (ACCENT) Group used individual patient data from 18 phase III trials of adjuvant FU-based chemotherapy for colon cancer to show that the regimens provide their survival benefit primarily by reducing the high risk of recurrence within the first 2 years after surgery.

By 5 years after treatment with FU-based adjuvant chemotherapy, the risk of recurrence dropped to 1.5 percent, and dropped again to 0.5 percent by 8 years after treatment. Instead of delaying recurrence, “FU-based chemotherapy truly eradicates the disease and results in long-term cure in some patients,” explained Dr. Daniel Sargent, professor of biostatistics and oncology at the Mayo Clinic and lead author of the study.

Measuring True Risk of Recurrence over Time

The ACCENT investigators reviewed survival data from 8 years of follow up for 20,898 patients in the 18 trials. Instead of the Kaplan-Meier method usually used to calculate survival after treatment, the investigators used a system called hazard-rate estimation, which requires a large data set but provides results that are easier to interpret. Hazard-rate estimation “allowed us to estimate and graphically present the true risk of recurrence at any given time” after treatment, said Dr. Sargent.

Out of the 20,898 patients, 35 percent had their cancer recur during 8 years of follow up, and 38 percent died from any cause during the same time period. For both patients who did and did not receive chemotherapy, “most relapses [occurred] in the first 2 years after surgery,” stated the authors. However, the risk of death remained lower during that period of time and during the entire 8 years of follow up for patients who had received chemotherapy.

Overall, adjuvant chemotherapy with an FU-based regimen improved 8-year overall survival by 7 percent (5 percent for patients with stage II cancer and 10 percent for patients with stage III cancer).

Implications for Follow-up Care

The authors cautioned against extending these results to newer combinations of chemotherapeutic and biologic drugs that do not contain FU. “Longer-term follow up is likely to be required to establish a long-term survival benefit,” they explained. The ACCENT group plans to update their analysis with data from newer treatment regimens as they become available. Dr. Sargent pointed out that “such analyses are only possible through individual clinical trialists making their data available for such pooled or meta-analyses, which has been made increasingly possible due to improvements in technology and by standardization of clinical trial data elements.” 

The results from the current study have important implications for follow-up care of patients with stage II or III colon cancer, he noted. “The risk of a patient’s disease returning is highest in the first 2 years, and therefore the patient and their physician have to be very vigilant in their follow up during that period to make sure that if the cancer does come back, it is detected quickly.

“After 5 years and particularly after 8 years, the risk of the patient’s disease coming back is very, very low, and physicians can then turn their attention to other priorities for that patient,” he said.

—Sharon Reynolds

Cancer Research Highlights

Validated Colorectal Cancer Risk Assessment Tool Available Online

NCI researchers have developed one of the first colorectal cancer (CRC) absolute risk assessment models for people aged 50 to 85 without known genetic susceptibility to the disease, using data from two large case-control studies and validating the model in the NIH-AARP Diet and Health Study 22 population. The tool uses answers about lifestyle, screening, and family history of CRC to calculate a person’s 5-year, 10-year, and lifetime risk of developing the disease. Both the development 23 and validation 24 papers were published December 29 in the Journal of Clinical Oncology, and an online risk assessment tool based on the model is now available for use by physicians at

“This colorectal cancer risk model provides physicians and their patients with a new tool to help make informed decisions about colorectal cancer screening and other prevention strategies. It may also assist policy makers in evaluating the usefulness of current and future population colorectal cancer prevention approaches,” said Dr. Andrew Freedman, lead author of the study, in an accompanying press release.

Dr. Freedman of NCI’s Division of Cancer Control and Population Sciences 25 and Dr. Ruth Pfeiffer of NCI’s Division of Cancer Epidemiology and Genetics 26 (DCEG) led the team that developed the model using data from two population-based, case-control studies, one for colon cancer and one for rectal cancer, and cancer incidence rates from the SEER 27 database. Since non-Hispanic white men and women aged 50 years or older made up the majority of participants in both case-control studies, the researchers restricted their model to this group.

They determined the relative risks for a cancer diagnosis in three different areas of the colon and rectum based on known risk factors, including history of CRC screening, body mass index, and family history of CRC. The researchers also constructed a short risk-assessment patient questionnaire that easily captures the information used in the model.

To assess the model’s performance, the researchers, led by DCEG’s Dr. Yikyung Park, used the model to estimate the number of CRC cases expected in the 155,345 men and 108,057 women in the NIH-AARP cohort. They then compared those results to the actual number of cases diagnosed in that cohort between 1995 and 2003. They found that their model was well calibrated, with the estimated-to-observed ratio for CRC diagnoses being 0.99 in men and 1.05 in women.

The researchers are in the process of updating the Web tool with data from SEER to improve accuracy for other racial and ethnic groups.

