National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 16, 2010 • Volume 7 / Number 22

Cancer Research Highlights

Mutated Gene Linked to Poor Survival in Acute Myeloid Leukemia

Researchers have identified a gene that is frequently mutated in a subset of patients who have acute myeloid leukemia (AML), and these patients tend to have significantly worse outcomes than patients who have normal copies of the gene. If the findings are confirmed, then clinical trials could investigate whether giving patients with the mutated gene more intensive therapy early in treatment helps them live longer, said Dr. Timothy Ley of the Washington University School of Medicine in St. Louis and his colleagues. Their findings were reported online in the New England Journal of Medicine on November 10.

The mutations were found in 62 of 281 patients (22 percent) with AML and occurred throughout a gene called DNA methyltransferase 3A (DNMT3A), which plays a role in fetal development and is active in blood-forming cells later in life. Although the researchers do not yet know how the mutations contribute to the disease, the median overall survival of patients who had the mutations was 12.3 months compared with 41 months for patients without the changes. All of the mutations were associated with poor overall survival, which suggests that they “have an important common effect on the potential of AML cells to cause lethal disease,” the researchers wrote.

The mutations were most often found in patients classified as having “intermediate-risk” disease, based on an analysis of their chromosomes (56 of 166 patients, or 33.7 percent), and the changes were absent from all 79 patients who had a favorable-risk profile. The intermediate-risk group includes patients who may or may not respond to standard treatments, and doctors currently cannot distinguish these individuals. The new findings suggest that DNMT3A mutations could be a biological marker for identifying patients at risk of poor outcomes, the researchers said.

“Patients who have the DNMT3A mutations have poor outcomes across the board,” said Dr. Ley. “It’s really striking.” His team discovered the first DNMT3A mutation when resequencing the cancer genome of a woman who relapsed and died of recurrent AML 2 years after initial diagnosis. The researchers had sequenced normal and cancer genomes from this patient in a study reported in 2008. But it was only when they went back and analyzed her DNA using newer sequencing technologies that they found the change involving DNMT3A.

See also: A Cancer Genome Is Sequenced, Revealing Rare Mutations

Novel Drug Effectively Shrinks Tumors in Hodgkin Lymphoma

An investigational drug composed of a monoclonal antibody linked to a potent chemotherapy agent led to complete or substantial tumor shrinkage in nearly 40 percent of patients with Hodgkin lymphoma in a phase I clinical trial, researchers reported last week. The results were published November 4 in the New England Journal of Medicine.

In the trial, 42 patients with Hodgkin lymphoma and three patients with anaplastic large-cell lymphoma (ALCL) who had relapsed after earlier treatments (including stem cell transplantation) or were resistant to standard treatments received the drug brentuximab vedotin (SGN-35). The antibody component of the drug targets a protein called CD30 that sits on the surface of lymphoma cells. Attached to the antibody is a powerful investigational chemotherapy agent called monomethyl auristatin E (MMAE).

Developed by Seattle Genetics, MMAE is 100 to 1,000 times more potent than other chemotherapy drugs, according to the company. The antibody directs the drug to cancer cells, where it is absorbed and degraded by enzymes in the cells’ nuclei, releasing the MMAE and leading to cell death.

Among the 17 patients who had measurable responses, 11 had no evidence of existing cancer (complete response) after treatment, and the remainder had at least 50 percent tumor shrinkage (partial response). Because it was a phase I trial, patients received different doses. Among the 12 patients who received the most effective dose for which side effects were the least severe (the maximum tolerated dose), six had a measurable response. Overall, 86 percent of patients in the trial had at least some tumor shrinkage and side effects were limited.

Over the last 3 decades, there has been little progress in developing new treatments for Hodgkin lymphoma. So, these results offer significant promise for patients, said the study’s lead investigator, Dr. Anas Younes of the University of Texas M. D. Anderson Cancer Center. “I think it is remarkable that the majority of patients had tumor reductions when they were treated on the phase I study,” he wrote in an e-mail.

Initial results from a phase II trial of the drug in the same patient population appear to be even stronger than the phase I results, according to Seattle Genetics. In late September, the company announced that 75 percent of the 102 patients in the phase II trial, all of whom had relapsed/refractory Hodgkin lymphoma, had an objective response. And, in early October, the company reported that patients with ALCL in another phase II trial of brentuximab had an 86 percent measurable response rate. More complete results and details from both trials will be presented at the American Society of Hematology annual meeting in early December.

Indefinite Imatinib Therapy May Not Be Necessary for Some CML Patients

Findings from a small clinical trial in France suggest that some patients with chronic myelogenous leukemia (CML) may be able to stop treatment with the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) without the disease returning. The results indicate that some patients may be cured by imatinib and similar therapies and may not need to remain on therapy permanently, the study authors concluded in the November 2010 Lancet Oncology.

The trial involved 100 patients who had maintained a complete molecular response (no evidence of disease) for 2 years on imatinib and then stopped taking the drug. Sixty-nine of the patients had been followed for a median of 24 months, and, among these, nearly 40 percent remained disease free for at least a year after discontinuing imatinib therapy. For patients whose disease returned, in nearly every case the recurrence happened within 6 months of stopping treatment, and all patients responded to the re-initiation of imatinib therapy, although not all of them obtained a second complete response.

