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Gene Profiles May Help Predict Response to Chemotherapy

M. J. Friedrich

Past studies of genetic analyses of lymphoma have shown that there may be more subtypes of the disease than previously thought. Now, a new study has demonstrated the ability of gene expression profiling to delineate subtypes of diffuse large-B-cell lymphoma (DLBCL) with different clinical outcomes.

Only about 40% of patients with DLBCL—the most common type of non-Hodgkin’s lymphoma in adults—are cured by anthracycline-based chemotherapy regimens used to treat the disease. The different responses patients have to treatment have suggested that DLBCL might be more than one disease; however, standard diagnostic techniques have failed to distinguish DLBCL subtypes.

Molecular techniques may prove more useful. In a pilot study completed a few years ago, investigators used a customized DNA microarray called the Lymphochip, which contains thousands of genes that are expressed in normal and malignant lymphoid cells, to identify two subgroups of DLBCL that behave differently in response to chemotherapy.

Each subgroup expressed genes characteristic of a specific stage in B-cell development: the germinal-center B-cell-like subgroup expressed genes typically active in normal germinal-center B cells and was associated with a good patient outcome after chemotherapy; the activated B-cell-like subgroup expressed genes characteristic of a later stage in B-cell development and was associated with a poor outcome.

"In the current study we wanted to extend these results to more fully understand the molecular determinants of survival following chemotherapy," said Louis M. Staudt, M.D., Ph.D., Center for Cancer Research at the National Cancer Institute. Staudt was an author on the earlier study, published in Nature in 2000, and the most recent study, which appeared in the New England Journal of Medicine last month.



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Dr. Louis M. Staudt

 
Although the investigators had identified different clinical outcomes for the two groups of lymphoma patients, Staudt said there was still a lot of variation in responsiveness within the groups that needed to be explained. In the recent study, researchers examined the gene expression of 240 DLBCL tumor samples using the Lymphochip.

Gene profiling of these biopsy samples revealed a third DLBCL subgroup. "Again we saw clinical differences in the outcome of these different subgroups, with the germinal-center B-cell-like disease having a favorable outcome compared to the other two," said Staudt. But within each subgroup heterogeneity in terms of patient outcome was still observed.

To identify other molecular determinants of outcome, the investigators identified individual genes whose expression patterns correlated with a good or bad clinical outcome. More than 600 genes were relevant and they fell mainly into four gene expression signatures that revealed different biological features of the tumor.

Three groups of genes—germinal-center B-cell genes, major histocompatibility complex (MHC) class II genes, and lymph node genes—were associated with favorable patient outcome, with the most important predictor of survival being the germinal center B-lymphocyte genes. Adverse outcome was associated with genes highly expressed in proliferating cells. The investigators winnowed the total number of genes down to 17 that could accurately predict survival after chemotherapy.

Staudt pointed out that these results agreed with the earlier research demonstrating the cell of origin to be an important determinant of clinical behavior. Also of note, he said, is the finding that two of the gene-expression signatures that predicted a favorable outcome indicated that the immune system played an important role in battling the cancer.

Noting that gene-expression profiling can identify new biological markers for predicting survival in patients with DLBCL, one of the study’s lead authors, Wing C. (John) Chan, M.D., professor of pathology at the University of Nebraska Medical Center, said "hopefully we’ll be able to use these markers to better stratify patients for treatment in the future."

Commenting on the study, Emanuel Petricoin, Ph.D., of the U.S. Food and Drug Administration’s Center for Biologics Evaluation and Research, said this work is a tremendous example of the potential clinical utility of gene expression profiling. However, given the few treatment options beyond the standard chemotherapy regimen that are available for patients with DLBCL, he added that such prognostic indicators present physicians with the quandary of how to use this information in an ethical and medically important way.

One of the few alternatives to standard therapy for DLBCL is high-dose chemotherapy plus bone marrow transplantation. Staudt said that another option for poor-risk patients would be clinical trials for new therapeutic agents for DLBCL, such as PS-341. This agent inhibits the nuclear factor-{kappa}B (NF-{kappa}B) signaling pathway, which when active hinders the apoptotic effect of chemotherapy and prevents tumor cells from dying. Researchers have found that in the germinal-center B-cell form of DLBCL, the NF-{kappa}B signaling pathway is decreased—meaning that the cells are more vulnerable to chemotherapeutic agents—while in cells of activated B-cell-like lymphomas this pathway is turned on all the time.

This fall the NCI will open a phase II trial for PS-341 to patients with DLBCL who have relapsed from a first treatment with standard chemotherapy. Gene profiles of patient tumors will be examined before treatment to determine whether this pathway is activated or not. Researchers are hoping that by inhibiting this pathway they may provide a selective benefit for patients in the poor-risk group.

Incorporating molecular profiling technologies like this one in clinical trials shows promise in helping clinicians select patients who will derive the most benefit out of novel therapeutics in clinical trials in the future. As Petricoin noted, "this work is an important beginning. As we gain more and more information and develop more and more therapeutics, this sort of upfront profiling is where the field is going."



             
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