Association of expression of pSTAT3, pAKT1 with the survival of patients with diffuse large B-cell lymphoma

Abstract

Aim. To assess the relationship between isolated and combined expression of pSTAT3, pACT1 in tumor cells with the survival of patients with diffuse large B-cell lymphoma (DLBCL).

Methods. The study included 100 patients with the first diagnosed diffuse large B-cell lymphoma, observed in the institute's clinic between 2010 and 2018 who received standard first-line R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. The relative number of expressing pSTAT3 and pAKT1 ­tumor cells was determined by using immunohistochemical and morphometric methods. The optimal cut-off level of expression on tumor cells estimated by using receiver operating characteristic (ROC) curve analysis for pSTAT3 was 68% and for pACT1 — 70%. Given these values, all patients with DLBCL were divided into groups with a high and low degree of expression of the biomarkers. As a result, 53 patients were enrolled in the pSTAT3 high expression group (≥68% tumor cells) and 47 patients to the pSTAT3 low expression group (<68% tumor cells). Spearman’s correlation coefficient was used to examine relationships. Overall survival and event-free survival were estimated by Kaplan–Meier curves. The log-rank test was used for groups comparison.

Results. The five-year overall survival rate in the pSTAT3 high expression group was 55% versus 87% in the low expression group, p=0.015. A significant difference was found in the assessment of event-free survival: 43% for the group of pSTAT3 high expression, 66% for the group of low expression, p=0.011. A statistically significant value of a high level of pACT1 expression was revealed for 5-year overall and event-free survival (p <0.001 and p=0.003). Overall survival rate was 81% for the pACT1 low expression group and 43% for the high expression group while event-free survival rate was 64 and 41%, respectively. Also, patients with рАКТ1+/рSTAT3+ (high level) co-expression had extremely low rates of overall and event-free survival rates compared with the рАКТ1–/рSTAT3– (low ­level) group (p=0.001; p <0.001).

Conclusion. The pSTAT3 and pAKT1 biomarkers can be used as additional prognosis criteria for diffuse large B-cell lymphoma.

Keywords

diffuse large B-cell lymphoma / рАКТ1 / рЅТАТ3 / hyperexpression

References

[1] Poddubnaya I.V. Diffuse large B-cell lymphoma. In: Rossiyskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevaniy. (Russian clinical recommendations on diagnostics and treatment of lymphoproli­ferative disorders.) Ed. by I.V. Poddubnaya, V.G. Savchenko. M.: OOO “BukiVedi”. 2018; 58–65. (In Russ.)

[2] Поддубная И.В. Диффузная В-клеточная крупноклеточная лимфома. В кн.: Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: ООО «БукиВеди». 2018; 58–65.

[3] Sehn L.H., Gascoyne R.D. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015; 125 (1): 22–32. DOI: 10.1182/blood-2014-05-577189.

[4] Rastor­guev S.M., Koroleva D.A., Bulygina E.S. et al. Clinical and prognostic value of molecular markers of diffuse large B-cell lymphoma. Clinical oncohematology. 2019; 12 (1): 95–100. (In Russ.) DOI: 10.21320/2500-2139-2019-12-1-95-100.

[5] Расторгуев С.М., Королёва Д.А., Булыгина Е.С. и др. Клиническое и прогностическое значение молекулярных маркёров диффузной В-крупноклеточной лимфомы. Клин. онкогематол. 2019; 12 (1): 95–100. DOI: 10.21320/2500-2139-2019-12-1-95-100.

[6] Kaplanov K.D., Volkov N.P., Klitochenko T.Yu. Analysis results of the regional registry of patients with diffuse large B-cell lymphoma: risk factors and chemommunotherapy issues. Clinical oncohematology. 2019; 12 (2): 154–164. (In Russ.) DOI: 10.21320/2500-2139-2019-12-2-154-164.

[7] Капланов К.Д., Волков Н.П., Клиточенко Т.Ю. Результаты анализа регионального регистра пациентов с диффузной В-крупноклеточной лимфомой: факторы риска и проблемы иммунохимиотерапии. Клин. онкогематол. 2019; 12 (2): 154–164. DOI: 10.21320/2500-2139-2019-12-2-154-164.

[8] Ling Dong, Huijuan Lv, Wei Li et al. Co-expression of PD-L1 and p-AKT is associated with poor prognosis in diffuse large B-cell lymphoma via PD-1/PD-L1 axis activa­ting intracellular AKT/mTOR pathway in ­tumor cells. Onco­target. 2016; 7 (22): 33 350–33 362. DOI: 10.18632/oncotarget.9061.

[9] Rawlings J.S., Rosler K.M., Harrison D.A. The JAK/STAT signaling pathway. J. Cell Sci. 2004; 117 (8): 1281–1283. DOI: 10.1242/jcs.00963.

[10] Wu Z.L., Song Y.Q., Shi Y.F. et al. High nuclear expressions of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphoma. J. Hematol. Oncol. 2011; 4: 31. DOI: 10.1186/1756-8722-4-31.

[11] Xiaoxiao Wang-Xin Cao, Ruifang Sun. Clinical significance of PTEN deletion, mutation, and loss of PTEN expression in de novo diffuse large B-cell lymphoma. Neoplasia. 2018; 20 (6): 574–593. DOI: 10.1016/j.neo.2018.03.002.

[12] Courtney K.D., Corcoran R.B., Engelman J.A. The PI3K pathway as drug target in human cancer. J. Clin. ­Oncol. 2010; 28: 1075–1083. DOI: 10.1200/JCO.2009.25.3641.

[13] Jinfen Wang, Xu-Monette Z.Y., Jabbar K.J. et al. AKT hyperactivation and the potential of AKT-targeted therapy in diffuse large B-cell lymphoma. Am. J. Pathol. 2017; 187 (8): 1700–1716. DOI: 10.1016/j.ajpath.2017.04.009.

[14] Chi Young Ok, Xu-Monette Z.Y., Tzankov A. et al. STAT3 expression and clinical inplications in de novo diffuse large B cell lymphoma: a report from the International DLBCL Rituximab-CHOP consortium program. Blood. 2013; 121 (20): 4021–4031. DOI: 10.1182/blood-2012-10-460063.

RIGHTS & PERMISSIONS

Vaneeva E.V., Rosin V.A., Dyakonov D.A., Samarina S.V.