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STAT3 Activation Is Associated With Poor Survival in Diffuse Large B-Cell Lymphoma Treated With R-CHOP

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Key Points

  • STAT3 activation is correlated with poor survival in patients with diffuse large B-cell lymphoma treated with R-CHOP.
  • The effect of STAT3 activation on survival is particularly evident in patients with the activated B-cell–like diffuse large B-cell lymphoma.

In a study reported in the Journal of Clinical Oncology, Xin Huang, PhD, of the National Clinical Research Center of Cancer in Tianjin, and colleagues investigated whether STAT3 activation can identify patients with diffuse large B-cell lymphoma treated with R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone) who are at risk for poor survival. These investigators have previously shown that constitutive STAT3 activation is a prominent factor in the activated B-cell subtype of diffuse large B-cell lymphoma. In the current study, the investigators found that STAT3 activation significantly predicted poor survival, particularly in patients with activated B-cell–like diffuse large B-cell lymphoma.

Study Details

The study involved 309 patients with diffuse large B-cell lymphoma who received R-CHOP, including 87 treated at the University of Nebraska Medical Center (UNMC) and 222 treated at other Lymphoma/Leukemia Molecular Profiling Project (LLMPP) institutions. A subset of 185 patients (87 UNMC cases and 98 LLMPP cases) were assessed for phosphotyrosine-STAT3 expression using immunohistochemistry.

A gene expression profiling–based phosphotyrosine-STAT3 11-gene activation signature was developed using differential gene expression on STAT3 knockdown in activated B-cell–like diffuse large B-cell lymphoma cell lines. Phosphotyrosine-STAT3 on immunohistochemistry, the phosphotyrosine-STAT3 activation signature, and STAT3 mRNA levels were assessed for correlation with survival.

Immunohistochemistry Phosphotyrosine-STAT3 Expression

In the 185-patient group, phosphotyrosine-STAT3 was detected by immunohistochemistry in 37% of patients with diffuse large B-cell lymphoma. The phosphotyrosine-STAT3–positive and -negative groups did not differ in clinical features except for a significantly greater portion of activated B-cell/non–germinal center B-cell–like cases in the phosphotyrosine-STAT3-positve group (54% vs 35%, P=.03).

Phosphotyrosine-STAT3–positive status was significantly associated with poor overall survival (P = .01) and event-free survival (P = .006) among all patients, event-free survival (P = .027) in patients with activated B-cell–like diffuse large B-cell lymphoma (P = .027), and neither in patients with germinal center B-cell–like diffuse large B-cell lymphoma.

In multivariate analysis in the entire cohort of 309 patients, phosphotyrosine-STAT3 status (HR = 2.3, P = .02), International Prognostic Index (HR = 2.3, P = .02), and BCL2 expression (HR = 2.1, P = .046) were independently predictive of overall survival and phosphotyrosine-STAT3 status was predictive of event-free survival (HR = 2.2, P = .02). 

STAT3 mRNA

In assessment of STAT3 mRNA in the 222-patient cohort, the subgroup with the highest levels of STAT3 mRNA was enriched for the activated B-cell–like diffuse large B-cell lymphoma subtype and phosphotyrosine-STAT-positive cases. The investigators noted that this finding likely reflects the fact that STAT3 is a positively autoregulated gene.

High STAT3 mRNA expression was significantly associated with worse overall survival (P = .004) and event-free survival (P = .003) among all patients but not in the activated B-cell–like diffuse large B-cell lymphoma or germinal center B-cell–like diffuse large B-cell lymphoma subgroups.

11-Gene Phosphotyrosine-STAT3 Signature

Assessment of the 11-gene phosphotyrosine-STAT3 signature in the entire cohort showed 5-year overall survival rates of 84%, 81%, 57%, and 48% by low- to high-expression quartile and 5-year event-free survival rates of 81%, 77%, 51%, and 40%, respectively. The phosphotyrosine-STAT3 signature was significantly associated with overall survival (P < .001) and event-free survival (P < .001) in all patients and with overall survival (P = .029) and event-free survival (P = .025) in the activated B-cell–like-diffuse large B-cell lymphoma group, but with neither in the germinal center B-cell–like diffuse large B-cell lymphoma subgroup. In the activated B-cell–like-diffuse large B-cell lymphoma group, patients in the first quartile (lowest expression) had a more favorable outcome than did those in the higher quartiles.

The investigators concluded, “[W]e have demonstrated in this study that STAT3 activation status either using an [immunohistochemistry] method or an 11-gene [gene expression profile] signature is correlated with poor prognosis of patients with diffuse large B-cell lymphoma treated with the R-CHOP regimen. Our findings support the hypothesis that targeting the STAT3 signaling pathway, either with monotherapy or in combination with R-CHOP, may improve the survival of patients with [diffuse large B-cell lymphoma] carrying [phosphotyrosine]-STAT3–positive tumors," they said. 

"Finally, none of the 11 genes in the phosphotyrosine-STAT3 signature have been previously shown to be a transcriptional target of STAT3 in diffuse large B-cell lymphoma, and their potential contributions to lymphoma pathobiology await future investigation,” they added.

The study was supported in part by a Lymphoma Research Foundation Career Development Award, a Chinese Scholarship Council scholarship award, and grants from the National Institutes of Health, Leukemia & Lymphoma Society, and Lauri Strauss Leukemia Foundation

Kai Fu, MD, PhD, of the University of Nebraska Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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