Colonoscopy Reduces Death from Cancer in the Left Colon, but Not the Right

In a large case-control study performed by researchers at the University of Toronto, patients who had undergone colonoscopy at least once were significantly less likely to die of colorectal cancer (CRC) arising in the left side of the colon (the part of the colon closest to the rectum) than patients who had never had a colonoscopy. However, colonoscopy did not reduce mortality from CRC in the right side of the colon, according to results 28 published in the December 15 Annals of Internal Medicine.

Using four Ontario-based databases, the investigators matched 10,292 patients who had died of CRC with 51,460 controls who did not have CRC. Each patient was matched to five controls by age, sex, income, and location of residence, and all controls were alive at the date of the patient’s death.

Because the investigators could not distinguish screening colonoscopies from diagnostic colonoscopies using the database records, they excluded all colonoscopies done within 6 months before a diagnosis of CRC.

Seven percent of case patients and almost 10 percent of controls had undergone colonoscopy. “Case patients were less likely than controls to have undergone any attempted colonoscopy…or complete colonoscopy,” stated the authors. Both attempted and complete colonoscopy reduced the likelihood of death from left-sided CRC, but not right-sided CRC.

The reasons for the lack of efficacy in preventing right-sided CRC are not clear, but may include less effective bowel preparation or colonoscopy technique in the right colon or differences in the biology and natural history of cancer arising in the right colon, explained the authors.

These results “seem consistent with a CRC mortality risk reduction of about 60 percent to 70 percent for the left colon and highlight the fact that we have very little data…about efficacy in the right colon,” said Dr. David Ransohoff of the University of North Carolina at Chapel Hill, in an accompanying editorial 29.

PLCO Update Suggests Positive Predictive Value of Prostate Screening Drops over Time

Also in the News

Dr. Donald F. Gleason, who developed the Gleason prostate cancer scoring system 30, died on December 28 in Edina, MN. The scoring system helps physicians determine the aggressiveness of prostate cancer, and the Gleason score is considered the most reliable indicator of the potential for prostate cancer to grow and spread.

In the most recent update of prostate cancer screening data from NCI’s PLCO 31 trial, the number of positive screening tests among the more than 38,000 men enrolled in the intervention arm has remained consistent during the 4 years of study. However, the positive predictive value of these tests—that is, the ratio of true positives to the total number of true and false positives—decreased over time. The full report 32 appeared in the December issue of the British Journal of Urology International.

Researchers attributed this decrease in the positive predictive value from baseline screening, which was 17.9 percent, to the subsequent annual screens, which ranged from 10.4 percent to 12.3 percent, to the fact that initial screening identified many of the cancers and left men with elevated prostate-specific antigen 33 (PSA) levels but negative biopsies to be identified in subsequent screening rounds. The cancers found at baseline were more likely than those found in subsequent screenings to be advanced stage (5.8 versus 2.9 percent) and to have a Gleason score 30 of 7 to 10 (34 versus 25.5 percent).

PLCO is one of two major ongoing trials expected to show whether screening for prostate cancer saves lives. The other is the European Randomized Study of Screening for Prostate Cancer 34 (ERSPC), which screens participants less frequently, at 2- and 4-year intervals. In a related commentary 35, ERSPC director Dr. Fritz H. Schröder addressed the issue of more aggressive prostate cancer, noting that the data in both trials “suggest that certain cancers escape screening irrespective of the screening interval used.”

Radiation Plus Hormone Therapy for Locally Advanced Prostate Cancer Improves Survival

A randomized clinical trial 36, published online December 15 in The Lancet, that tested hormone therapy (HT) alone versus HT plus radiation therapy (RT) for locally advanced prostate cancer adds to the body of evidence that adding RT to HT is more effective than HT alone for this group of patients.

Investigators from two European research groups, led by Dr. Anders Widmark of Umeå University in Sweden, assigned 875 men with locally advanced prostate cancer—cancer that had invaded local tissue but had not spread to the lymph nodes or distant sites—to receive either HT alone or HT plus standard 3D conformal RT. HT consisted of leuprorelin (known in the United States as leuprolide 37) given for 3 months and flutamide 38 given until disease progression or death. Patients could switch to the drug bicalutamide 39 if they experienced unacceptable side effects while taking flutamide.

After a median follow up of 7.6 years, 18 percent of the men in the HT group had died of prostate cancer compared to 8.5 percent of the men in the HT-plus-RT group. Ten-year mortality from prostate cancer was 23.9 percent for men in the HT group versus 11.9 percent in the HT-plus-RT group.

Follow-up visits revealed “a small but significant increase of moderate to severe late effects related to urinary and sexual function” in the HT-plus-RT group, stated the authors. However, patients did not report significant differences in their overall health and quality of life on surveys taken 4 years after treatment, with the exception of social function, which was decreased in the HT-plus-RT group.