The fact that these patients “retained sensitivity to the drug … [suggests] that discontinuation does not lead to acquired resistance to imatinib and does not raise any further safety issues,” wrote Dr. Francois-Xavier Mahon and his colleagues. Sustained remissions on imatinib are not common, they continued, “so patients treated with imatinib who are candidates for treatment interruption are rare.”

The researchers identified several factors that were predictive of which patients were most likely to remain in remission after therapy discontinuation, including male gender, a remission lasting more than 4 years, and a good prognosis at diagnosis based on a standard prognostic tool.

While research in this area continues—including whether superior results could be achieved with second-generation TKIs such as dasatinib (Sprycel) and nilotinib (Tasigna) that have the same molecular target as imatinib and are approved for CML treatment—discontinuation of imatinib should be done “only in the context of an ongoing clinical trial,” the authors cautioned.

In an accompanying commentary, Dr. Peter Valent from the Medical University of Vienna agreed that “there is now hope for drug-induced cure in CML.” However, he continued, more work is needed to answer important questions. “Clinical trials will define the curative potential of novel TKIs and of various drug combinations in the future,” he said.

Lasofoxifene Is Potential New Option for Breast Cancer Risk Reduction

An investigational agent in the same family of drugs as tamoxifen and raloxifene may be as or more effective in reducing breast cancer risk in some women, according to the findings of a large clinical trial. The drug, lasofoxifene, also appears to have important benefits for both bone and heart health and, with one exception, appears to lack the rare but potentially serious side effects associated with tamoxifen and raloxifene. The results were published online November 4 in the Journal of the National Cancer Institute.

The findings come from a randomized clinical trial called PEARL, in which more than 8,500 postmenopausal women with osteoporosis were randomly assigned to take a placebo or one of two different doses of lasofoxifene (0.25 mg or 0.5 mg) daily for 5 years. Initial results, based on 3 years of follow-up, showed a reduced risk of estrogen receptor (ER)-positive breast cancer in women who received the higher dose of lasofoxifene compared with the placebo.

The new, more mature results, which provide 5 years of participant follow-up, show the overall risk of breast cancer was reduced by 79 percent, and the risk of invasive ER-positive breast cancer was reduced by 83 percent in women who took 0.5 mg of lasofoxifene compared with women who took the placebo.

There was some risk reduction seen with the lower dose of lasofoxifene, but it was not statistically significant, reported Dr. Andrea LaCroix of the Fred Hutchinson Cancer Research Center and her colleagues. Women who took the higher lasofoxifene dose also had statistically significant reductions in the risk of vertebral and nonvertebral fractures, cardiac events, and strokes. The only notable side effect was an increased risk of blood clots.

The researchers also conducted a nested case-control study that included all 49 cases of breast cancer in the trial and 156 women from the trial’s placebo arm. Women with higher levels of the hormone estradiol at study entry, they found, seemed to gain a greater cancer prevention benefit from lasofoxifene, but the difference was only statistically significant for total breast cancer incidence, not ER-positive breast cancer.

“We need more complete information about the long-term effects of lasofoxifene on both beneficial and unfavorable outcomes,” cautioned Dr. Victor Vogel of the Geisinger Medical Center in an accompanying editorial. Although women in the trial were, on average, significantly younger than participants in the STAR trial, which affirmed the breast cancer risk reduction benefits of both tamoxifen and raloxifene, they were also at lower overall risk of breast cancer (based on their Gail model scores).

Nevertheless, given the “dramatic” risk reduction seen with lasofoxifene in the PEARL trial, Dr. Vogel called the findings “encouraging.” Lasofoxifene is still an investigational agent. In May, Pfizer, which manufactures the drug, withdrew its application to the FDA to market the drug for the treatment of osteoporosis. According to a company spokesperson, Pfizer is investigating several options for the drug, including selling it to another company.

Some Cells in Stroma May Block Immune System’s Antitumor Effects

Researchers have identified a population of cells in the stroma—the supporting connective tissue of an organ—that may prevent the immune system from attacking or inhibiting the growth of tumors. When this subset of stromal cells was deleted in mice, relatively small tumors in the animals stopped growing, Dr. Douglas Fearon of the University of Cambridge, United Kingdom, and his colleagues reported November 5 in Science.

Cancer biologists have long wondered why the human immune system frequently appears to be suppressed in the tumor microenvironment. One factor in this phenomenon, Dr. Fearon and his colleagues now propose, may be stromal cells that express a protein called the fibroblast activation protein (FAP) on their cell surface. Although the results need to be confirmed in humans, they could help explain, for instance, why vaccines designed to boost a patient’s immune response against cancer have had limited success, the researchers said.

The suppression of the immune system by FAP-positive cells “may be a developmentally programmed, tissue-protective function that, in the context of a tumor, is catastrophically inappropriate,” the study authors wrote.

These results support other studies suggesting “that immunizing against fibroblasts in tumors can unmask an immune response to cancer,” wrote Drs. Hans Schreiber and Donald Rowley of the University of Chicago in an accompanying editorial. They noted that eliminating FAP-positive cells should inhibit the growth of small spontaneous tumors and, therefore, may help eliminate clinically undetectable cancer cells that have already metastasized before a primary tumor is surgically removed.