Why do some patients with diffuse large B-cell lymphoma (DLBCL) respond to treatment but others do not? The identification of four genetic subtypes of DLBCL could help answer this question, according to a study led by Louis M. Staudt, MD, PhD, from the National Cancer Institute (NCI).
Previous gene-expression profiling identified DLBCL subgroups based on cell of origin and were known as activated B-cell–like (ABC) and germinal center B-cell–like (GCB); 10%-20% of cases were termed unclassified. In the new research, each gene-expression subgroup differed in response to standard treatment, with an average survival rate of about 40% for ABC DLBCL and about 75% for GCB DLBCL.
These subgroups were categorized according to individual genetic differences, but the NCI investigators created a study algorithm designed to identify subtypes of DLBCL based on shared mutations on numerous genes and to uncover possible therapeutic targets based on tumor genetics.
“The goal is to find the right drug for the right person at the right time,” according to Dr. Staudt, of the Lymphoid Malignancies Branch at NCI. “And we feel this genetic understanding of diffuse lymphoma is a step forward in precision therapy.” He and an international group of colleagues published their findings online in The New England Journal of Medicine.
They examined 574 DLBCL biopsy samples using a multiplatform genomic analysis comprising exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes. Almost all biopsies—96.5%—were performed before patients were treated. Of biopsy subgroups, 51.4% were ABC, 28.6% were GCB, and 20.0% were unclassified.
Four prominent genetic subtypes were identified in this process: MCD, BN2, N1, and EZB. Terminology was based on respective genetic alterations: MCD, co-occurrence of MYD88L265P and CD79B mutations; BN2, BCL6 fusions and NOTCH2 mutations; N1, NOTCH1 mutations; and EZB, EZH2 mutations and BCL2 translocations. The MCD subtype was found in 71 patients; BN2 in 98 patients, N1 in 19 patients, and EZB in 69 patients.
Within each genetic subtype, distribution of the three gene-expression subgroups was determined:
- MCD and N1 subtypes were predominantly ABC.
- EZB subtypes were mostly GCB.
- BN2 included ABC, GCB, and unclassified groups.
Overall, 44.8% of samples were classified into these three DLBCL subgroups.
Included in the survival analysis were all previously untreated patients with outcomes data who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy or CHOP-like chemotherapy (n=240). Among them were 119 patients with tumors classified into one of the genetic subtypes.
Progression-free survival differed significantly among the four subtypes, with subtypes BN2 and EZB having much more favorable outcomes than subtypes MCD and N1.
The predicted 5-year overall survival rates for subtypes BN2 and EZB were 65% and 68%, respectively, and for subtypes MCD and N1, 26% and 36%, respectively.
Distribution of subtypes can be a factor in determining appropriate therapy. Some subtypes are found in both ABC and GCB subgroups, so a patient with ABC DLBCL, which has a lower survival rate, could also have the BN2 subtype, which responds well to chemotherapy. In clinical trials, targeted agents could be evaluated in the context of genetic subtypes.
The authors concluded that their multiplatform genomic analysis adds a genetic nosology to the gene-expression classification of DLBCL.
“The results of our studies suggest that, in clinical trials, targeted agents in DLBCL could be evaluated in the context of particular genetic subtypes or genetic aberrations that affect the targeted pathway,” wrote Dr. Staudt and colleagues.
“From the perspective of precision medicine, selecting treatment for DLBCL on the basis of individual genetic alterations is not optimal since it is likely that constellations of genetic aberrations influence therapeutic response. The genetic subtypes that we define may provide a conceptual edifice on which to develop precision therapies for these aggressive cancers,” they concluded.
This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), the Center for Cancer Research of the National Cancer Institute (NCI), and an NCI Strategic Partnering to Evaluate Cancer Signatures grant.