Researchers Learn Why Some Platinum Drugs Are Toxic to Ear Tissue

Ototoxicity, or damage to inner-ear cells that detect sound, is a known side effect of platinum-based chemotherapy drugs. The damage is much more common with cisplatin 40 than with oxaliplatin 41, though the reason for this difference has been unknown. Swedish researchers have now tested some of the possible explanations by comparing the activity of these two drugs in the inner ears of guinea pigs. Their analysis 42 appeared December 30 in the Journal of the National Cancer Institute.

Cisplatin and oxaliplatin are thought to work by attaching to DNA and binding the genetic material so that it cannot replicate properly, thereby preventing cell division. But because the cells in the inner ear are already differentiated and less susceptible to this mechanism, the researchers hypothesized that cisplatin and oxaliplatin may also have an effect outside of the nucleus by generating reactive oxygen species, or free radicals 43.

They cultured colon carcinoma cells and measured the extent to which each drug induced cell death, or apoptosis, and found that cisplatin is significantly more dependent on free radicals than is oxaliplatin for triggering death in these cells. Guinea pigs showed more signs of free radical-induced apoptosis in their cochlea after exposure to cisplatin than to oxaliplatin.

The two drugs also showed marked effects on the transmission of sound signals from the cochlea to the brain, with cisplatin causing more damage to the hair cells that detect vibrations, and ultimately causing deafness, while comparable exposure to oxaliplatin did not. Cisplatin absorbed into the inner ear more easily than oxaliplatin did, and it remained in the tissues for a longer time.

“[It] should not be taken for granted that human subjects have the same cochlear pharmacokinetics [as guinea pigs],” the researchers noted, though they believe that the major aspects of their conclusions are valid for humans.

Director's Update

Resource Digs Deep into NCI's Research Funding

Dr. John E. Niederhuber

It is critically important that scientific investments made by NCI be transparent, ensuring accountability of the Institute and providing essential information to the entire cancer community who tirelessly advocate on behalf of patients. Since its creation in 1937, NCI has been tracking its research portfolio and over time has developed a robust system for coding each research project the Institute supports. NCI uses highly trained, experienced indexers who carefully review each grant to ensure that a given project’s scientific contributions are accurately captured, allowing the dollars associated with the project to be assigned to specific categories.

The importance of ensuring that the public has ready access to the scientific investments made by NCI, and the results of those investments, has been articulated in legislation numerous times over the past three decades. While NCI has focused on the rigors of the scientific coding process, the same level of attention was required to report its research investments in a clear and comprehensive manner. To address this, NCI recently launched a newly enhanced Funded Research Portfolio 44 on its Web site.

Since 1998, visitors to NCI’s Web site, 45, could search the cancer research investments made by the Institute, but often data had to be obtained from multiple sources. The enhanced portal now provides consolidated information on one site, including funding and other data on NCI’s intramural research program, grants to extramural scientists, and research contracts. The result is significantly improved access to this broader range of data and enhanced user-friendliness of the portal. Users can navigate to the funded research database from various points on NCI’s Web site, including the “Research and Funding 46” tab along the top of the home page or the “Science Serving People 47” or “Director’s Corner 48” portals.

The data can be searched using individual disease categories or conditions, or via a more overarching approach that can include a variety of parameters such as year, disease category, disease condition, key word, etc. Search results include all of the research projects and grants covered by those criteria, with links to the abstracts that outline the methodology and goals of each project or grant.

Users can also select one of two ways to view the output of their searches: a detailed “coding” report that shows all of the codes NCI’s expert indexers used to categorize each research project or grant, or a budget report that reveals the pro-rated funding for each project and the proportional relevance of that research to a given cancer type. In either case, users can then export their reports into a Microsoft Excel spreadsheet.

We are also concentrating our efforts on building analysis tools. One area on which there will be an ongoing focus, for example, is how to both define and incorporate “outcomes” into the research portfolio, including things like published papers, impact factors of publications, grant renewals, and changes to laboratory and clinical practice brought about by these investments. NCI is working with other NIH institutes to understand how they utilize evolving tools to conduct portfolio analysis and to determine if there are ways that we can work collectively to better demonstrate the return on investment for NCI funding.

Finally, let me emphasize that this enhanced resource is a work in progress, and we are integrating feedback from formal user testing sessions into plans for future improvement. We are actively seeking input on how to make the Funded Research Portfolio even more useful and accessible, and we encourage users to submit their comments on this resource to We are committed to refining this resource to meet the broad needs of the cancer community and using this tool to better communicate the investments in cancer research being made on behalf of the American people.

I hope you find this tool helpful. We believe it is another important way to connect you with your NCI.

Dr. John E. Niederhuber
Director, National Cancer Institute

Special Report

Genome Studies Yield Insights into Childhood Leukemia

The vast majority of children treated for acute lymphoblastic leukemia 49 (ALL) survive the disease. But the standard treatments fail in about 20 percent of cases, and the reasons are not always understood. A new study suggests that changes to a gene called IKAROS (or IZKF1) may help explain why chemotherapy fails some patients with ALL.

