Mutant Protein Implicated in Diffuse Large B-cell Lymphoma
Recent studies have implicated the NF-κB signaling pathway in the development of a subset of diffuse large B-cell lymphomas. Two new studies now provide another piece of the puzzle. While mutations in genes such as CARD11 can spur cell growth by activating the NF-κB pathway, mutations in a gene called A20 may remove a natural "brake" on the pathway. The findings suggest that multiple lesions in the NF-κB pathway may be involved in DLBCL, the most common lymphoma in adults, according to results published online in Nature this week.
"We have identified genetic lesions that target multiple components of the same pathway in the majority of DLBCL with constitutive activation of NF-κB, and this will have implications for the possible design of therapies that may benefit patients with these abnormalities," said Dr. Laura Pasqualucci of the Herbert Irving Comprehensive Cancer Center at Columbia University, who led one of the studies. Drugs targeting the NF-κB pathway are in development, she noted.
Her team analyzed tumor samples from 168 cases of DLBCL. Mutations in multiple genes associated with the NF-κB pathway were found in half of the activated B-cell-like (ABC) subtypes analyzed, and in a smaller fraction of the germinal center B-cell-like (GBC) subtypes. The A20 gene was the most commonly altered, with a third of the ABC-DLBCL patients showing inactivation of both gene copies by mutation or deletion.
In the second study, researchers at the University of Tokyo conducted genome-wide analyses of genetic lesions in 238 B-cell lymphomas. The A20 protein was frequently inactivated in several types of cancer, including mucosa-associated tissue lymphoma, a form of Hodgkin's lymphoma, and to a lesser extent, B-cell lymphomas. Both teams found that, in laboratory experiments, the normal A20 protein suppressed cell growth and caused abnormal cells to commit suicide when reintroduced into A20-deficient cells.
Testing Breast Tumors May Predict Response to Chemotherapy
Women treated for breast cancer whose tumors carry normal versions of the genes HER2 and TOP2A may not benefit from an anthracycline as part of additional chemotherapy designed to prevent a recurrence. Instead, these patients may benefit from a less toxic regimen that does not include an anthracycline, researchers reported online in the Journal of the National Cancer Institute on April 28.
In previous studies, the benefits of adjuvant therapy with an anthracycline-based regimen were restricted to women with HER2 alterations (about 20 percent of breast cancers). But because the TOP2A gene resides near HER2, some researchers have wondered whether the response to anthracyclines might be associated with TOP2A alterations.
To explore the question, Dr. Kathleen Pritchard of Sunnybrook Odette Cancer Centre in Toronto and her colleagues analyzed these genes in tumor samples from 438 of the 710 participants in the National Cancer Institute of Canada's Mammary 5 trial.
Women whose tumors had either TOP2A deletions or amplifications (extra copies) had longer recurrence-free survival and overall survival in response to chemotherapy that included the anthracycline epirubicin than to chemotherapy without anthracyclines, while patients with normal TOP2A genes showed no difference in responsiveness. Alterations in TOP2A and in HER2 appear to have similar value in guiding the selection of anthracycline-containing regimens, the researchers concluded, noting that larger studies are needed to determine which measurement is more closely associated with response to these regimens.
An accompanying editorial agrees that women whose tumors have normal HER2 and TOP2A genes should not receive anthracycline-based chemotherapy. The authors note that molecularly targeted drugs such as trastuzumab (Herceptin) often provide the most benefit to patients with alterations in the pathways affected by the drugs, and it now appears that the same may be true of standard chemotherapy agents.
More Gene Mutations Found in Childhood Leukemia
In January, researchers described a new subtype of acute lymphoblastic leukemia (ALL), the most common childhood cancer. Children with this subtype have alterations to a gene called IKAROS (or IZKF1) and a high risk of relapse. The researchers predicted that some cases would also involve mutations in protein kinase genes, which play a role in cell signaling and are commonly altered in cancer. New research now confirms that prediction.
