|Variations in Gene Activity Can Predict
the Survival of Patients with Lymphoma
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
For more information on Dr. Staudt's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5780 and http://lymphochip.nih.gov/current.html.
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