A bone marrow smear of lymphoblasts (leukemic cells in ALL) Leukemia cells from a patient missing the IKAROS gene, tagged in green, with a red-colored control "probe" that shows the normal two signals per cell

An analysis of patients’ DNA and health records revealed that the IKAROS gene was mutated or deleted in two independent groups of ALL patients who had high rates of relapse. These children, the researchers concluded, may have a previously unrecognized subtype of ALL with a very poor prognosis.

If confirmed, the discovery could lead to genetic tests that identify children at high risk of relapse who may benefit from more aggressive treatments. ALL is a cancer of the blood, and IKAROS plays a role in the development of the cells that are abnormal in the disease.

“This study is an important first step toward learning how to treat ALL patients better and attaining our goal of curing all children with leukemia,” said coauthor Dr. Stephen Hunger of the University of Colorado Denver School of Medicine and chair of the Children’s Oncology Group ALL Committee. “To improve the outcomes for patients who do not respond to treatment, we need to better understand how their leukemias differ from those of children who do.”

Fluorescence in situ hybridization of leukemic cells from a patient with IKAROS deletion. The IKAROS gene is tagged in green. The red-colored control “probe” shows the normal two signals per cell. The cell nuclei are stained blue. Lymphoblasts (leukemic cells in ALL) from
bone marrow

Results from TARGET

The IKAROS findings 50, which were published online in the New England Journal of Medicine last week, are the first results from the Childhood Cancer TARGET Initiative 51. TARGET is an NCI-supported project that brings together investigators with expertise on childhood cancers and genome analysis. The ALL study included investigators from St. Jude Children’s Research Hospital, the Children’s Oncology Group, the University of New Mexico Cancer Research and Treatment Center, and NCI.

Using state-of-the-art technologies, the team screened ALL cells for gains and losses of DNA, profiled their gene activity, and sequenced selected genes. By integrating these results and information about each patient’s clinical course, the researchers uncovered a potential contributing factor to poor outcomes in ALL.

“We were able to accelerate the pace of discovery substantially and to identify a previously unknown group of ALL patients at risk for treatment failure,” said coauthor Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program 52 and an NCI leader of the TARGET Initiative.

One major identifier of high-risk ALL has been the Philadelphia chromosome 53, and some researchers have wondered whether there were other comparable lesions associated with poor outcome. “We now know that there are, and the IKAROS deletion provides an opening for further exploring the biology of this subtype of high-risk ALL,” said Dr. Smith.

The Same Gene

The discovery builds on a report 54 published last year showing that IKAROS is often deleted in a specific subset of ALL patients at high risk of treatment failure—those who carry the Philadelphia chromosome. IKAROS, it now appears, may be altered in children who lack the Philadelphia chromosome but who also have a high risk of relapse.

“Here we have two subtypes of leukemia that share some but not all of the same genetic changes,” said Dr. Charles Mullighan of St. Jude, the study’s first author. “Our results suggest that IKAROS has a fundamental role in the behavior of these leukemias.”

The researchers are not recommending that physicians test IKAROS in ALL patients at this time. Dr. Mullighan noted that it is not clear which types of deletions and mutations are most relevant to prognosis, and more research is needed in additional populations.

Nonetheless, knowing that IKAROS deletions occur in a second subtype of high-risk ALL “helps us to better understand the genetic heterogeneity of the disease,” said Dr. Hunger.

Counting Copies

Gains and losses of DNA—also known as copy number changes—have been reported in ALL, but it has not been known whether they influence patient outcomes. Using high-resolution microarrays and cells from 221 patients with high-risk ALL, the researchers detected copy number changes in 50 chromosome regions.

The most striking finding was the association between IKAROS changes and poor outcome. The relapse rate was approximately 75 percent for patients with IKAROS alterations, which is extremely high for ALL, noted Dr. Mullighan. This was confirmed in another group of 258 children with ALL who were treated at St. Jude.

When the team profiled gene activity in ALL tumors, they discovered patterns like those of Philadelphia chromosome-positive ALL, which involves an overactive kinase protein. The similarity suggests that an overactive kinase protein may play a role in the new subtype, a theory the TARGET team is now investigating. Kinases have been the basis for successful cancer drugs such as imatinib 55 (Gleevec).

A Gold Mine

Although changes to IKAROS may play a central role in some forms of ALL, other genes are also involved. The investigators are now cataloguing the molecular changes in the new subtype and intend to publish more results later this year.

“This is really just the beginning of what we are going to learn,” said coauthor Dr. Daniela S. Gerhard, who directs NCI’s Office of Cancer Genomics 56 and is an NCI leader of the TARGET Initiative. The project has a wealth of biological and clinical information on these patients that can be a resource as new discoveries emerge, she explained. In the meantime, the data are available to researchers online at the TARGET Web site 51.

Dr. Gerhard is also a leader of The Cancer Genome Atlas 57 (TCGA) project, which employs a similar approach and has shared tools and resources with the TARGET investigators. “In terms of providing a foundation for personalized medicine, the ability to integrate genomic data and clinical information in this way has been a goldmine,” she said.

