National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
April 5, 2011 • Volume 8 / Number 7

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Cancer Research Highlights

Latest Surveillance Data Show Cancer Cases and Deaths Continue to Decline

The overall rate of both new cancer diagnoses (incidence) and cancer deaths continued to decrease between 2003 and 2007, according to the Annual Report to the Nation on the Status of Cancer, published online March 31 in the Journal of the National Cancer Institute. The decrease in cancer death rates of 1.6 percent per year continues a trend that began in the early 1990s. Overall, the decrease in incidence rates for men and women combined was 1 percent per year.

The report also showed, for the first time, that lung cancer death rates in women decreased between 2003 and 2007. In addition, although cancer incidence rates continued to increase in children 19 years of age and younger, the rate of cancer deaths in this age group fell. Among all racial/ethnic populations, cancer incidence rates and cancer death rates decreased, except among American Indian and Alaskan Natives, for whom the mortality decrease was not statistically significant.

The report, which was co-authored by the North American Association of Central Cancer Registries, NCI, CDC, and the American Cancer Society, provides updated statistics on cancer trends through 2007. This year’s report featured a special section on brain and other nervous system tumors, including nonmalignant brain tumors.

Nonmalignant tumors make up two-thirds of all adult brain tumors and one-third of childhood brain tumors, with meningiomas being the most common type of brain and other nervous system tumor in the United States. The authors found a decrease in the incidence of malignant neuroepithelial brain and other nervous system tumors from 1987 to 2007 and modest improvements in the 5-year survival rate for most types and age groups.

“It is gratifying to see the continued steady decline in overall cancer incidence and death rates in the United States—the result of improved methods for preventing, detecting, and treating several types of cancer,” said NCI Director Dr. Harold Varmus. “But the full repertoire of numbers reported today also reflects the enormous complexity of cancer, with different trends for different kinds of cancers, important differences among our diverse people, and different capabilities to prevent, detect, and treat various cancers. Moreover, as our population continues to age, we have an obligation to discover and deliver better ways to control all types of cancers.”

PatientsTaking Imatinib for CML Have Similar Risk of Death as General Population

In an international study, the risk of death for chronic myelogenous leukemia patients treated with imatinib (Gleevec) who had been in remission for at least 2 years was not different from that of the general population. The Imatinib Long-Term (Side) Effects (ILTE) study, led by Dr. Carlo Gambacorti-Passerini from the University of Milano-Bicocca in Italy, is the first independent assessment of imatinib’s long-term effects. The results were published online March 21 in the Journal of the National Cancer Institute.

The researchers enrolled 832 patients from 27 hospitals on five continents who were in remission after taking the drug for 2 years. The patients were followed for a median of almost 4 years from enrollment, corresponding to almost 6 years from the start of imatinib treatment. Only 27 patients experienced a major side effect associated with the drug during follow-up. More than half of patients experienced at least one mild side effect that affected quality of life, of which 68 percent were possibly or likely related to the drug. However, only 2.3 percent of patients discontinued treatment due to side effects.

At 6 years from the start of treatment, 95 percent of patients remained in remission. Of 20 observed deaths, only six were related to CML progression. “A comparison of the observed mortality rate in CML patients with the rate in the general Italian population showed no excess mortality,” the authors wrote.

The excellent survival of the patients in this study “speaks to both the astounding effect [imatinib] has had on the clinical course of this disease and its negligible effect on the development of treatment-related malignancies,” commented Dr. B. Douglas Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in an accompanying editorial.

Dr. Smith noted that a large number of the patients (478) had received imatinib as second-line therapy, and 90 percent of those patients had previously received treatment with interferon. Further analysis of the data would be helpful to determine whether interferon played a role in the observed long-term remissions, suggested Dr. Smith.

Riskof Second Cancer Following Radiation Therapy Is Small

In a study of adults who survived at least 5 years after being treated for solid cancers that are routinely treated with radiation therapy, 9 percent developed a second solid cancer over an average follow-up time of 12 years. About 8 percent of those cancers appear to be related to radiation therapy. Results from the study, led by Dr. Amy Berrington de González of NCI’s Division of Cancer Epidemiology and Genetics, were published online March 29 in Lancet Oncology.

In the first comprehensive analysis of its kind, Dr. Berrington de González and her colleagues examined data from nearly 650,000 adult patients recorded in nine of the Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 2002. Depending on their initial cancer type, between 23 percent and 79 percent of the patients received radiation therapy during treatment.

The researchers calculated the relative risk of developing a second cancer for patients who received radiation therapy during their initial treatment compared with patients who did not. The relative risk of developing a second cancer associated with radiation varied with type of first cancer and was highest in survivors of testicular seminoma. After adjusting for factors such as age, time since initial diagnosis, and year of diagnosis, the researchers estimated that about 3,300 of the 60,271 second cancers observed over the study period could be attributed to radiation therapy.