A genetic analysis of 187 cases of high-risk childhood ALL by investigators with the Childhood Cancer TARGET Initiative has identified mutations in three members of the family of JAK kinase genes. The JAK mutations are thought to activate pathways involved in cell growth and proliferation. Such changes have also been implicated in other cancers, most notably in a group of blood cancers known as myeloproliferative disorders.
About 10 percent of the ALL cases had mutations in one of the three JAK genes. Some also involved changes to IKAROS, and these children had poor outcomes. More than 70 percent of children with both IKAROS and JAK mutations relapsed within 4 years, compared with 23 percent with neither alteration.
Drugs that inhibit overactive JAK kinase proteins are in development. Based on laboratory experiments, the researchers are hopeful that these agents might benefit patients with these mutations. In the lab, JAK mutations caused normal cells to become cancerous, while an experimental JAK inhibitor caused cells with the mutations to die.
The research team includes investigators from St. Jude Children's Research Hospital, the University of New Mexico Cancer Center, the Children's Oncology Group, and NCI. Dr. Charles Mullighan of St. Jude presented the findings on behalf of the TARGET team at the American Association for Cancer Research annual meeting last month in Denver.
Dr. Mullighan pointed out that JAK genes were mutated in children with ALL who did not also have Down syndrome. Several recent reports described mutations in the JAK2 gene among children who had both ALL and Down syndrome.
"The discovery of activating JAK mutations in a subset of ALL patients is a very important observation with obvious clinical implications," said Dr. Malcolm Smith of NCI's Cancer Therapy Evaluation Program and an NCI leader of the TARGET Initiative. The project is systematically sequencing more than 120 genes suspected of playing a role in ALL.
The incorporation of JAK inhibitors into treatment programs for patients with JAK-mutated ALL is a highly promising line of clinical research that needs to be aggressively pursued, added senior author Dr. Cheryl Willman of the University of New Mexico. She cited the success of imatinib (Gleevec), another kinase inhibitor, as a model.
The researchers are testing JAK inhibitors in their experimental models and hope eventually to move to patients. Genetic tests could be developed to screen patients for changes to the IKAROS and JAK genes, and the results could guide treatment as well as identify patients at risk of relapse, noted Dr. Mullighan.
Dutasteride May Reduce Prostate Cancer Risk
Initial data from a large, international clinical trial indicate that dutasteride (Avodart) may help prevent prostate cancer among men at higher risk for the disease, according to an April 27 report at the American Urological Association annual meeting in Chicago.
The trial, called REDUCE, compared dutasteride treatment against placebo among 8,200 men considered to be at high risk for the disease because of their elevated levels of prostate-specific antigen (PSA). All the men had received negative (clean) prostate biopsies within 6 months before joining the study.
After follow-up biopsies at 2 and 4 years, dutasteride was shown to lower the risk of prostate cancer by 23 percent compared with men taking the placebo.
Men treated with dutasteride were also found to be at no greater risk than those on placebo for developing aggressive prostate tumors. "We are very encouraged by this finding," lead investigator Dr. Gerald Andriole of the Washington University School of Medicine said in a statement. The study was funded by GlaxoSmithKline, which manufactures dutasteride.
The results are comparable to those from the NCI-funded Prostate Cancer Prevention Trial (PCPT), an earlier prevention study for prostate cancer involving a drug of the same class, finasteride (Proscar). Initial findings from PCPT suggested that finasteride decreased the risk of prostate cancer but may have increased the risk of developing more aggressive tumors. Subsequent investigations by NCI scientists and others showed that finasteride did not promote more aggressive tumors and may actually reduce their risk. Both finasteride and dutasteride are approved to treat benign prostatic hyperplasia.