—Edward R. Winstead


Looking to Refine HER2-targeted Therapy

An illustration of HER proteins involved in an intracellular signaling pathway that controls cell growth HER proteins are part of an intracellular signaling pathway (depicted above) that is critical to many cellular functions. HER2 overexpression can lead to unchecked growth and, eventually, cancer. Click to enlarge. 58

When is a patient a candidate for a targeted therapy? That’s a question some breast cancer researchers are attempting to answer in the wake of results from several studies presented in 2007 that suggested the definition of HER2-positive—that is, women whose breast tumors produce an excess of the HER2 protein—may be too strict. These retrospective studies showed that even women who were HER2-negative benefited from the HER2-targeted agent trastuzumab 59 (Herceptin).

A monoclonal antibody, trastuzumab has been one of the most frequently cited success stories of the early era of molecularly targeted therapies. Its use improves progression-free and overall survival in women with HER2-positive metastatic breast cancer, and current data suggest it has a dramatic impact on the likelihood of cure for women with early stage HER2-positive disease.

Not all of the studies that continue trickling into the literature support the findings from those 2007 studies, but there is enough evidence, argued Dr. Peter Kaufman, professor of medicine at the Norris Cotton Cancer Center at the Dartmouth Hitchcock Medical Center, to suggest “that we may need to rethink conventional dogma.”

Hints of Something, but What?

Breast cancer experts agree that the recent studies are hypothesis-generating and should not dictate current clinical practice. After all, choosing breast cancer patients’ treatment based on HER2 status has been a successful paradigm, said Dr. Laura Esserman, who directs the breast cancer program at the Helen Diller Comprehensive Cancer Center at the University of California, San Francisco.

“In general, targeting HER2 has proven to be the right thing to do,” she said. “I think it’s pretty clear that we’ve done a good job. It hasn’t been perfect, though. There’s room for improvement.”

The Measure of a Target

IHC (immunohistochemistry) and FISH (fluorescence in situ hybridization) are the two testing methods recommended in the ASCO/CAP HER2-testing guidelines, which detail how the tests should be performed and what constitutes HER2-positive, -negative, and equivocal or borderline results. The IHC assay measures the amount of HER2 protein expressed in cancer cells, while the FISH assay measures either the total number of copies of the HER2 gene in a tumor cell or the ratio of HER2 genes to chromosome 17 copies.

Result IHC FISH (two approaches)
Positive 3+ <6 HER2 copies per cell or HER2:ch 17 ratio of 2.2 to 1
Negative 0+, 1+ <4 HER2 copies per cell or HER2:ch 17 ratio <1.8 to 1
Equivocal 2+ 4 – 5 HER2 copies or 1.8 – 2.2 HER2:ch 17 ratio

For example, researchers would like to find ways to improve the response rate to trastuzumab, which hovers between 25 and 30 percent. There are also misgivings about the accuracy of HER2 testing, concerns that were significant enough to prompt the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) to develop clinical guidelines 60 for HER2 testing.

“This is a tumor marker that’s being used as the sole determinant of therapy selection,” explained the guidelines panel co-chair, Dr. Antonio C. Wolff of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. “That’s why it’s important that pathologists do their best to adhere to the guidelines and clinicians ask questions about the quality of testing.”

It’s also critical to continue clinical research on the use of HER2-targeted therapies like trastuzumab and lapatinib 61 (Tykerb), Dr. Wolff added. “You need to be confident that you’re talking about true HER2-positive or -negative tumors. Then you can start looking at clinical outcomes,” he said.

The response rate and accuracy issues overlap with the questions about the definition of HER2-positive, which is most commonly determined with two tests, IHC and FISH 62. (See sidebar.)

The IHC and FISH cutoffs that correspond with response to trastuzumab were established based on clinical trials involving women with metastatic breast cancer, explained Dr. Tracy Lively, associate chief of the Diagnostics Evaluation Branch in NCI’s Division of Cancer Treatment and Diagnosis 63. The recent data, she added, suggest that perhaps those cutoffs may need to be modified for women being treated for early stage disease.

At the 2007 ASCO annual meeting, Dr. Soonmyung Paik, director of the Division of Pathology for the National Surgical Adjuvant Breast and Bowel Project 64 (NSABP) in Pittsburgh, first suggested the same thing. Dr. Paik and his colleagues had conducted an unplanned, retrospective analysis of available tumor samples from the B-31 trial 65, which compared adjuvant chemotherapy and trastuzumab to chemotherapy alone in women with HER2-positive, early stage breast cancer.

After retesting the tumor blocks, they found that 10 percent were truly HER2-negative (meaning the women shouldn’t have been enrolled in the trial). Nevertheless, there was a statistically significant trend toward improved outcomes in HER2-negative patients treated with trastuzumab. In fact, every HER2-negative patient subset saw some benefit, although not all reached statistical significance.