The study also described for the first time the overall absolute risk of second cancers related to radiation therapy: an estimated 5 of every 1,000 patients treated with radiation therapy who survive for 15 years would be anticipated to develop a radiation-related cancer. “That number can be used by doctors to convey the message to patients that the absolute risk of developing a second cancer related to radiotherapy is quite small,” explained Dr. Berrington de González.

Further research will be needed to determine the risks from newer radiation therapy technologies, such as intensity-modulated radiation therapy (IMRT), which expose normal tissues to different patterns of radiation than older techniques. Previous studies have raised concerns "that the second cancer risk might be higher in patients treated with IMRT. We will need to study this exposure in the future to assess that risk,” concluded Dr. Berrington de González.

ImmunotherapyTargets Pancreatic Tumors from the Outside

Promising results from an early-stage clinical trial may lead to new treatment options for patients with advanced pancreatic cancer. The treatment appears to work differently than the trial investigators had expected, attacking tumors primarily by altering their surrounding tissue. The findings were published online March 25 in Science.

The phase I clinical trial, funded by Pfizer, involved 21 patients newly diagnosed with advanced pancreatic cancer, for whom current therapies are mostly ineffective and 5-year survival rates are less than 5 percent. Patients received the chemotherapy drug gemcitabine and a monoclonal antibody called CP-870,893 that binds to the CD40 receptor on the surface of certain immune cells.

Overall, four patients had some tumor shrinkage (partial response) and 11 saw their disease stabilize, with no further tumor growth. The median progression-free survival was 5.6 months and overall survival was 7.4 months, both of which are superior to what is historically seen in patients treated with the current standard of care, gemcitabine alone, explained the study’s lead investigator, Dr. Robert Vonderheide of the University of Pennsylvania’s Abramson Cancer Center.

The researchers expected the CD40 antibody to stimulate T cells to attack the tumor, but an analysis of tumor samples from two patients whose tumors responded to therapy found few or no T cells. The researchers did find an abundance of another type of immune cell, macrophages, which typically have been thought to help tumors ward off assault by the immune system.

To help determine what may be happening in these patients, the researchers treated mice that were genetically engineered to develop pancreatic cancer with a similar CD40-targeted antibody. This antibody was found to bind to macrophages outside of the tumor, Dr. Vonderheide noted. Consequently, he added, the macrophages “changed their properties, took on killing properties, and quickly migrated to the tumor.” In the mice, he continued, “we saw the death of tumor cells themselves, but we also saw that the surrounding stroma was coming under attack by macrophages, almost dissolving.”

The findings are preliminary, and further work is needed to better understand how the therapy works and how it can be best combined with other therapies, Dr. Vonderheide explained. The Abramson research team is launching another phase I trial to test the antibody in patients with metastatic melanoma, in combination with another experimental agent that stimulates T cells to attack tumor cells.

BreastCancer Genomes Sequenced to Study Drug Response

Researchers have used whole-genome sequencing to catalog the genetic alterations in tumors from 50 patients with estrogen receptor (ER)-positive breast cancer. The goal of the study, which was presented at the AACR annual meeting, was to identify genetic factors that explain why some tumors respond to estrogen-lowering drugs and others do not.

Women with ER-positive breast cancer take estrogen-lowering drugs, such as tamoxifen or aromatase inhibitors, to slow the growth of tumors, make the tumors easier to remove surgically, or prevent the regrowth of tumors after surgery or radiation. But the treatment does not always work, and resistant tumors are associated with a poor prognosis. The genetic factors underlying resistance to estrogen-lowering therapy are not clear.

To investigate this question, Dr. Matthew Ellis of the Washington University School of Medicine in St. Louis and his colleagues studied the tumor genomes and normal genomes of 50 women with ER-positive breast cancer. The women were participants from two clinical trials testing aromatase inhibitors as neoadjuvant therapy. Patients received one of three types of aromatase inhibitors following a biopsy and prior to treatment with surgery. Twenty-six of the 50 patients had tumors that responded to aromatase inhibitors, and 24 had tumors that did not respond.

The analysis, which included approximately 10 trillion chemical bases of DNA, revealed a “constellation of mutations,” including some that are common and some that are rare, noted Dr. Ellis. The vast majority of potential cancer-related mutations detected in the study were found in less than 5 percent of tumors.

“Breast cancer is extraordinarily complicated,” said Dr. Ellis, “and the sequencing revealed a lot of new biology that we had not seen before.” The researchers have begun the process of relating the mutations discovered in the study to the responses to estrogen-lowering therapies.

