Patterns of gene activity in a type of non-Hodgkin lymphoma has given researchers a better understanding of factors that contribute to the survival of patients treated for the disease. Gene activity, or expression, is a measure of the biological activity of a gene. Determining the activity levels of all genes in lymphoma patients’ genomes allowed researchers, led by Louis M. Staudt, M.D., Ph.D., at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), to identify sets of genes in diffuse large B-cell lymphoma (DLBCL) that influenced the effectiveness of treatment. These findings were published in the Nov. 27, 2008, issue of the New England Journal of Medicine.The research team analyzed thousands of genes in DLBCL tumors. They found that the tumor microenvironment, which consists of the nearby noncancerous immune and structural cells that, along with tumor cells, constitute the tumor, has a major impact on a patient’s response to treatment. “The ability of a patient with DLBCL to be cured by our current therapy can be predicted by looking at the pattern of gene activity in the tumor biopsy sample taken at diagnosis,” said Staudt. “In the near term, we need to incorporate gene expression profiling, which measures gene activity, in clinical trials for this disease to allow researchers to standardize results according to the variety of DLBCL tumors included in the trial. In the longer term, new therapies will emerge that are tailored to the particular gene expression profile of a patient’s lymphoma.”
Diffuse large B-cell lymphoma is an aggressive form of non-Hodgkin lymphoma that represents 30 percent of newly diagnosed cases. DLBCL consists of different subtypes that vary biologically and differ significantly in their survival rates following chemotherapy. Among the subtypes, the germinal center B cell-like (GCB) subtype is more responsive to treatment than the activated B cell-like (ABC) subtype. The current standard of care for DLBCL is combination chemotherapy including four drugs collectively known as CHOP (cyclophosphamide, hydroxydoxorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisone) given in conjunction with rituximab, a therapeutic antibody that binds to the surface of malignant B cells, a type of white blood cell, in these tumors. This combination treatment, known as R-CHOP, is able to cure 50 percent to 60 percent of patients.
In this study, the researchers investigated whether a molecular analysis of tumor biopsy specimens taken before treatment could help identify patients who would be cured by R-CHOP. To do this, they collected pretreatment biopsy specimens from 233 patients treated with R-CHOP, and, for comparison, they also studied samples from 181 patients treated with CHOP alone. These patients were treated at 10 institutions in North America and Europe that are part of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP), which is an international consortium of investigators.
The researchers studied gene expression levels in tumor biopsy specimens using DNA microarrays, a technology used to measure gene activity. A key finding of their analysis was that certain sets of genes, called gene expression signatures, reflected distinct sets of biological activities within DLBCL tumors, and these activities differed among diagnosed patients.
The researchers identified three gene expression signatures that were associated with either long or short survival in both the CHOP-treated and R-CHOP-treated patients. One signature, termed the germinal center B-cell signature, was expressed by malignant cells in the tumors and reflected whether the tumors were of the GCB or ABC DLBCL subtype. In contrast, the other two gene expression signatures reflected different activities of the non-malignant cells within the tumor microenvironment. One signature, termed stromal-1, was found in tumors that expressed genes involved in forming or modifying the extracellular matrix, the fibrous network of molecules between cells that regulates the structure and function of tissues. These tumors also contained many macrophages, a type of white blood cell. High expression of this signature was associated with good prognosis. Another signature, termed stromal-2, was present in DLBCL tumors that had abundant angiogenesis, the process whereby new blood vessels are formed, which is important for tumors to grow. The stromal-2 signature was associated with poor prognosis.
The researchers used the data from these three gene expression signatures to create a mathematical formula. Using this formula, they found that it was possible to divide patients who had been treated with R-CHOP or CHOP chemotherapy alone into subgroups that had better or poorer survival.
The International Prognostic Index (IPI), a predictive index used by physicians to evaluate patients with DLBCL, is based on clinical factors including age, stage of the tumor, and whether cancer has spread to other parts of the body. Combining the gene signature model with the IPI improved the predictive power of both models. This result suggests that survival in DLBCL is influenced by both clinical factors and characteristics of the tumor.
“Our findings reveal new biological variations in DLBCL that influence whether a patient is likely to be cured by chemotherapy,” said Staudt. “These biological variations are significant in patients treated with the current standard of care, R-CHOP. Our results provide many fresh ideas about how existing drugs might be utilized to overcome the remaining resistance of some DLBCL tumors to our current therapy.”
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