The findings were consistent with data from two other studies presented at the meeting, including another unplanned, retrospective analysis led by Dr. Kaufman of tumor samples from women with metastatic breast cancer in the CALGB 9840 66 trial. Some women in the trial whose tumors were HER2-negative according to FISH but who also had polysomy of chromosome 17—extra copies of chromosome 17, where the HER2 gene resides—had improved response rates to treatment with trastuzumab and chemotherapy compared to chemotherapy alone.

“That raised a fair number of eyebrows,” Dr. Kaufman said. “But, again, these findings are preliminary. It could just be a fluke due to the small sample size and retrospective analysis.”

Data on this topic continue to emerge, including a recent study 67 led by Dr. Michael Press from the Norris Comprehensive Cancer Center at the University of Southern California, which found no benefit from lapatinib in HER2-negative women.

Where to Go from Here

A large clinical trial is needed to determine whether some women, whose tumors reside somewhere in the molecular middle between HER2-negative and -positive, could benefit from HER2-targeted therapy, said Dr. Lively.

Such a study could be on the horizon. A validation study to confirm the results from Dr. Paik’s earlier study “is moving forward quickly,” explained NSABP Director of Medical Affairs Dr. Charles Geyer. If the results are positive, he continued, NSABP plans to conduct a clinical trial that would look at whether women with breast tumors that fall into a “HER2-low” category may benefit clinically from HER2-targeted therapy.

In the meantime, Dr. Esserman said, although the available data have raised some tough questions, she sees a positive side.

“It’s not necessarily that these assays are wrong,” she said. “Maybe there’s just a better way to measure.”

Dr. Esserman, for instance, is a co-principal investigator of a clinical trial of neoadjuvant chemotherapy for women with early stage breast cancer called I-SPY. The trial is using molecular analyses of serial biopsies and serial MRI scans to identify markers of response to treatment. One area showing promise, she noted, is the correlation of the levels of phosphorylated HER2 protein (the addition of phosphate groups to the protein, which regulates its activity) with other measures of HER2 expression and response to trastuzumab.

Much further along the clinical spectrum is an assay developed by San Francisco-based Monogram Biosciences called HERmark. According to the company, the assay provides a more exact measurement of HER2 levels, as well as the extent of the complexes formed by HER2 proteins on the surface of cancer cells (called dimers). Smaller studies presented at national meetings have suggested the assay can more accurately predict which women, including those who are HER2-positive, will respond to trastuzumab.

“Without the controversy,” Dr. Esserman said, “I don’t think there would be as much motivation to develop new and better assays.”

—Carmen Phillips

Featured Clinical Trial

Studying Immune System Reconstitution Following Unrelated Donor Transplantation and Graft-Versus-Host Disease Prevention

Name of the Trial

Phase I/II Randomized Pilot Study of Targeted Immune-Depleting Chemotherapy, Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation from an HLA-Matched Unrelated Donor, and Graft-Versus-Host Disease Prophylaxis Comprising Tacrolimus, Methotrexate, and Sirolimus versus Alemtuxumab and Cyclosporine in Patients with High-Risk Advanced Hematologic Malignancies or Other Diseases (NCI-07-C-0195).  See the protocol summary 68.

Dr. Michael Bishop Dr. Michael Bishop

Principal Investigators

Dr. Michael Bishop and Dr. Steven Pavletic, NCI Center for Cancer Research

Why This Trial Is Important

Allogeneic hematopoietic stem cell transplantation 69 (allogeneic HSCT) is one of the few potentially curative therapies available to patients with some advanced leukemias, lymphomas, or other blood or bone marrow diseases (collectively known as hematologic malignancies). In allogeneic HSCT, patients first receive high-dose chemotherapy and/or radiation therapy to destroy their hematopoietic stem cells 70; then, stem cells from a donor, either a relative or an unrelated volunteer, are used to restore bone marrow function.

Unrelated Donors Help Save Lives

This week’s Featured Clinical Trial focuses on restoration of the immune system in patients receiving blood-forming stem cells from unrelated donors. According to principal investigator Dr. Michael Bishop, only 1 in 4 patients who can be helped by a donor stem cell transplant has a suitable related donor available, so unrelated donors play an important role in permitting patients to receive this potentially life-saving therapy.

For more information about donating stem cells, visit the National Marrow Donor Program Web site 71.

Many patients undergoing allogeneic HSCT receive prophylactic 72 treatment with immunosuppressive 73 or other drugs to prevent graft-versus-host disease 74 (GVHD), a common and potentially serious complication of allogeneic HSCT. GVHD occurs when transplanted cells (the graft) attack the recipient’s (the host’s) organs and tissues. The effects of GVHD-prevention therapies on immune system reconstitution following allogeneic HSCT are not well understood.

