BETHESDA, Md -- November 28, 2008 -- Variations in biological variations in diffuse large B-cell lymphoma (DLBCL) influence whether a patient is likely to be cured by chemotherapy, according to a study published in the November 27 issue of the New England Journal of Medicine.
Louis M. Staudt, MD, National Cancer Institute (NCI), Bethesda, Maryland, and colleagues analysed thousands of genes in DLBCL tumours. They found that the tumour microenvironment, which consists of the nearby noncancerous immune and structural cells that, along with tumour cells, constitute the tumour, 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 tumour biopsy sample taken at diagnosis," said Dr. 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 standardise results according to the variety of DLBCL tumours 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."
The researchers investigated whether a molecular analysis of tumour biopsy specimens taken before treatment could help identify patients who would be cured by R-CHOP, which consists of cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone given in conjunction with rituximab.
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.
The researchers studied gene expression levels in tumour biopsy specimens using DNA microarrays. They identified 3 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 centre B-cell signature (GCB), was expressed by malignant cells in the tumours and reflected whether the tumours were of the GCB, activated B cell-like (ABC), or DLBCL subtype. In contrast, the other 2 gene expression signatures reflected different activities of the non-malignant cells within the tumour microenvironment.
One signature, termed stromal-1, was found in tumours that expressed genes involved in forming or modifying the extracellular matrix. These tumours also contained many macrophages. High expression of this signature was associated with good prognosis.
Another signature, termed stromal-2, was present in DLBCL tumours that had abundant angiogenesis. The stromal-2 signature was associated with poor prognosis.
The researchers used the data from these 3 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.
Combining the gene signature model with the International Prognostic Index (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 tumour.
"Our findings reveal new biological variations in DLBCL that influence whether a patient is likely to be cured by chemotherapy," said Dr. 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 utilised to overcome the remaining resistance of some DLBCL tumours to our current therapy."
SOURCE: National Institutes of Health
E-Mail this DGNews to a colleague