Cancer Incidence Could Rise Sharply in Coming Decades
The number of cancer cases in the United States is expected to increase dramatically over the next 2 decades, particularly among older adults and minorities, according to a study published online last week in the Journal of Clinical Oncology (JCO). Dr. Ben Smith of the University of Texas M.D. Anderson Cancer Center and his colleagues used information from the U.S. Census Bureau and NCI's SEER database, which covers approximately 26 percent of the U.S. population, to project the number of cancer patients diagnosed through 2030 by various measures.
The total cancer incidence is projected to rise by about 45 percent, from 1.6 million in 2010 to 2.3 million in 2030, the study found. This will be driven largely by cancer diagnoses in growing populations of older Americans and minority groups. The study projects a 67 percent increase in cancer incidence among older adults, compared with an 11 percent increase for younger adults. A 99 percent increase is expected among minorities, compared with a 31 percent increase for whites.
Certain difficult-to-treat cancers, such as liver, stomach, pancreas, and lung, will likely be among those with the highest relative increases in incidence. Therefore, the study warns, unless substantial gains are made in the treatment and prevention of these diseases, particularly among the elderly and minorities, the number of cancer deaths could grow dramatically in the next 20 years.
A second article published online in JCO proposes a roadmap for addressing and overcoming disparities in cancer care. The authors of this policy statement, developed by the American Society of Clinical Oncology (ASCO), wrote that despite decades of investment and advances in cancer research, a "profound divide" exists between those with access to the fruits of this research and those without.
The paper outlines strategies for addressing health disparities, such as funding research on the quality of care provided to minority populations and boosting minority enrollment in clinical trials. The statement "sets the stage for the continuing activities by ASCO to address this very important problem," said ASCO president Dr. Richard L. Schilsky of the University of Chicago at a press briefing.
More information and audio files from the briefing are available on the ASCO Web site.
Immunotherapy Improves Survival in Metastatic Prostate Cancer
An investigational immunotherapy treatment improved overall survival by approximately 4 months in men with metastatic prostate cancer compared with men treated with a placebo, researchers reported last week at the American Urological Association annual meeting in Chicago. The results come from the IMPACT trial, a phase III, double-blind, randomized trial of sipuleucel-T (Provenge), a form of immunotherapy in which antigen-presenting cells are isolated from patients' blood, engineered to stimulate a tumor-specific immune response, and infused back into patients.
The more than 500 men in the trial had asymptomatic or minimally symptomatic, androgen-independent metastatic prostate cancer. In men who received sipuleucel-T, which was delivered in three infusions over a 1-month period, median survival was improved by 22.5 percent compared with men who received placebo (25.8 months versus 21.7 months). As was the case in the two earlier-stage trials of sipuleucel-T, there was no statistically significant improvement in progression-free survival, that is, survival without tumor growth.
Adverse events were minor and limited, said one of the trial's leaders, Dr. David Penson from the University of Southern California. The most common events were fever, chills, and headache the day after the infusion of sipuleucel-T, and these side effects typically resolved within a day or two. Overall, approximately 99 percent of patients in the immunotherapy arm received all three infusions.
The survival data were "incredibly consistent" in all of the subgroups examined in the trial, Dr. Penson explained, which included breakdowns by age, baseline PSA level, and extent of bone metastases, among others. "That is very reassuring to me," he said.
Dr. Penson acknowledged that, because of the trial's design, all patients in the immunotherapy arm could receive docetaxel immediately upon progression, unlike patients who received the placebo, and this could introduce bias in favor of sipuleucel-T. But the statistical model, he noted, was adjusted for both the use and timing of docetaxel administration. Further details of the data analysis should be available when the trial results are published in a scientific journal.
In March 2007, an FDA advisory committee recommended that sipuleucel-T be approved for men with this prostate cancer indication, based on data from two smaller clinical trials. In May 2007, however, the FDA issued a "complete response" letter to Dendreon, which manufactures sipuleucel-T, requesting more efficacy data before it could approve the company's application to market the treatment. According to Dendreon officials, the company will submit the IMPACT data to the FDA later this year as an amendment to its earlier marketing approval application.