In this clinical trial, patients with high-risk (refractory 75 or progressive 76), advanced hematologic malignancies will undergo chemotherapy to induce remission 77; those achieving remission will then undergo reduced-intensity, immune-depleting chemotherapy followed by allogeneic HSCT from a matched, unrelated donor. After HSCT, the patients will be treated with one of two distinct drug regimens that are currently used to prevent GVHD.  The researchers will assess the effectiveness and safety of these treatments and examine how the immune system rebuilds itself in these patients.

“The drugs used to prevent GVHD have a significant effect on how the immune system regenerates after stem cell transplant,” said Dr. Bishop. “Our purpose with this trial is to study how two proven GVHD-prevention regimens affect immune reconstitution following transplantation from unrelated donors, and then, based on the knowledge we gain, to design future trials to enhance immune system recovery, further reduce toxicity, and strengthen the antitumor activity of HSCT.” 

For More Information

See the lists of entry criteria 78 and trial contact information 79 or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

Community Update

ASCO Proposes Strategies for Oncology Workforce Shortage

The Oncologist Workforce by the Numbers


  • Nearly 70 percent of oncology visits are for patients 1 year or more post diagnosis
  • 76 percent of patients receive chemotherapy only in a medical office
  • 50 percent of practicing oncologists are age 50 or older

By 2020:

  • Cancer incidence is expected to increase by 50 percent
  • The number of survivors, currently at 12.1 million, is expected to increase by 81 percent
  • 6,400 oncologists will be age 65 or older

The American Society of Clinical Oncology 80 (ASCO) is calling for the development of “innovative practice arrangements” and an expansion of oncology fellowship programs to help ease the impact of a forecasted shortage of oncologists in the United States by 2020.

The steps are outlined in a new strategic plan 81 released by the organization in November 2008. The plan was prompted by a 2007 ASCO-fund report 82 by the Association of American Medical Colleges (AAMC) that projected a shortfall of as many as 4,080 medical oncologists by the end of the next decade.  

The cause of the forecasted shortage is multi-fold, explained Dr. Dean Bajorin of Memorial Sloan-Kettering Cancer Center, a co-chair of the working group that developed the strategic plan. But the primary causes driving the shortage are clear.

“Our country is getting older,” Dr. Bajorin said. “As the population ages, we will have more cases of cancer. The second aspect is that we’re getting better at treating cancer. More and more patients are surviving and they are surviving longer.”

Other factors are at play, including stagnation in the growth of oncology fellowship programs due in large part to a lack of funding, the 2007 ASCO/AAMC report concluded.

Among the changes to clinical practice advocated in the strategic plan, Dr. Bajorin said, is the expanded use of so-called nonphysician practitioners (NPPs) such as oncology nurses, nurse practitioners, and physician assistants.

According to Dr. Betty Ferrell, from the City of Hope Cancer Center and co-chair of an Institute of Medicine (IOM)-sponsored workshop on the oncology workforce 83 held last year, the time for such arrangements has already arrived.

“Much of medical oncologists’ time is now spent with cancer survivors or patients with advanced disease, and we’re running into this dilemma where oncologists don’t have as much time to see newly diagnosed patients,” she said. In areas such as palliative care and survivorship, NPPs can provide valuable services, she stressed.

ASCO has launched a study to assess the extent to which these “physician extenders” are playing a role in oncology practices, and to determine their impact on the number of patients seen and the quality of care provided.

There are early clues about such arrangements from the surveys done as part of the 2007 workforce report, Dr. Bajorin explained. “Practices that used nurse practitioners and physician assistants were able to see more patients,” he said. “It turned out to be a ‘win-win-win’ for everybody involved. The patients preferred that model. The NPPs liked the model, and the oncologists did, as well.”

Other changes to clinical practice, Dr. Bajorin added, include finding ways to bring retired oncologists back into the workforce on a limited basis.

“The workforce problems we’re having now are only going to get worse in the future,” said Dr. Ferrell. Addressing the problem will require a broad range of activities, such as improved training for primary care physicians—a field that is already in the midst of a shortage—on meeting the unique needs of cancer survivors.

With established model programs in areas like training and palliative care, and the attention brought to topics like palliative care 84 and survivorship 85 through reports from the IOM and President’s Cancer Panel, there is an opportunity to make much needed changes that could also improve the overall quality of cancer care, Dr. Ferrell said.

“We have an opportunity to solve some serious problems and to much better serve patients and survivors,” she said.

—Carmen Phillips

FDA Update

New Prostate Cancer Drug Approved

The FDA recently approved the injectable drug degarelix 86 for the treatment of advanced, hormone-sensitive prostate cancer. Developed by Ferring Pharmaceuticals, degarelix prevents tumor growth by blocking signals from the pituitary gland that trigger the release of testosterone. A phase III study comparing it with a similar drug, leuprolide 37 (Lupron Depot), showed that degarelix was just as effective at lowering testosterone levels, though it did so more quickly than leuprolide.