The commonly mutated genes included PIK3CA and TP53. In addition, MAP3K1, a tumor-suppressor gene, was defective in 10 percent of patients. This gene has been implicated in other cancers, but this is the first time the gene has been associated with breast cancer, according to the researchers.

The finding that half the tumors had mutations in PIK3CA was important because it underscores the opportunities to inhibit the effects of these changes in breast cancer, noted Dr. Matthew Meyerson of the Dana-Farber Cancer Institute, who discussed the results at the meeting.

Dr. Meyerson also said that his group has independently found frequent inactivating mutations in MAP3K1 in breast cancer, thereby “validating the remarkable results by Dr. Ellis.” The current study, he noted, demonstrates the feasibility of conducting genomic analyses of breast cancer using next-generation sequencing in the context of cancer clinical trials.

Combinationof Two Targeted Cancer Drugs Appears Safe in Early Testing

A small study testing a combination of two targeted drugs, each directed against a different pathway that is activated in cancer, has yielded positive results, researchers said at the AACR annual meeting. There were also some early indications that the combination treatment may have antitumor effects. The regimen was generally well tolerated, according to the researchers, and side effects were similar to those observed when the drugs were tested as single agents.

The combination therapy targets the RAS/RAF/MEK and PI3K pathways, which are among the most commonly mutated in cancer. Both drugs in the combination are made by Genentech; GDC-0973 inhibits the MEK pathway, and GDC-0941 targets the PI3K pathway.

“These pathways are altered in most tumors,” said Dr. Johanna Bendell of the Sarah Cannon Research Institute in Nashville, who presented the findings. The researchers were testing the idea that combining the drugs would have synergistic effects, but they were concerned that the combination would be too toxic for patients, she noted.

In the current study, at least, this was not the case. The most common side effects included diarrhea, fatigue, rash, nausea, and vomiting. Most of these were mild, according to the researchers. 

Of the 27 patients enrolled in the trial, tumor size decreased in five patients, including two patients with melanoma, one with prostate cancer, and two with non-small cell lung cancer. One patient with lung cancer and two patients with melanoma had stable disease over 6 months, the researchers said.

The study is ongoing, and the researchers will continue to study the optimal dose and monitor antitumor activity.

“Many people believe that if you hit multiple pathways [in cancer] you will have better results, and this is a pioneering effort,” said Dr. Daniel Von Hoff of the Translational Genomics Research Institute, who moderated a press briefing on the study.

Dr. Bendell predicted that other companies will begin testing combinations of these targeted therapies. She acknowledged that testing two drugs that are produced by different companies can present additional challenges.

TestMay Detect Mesothelioma at the Earliest Stages

An investigational test based on a panel of 13 protein markers in the blood may be able to detect malignant mesothelioma in people exposed to asbestos, even when the disease is in its earliest stages, according to findings from a study presented at the AACR annual meeting. To conduct the study, researchers used a technology that relies, in part, on DNA molecules called aptamers that bind to proteins in blood samples.

The study used a test developed by Colorado-based SomaLogic (which also funded the study). The test was used to analyze blood samples from 90 patients who had been exposed to asbestos and developed malignant mesothelioma and blood samples from 80 healthy participants who had been exposed to asbestos (control subjects). The research team, led by Dr. Harvey Pass from the New York University Langone Medical Center, used 75 percent of the samples to identify a panel of proteins that were routinely seen in blood samples from patients with mesothelioma but not in samples from the control subjects. Dr. Pass’ laboratory is supported by NCI’s Early Detection Research Network.

The biomarker panel in this “training set” had 80 percent sensitivity and 100 percent specificity for distinguishing between mesothelioma patients and control subjects and detected 15 of the 19 early-stage mesotheliomas, reported Dr. Pass. Similar results were seen in the remaining 25 percent of the samples, known as the validation set. During a press briefing, Dr. Pass also presented data on the test’s performance in a different blinded validation set of samples from 38 patients with asbestos-related mesothelioma and 62 healthy asbestos-exposed control subjects. In this set, the marker panel had 92 percent specificity and 92 percent sensitivity.

In most patients with malignant mesothelioma, the disease is typically diagnosed at an advanced stage, when treatment has very limited success. So the ability to detect early-stage disease is important “because these are the people with mesothelioma who will have long-term survival,” Dr. Pass said during the briefing.

The current incidence of malignant mesothelioma is low: approximately 3,000 cases a year in the United States. However, according to Dr. Pass, an estimated 27.5 million people in the United States alone had occupational exposure to asbestos between 1940 and 1979, and because of its long latency period, the incidence of mesothelioma is not expected to peak for another 20 years.

Additional validation studies of the assay are being planned, Dr. Pass said in an interview, and more aptamers are being added to the test in an effort to improve its performance.

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