Gardasil Indication for Men Reviewed

The FDA is reviewing an application for approval of the Merck & Co. vaccine Gardasil 87 for use in males. Data for the review come from a study of 4,000 boys and men aged 16 to 26, in which the vaccine reduced the risk of external genital lesions by 90 percent, according to a company press release. Gardasil targets the two types of human papillomavirus that are most commonly linked to cancer, including cancers of the cervix, vulva, vagina, anus, penis, and head and neck, and two other types linked to genital warts. It is currently approved for use in girls and women aged 9 to 26 years.

A Warning for Bone Density Drug

The January 1, 2009 issue of the New England Journal of Medicine includes a letter 88 from Dr. Diane Wysowski of the FDA’s Division of Drug Risk Evaluation, citing reports of esophageal cancer and deaths in patients confirmed or suspected of taking the oral bisphosphonate alendronate (Fosamax) or other drugs in this class, which prevent bone weakness. In the United States, between 1995 and the middle of last year, 23 patients developed the disease and 8 died. In Europe and Japan, 31 patients developed esophageal cancer and 6 died. In some cases, these patients had Barrett esophagus 89, a known precursor to esophageal cancer.

“Esophagitis has been associated with oral bisphosphonates, usually when the drugs are not taken according to directions,” wrote Dr. Wysowski. She warned that physicians should not prescribe oral bisphosphonates to patients who have Barrett esophagus and that the drugs should be considered possible risk factors for esophageal cancer.

CMS Update

CMS Proposes Expanding Medicare Coverage of PET Scans in Cancer Patients

The Centers for Medicare and Medicaid Services (CMS) has issued a national coverage determination 90 (NCD) that would expand Medicare coverage of PET scans as an initial diagnostic test for cancer patients. Under an existing NCD issued in 2005, Medicare only covers such PET scans for certain cancers if the treating physician and patient agree to submit data on the scans to a clinical registry.

The registry, the National Oncologic PET Registry 91 (NOPR), was organized as a result of a collaboration among CMS and several radiology- or cancer-related professional associations. It was the first such registry established under CMS’ Coverage with Evidence Development program, the goal of which is “to develop evidence on the utilization and impact of the item or service evaluated in an NCD,” according to a CMS statement.  

The proposed NCD would lift the requirement for submission of data to the NOPR for the first PET scan intended to guide the course of a patient’s treatment. The proposal follows an analysis of NOPR data 92 published last spring, which found that PET scan results altered how physicians intended to manage patients more than one-third of the time, including the type of treatment they would prescribe.

CMS is accepting public comments 93 on the proposed NCD through February 5, 2009.


NCI Scientists Receive 2008 HHS Awards

On January 6, four NCI scientists from the Center for Cancer Research 94 (CCR) were honored by the Department of Health and Human Services with 2008 Departmental Awards.

Dr. Ira Pastan 95, of the Laboratory of Molecular Biology, was presented the Secretary’s Award for Meritorious Service for his outstanding contributions to the development of immunotoxins against cancer. Drs. Douglas Lowy 96 and John Schiller 97 received the Hubert H. Humphrey Award for Service to America, for their contributions to the development of the first HPV vaccines. And Dr. Robert Wiltrout 98 received the Career Achievement Award for exceptional leadership of CCR and consistently outstanding research in the immunology and cancer fields.

NCI Holds Annual Intramural Scientific Retreat

On January 8, NCI’s intramural scientific investigators came together to share their research at the Annual Intramural Scientific Retreat. The retreat was an opportunity for investigators to interact with colleagues from different disciplines and to learn about the work being done in labs across the institute.

Over the course of the day, three award lectures were presented. Dr. Ira Pastan delivered the 5th Annual Alan S. Rabson Award Lecture for Intramural Research. Dr. Carol Prives of Columbia University presented the 8th Annual Rosalind E. Franklin Award Lecture for Women in Cancer Research, and Dr. Brian Druker, director of the Knight Cancer Institute at Oregon Health and Science University, spoke about translational research and his work developing imatinib 55 (Gleevec) during the 13th Annual Alfred G. Knudson Award Lecture in Cancer Genetics.

Finally, a number of NCI scientists received NCI Director’s Intramural Innovation Awards, which are designed to support the development of highly innovative approaches and technologies aimed at significant cancer-related problems.

Recipients of NCI Director's Intramural Innovation Awards Recipients of NCI Director's Intramural Innovation Awards

Cover art of CCR Connections volume 2, number 2 New Issue of CCR Connections Released

NCI’s Center for Cancer Research 94 (CCR) recently released a new issue of their news magazine, CCR Connections. To view the Web version of Volume 2, Issue 2, please visit:

In the latest issue, readers will find information on recent journal articles and staff awards, as well as a conversation with CCR’s new chief of the Medical Oncology Branch; features on targeted imaging technologies, the DNA of drug discovery, and ovarian cancer; and a commentary by former CCR investigator Dr. Bruce Johnson.

CCR Connections is published biannually. Send a request for a print or online subscription to

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