Personalized target therapy of locally advanced and mrcc: from retrospective studies to implementation in clinical practice
Chekhun V.1, Stakhovsky E.2, Vitruk Iu.2, Lukianova N.1, Voylenko O.2, Stakhovskyi O.2, Kononenko O.2, Semko S.2, Pikul M.2, Hrechko B.2, Koshel D.2, Tumoshenko A.2, Buyvol O.2, Krotevych M.2, Trokhymych S.2, Vitruk V.3, Harbar R.3, Yatseniuk N.3
- 1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine
- 2Nonprofit Organization National Cancer Institute, Kyiv, Ukraine
- 3Urology modern center, Kyiv, Ukraine
Summary. Materials and methods. The paper presents results of a retrospective study of 126 patients with locally advanced and metastatic clear cell renal cell carcinoma (ccRCC) who underwent neoadjuvant systemic therapy with sunitinib or pazopanib and surgical removal of the tumor during 2010–2020. 97 (77%) patients took pazopanib, 29 (23%) patients — sunitinib. The clinical efficacy of systemic therapy was evaluated after 2 blocks according to RECIST 1.1. The expression of microRNAs-99b and -377 are associated with the RCC response to pazopanib, and microRNA-210 and -377 to sunitinib was studied on clinical material of patients (tumor blocks) using real-time polymerase chain reaction (PCR). Results. At 107 (84.9%) cases, after neoadjuvant therapy, the tumor size decreased from 2 to 60% (mean (20.1±10.7)%), and in 19 (15.1%) patients, the tumor size remained unchanged or increased by 4% (mean (0.7±1.3)%). In general, partial tumor regression was diagnosed in 27 (21.4%) cases, and stabilization of the disease in 99 (78.6%) cases. An additional subanalysis of 99 (78.6%) patients with stabilization after neoadjuvant systemic therapy showed that in 37 (29.4%) cases there was a resistant tumor and an ineffective drug was prescribed, so in some cases there was an increase in tumor size. In the remaining 62 (49.2%) patients, the tumor was sensitive to the prescribed therapy, but the regression rate was less than 30%. Analysis of microRNA expression revealed significant differences in their profile depending on the sensitivity to therapy: for tumors with 30% or more response to pazopanib treatment, the levels of oncogenic microRNA-144 and oncosuppressive microRNAs-99b and -377 were 5.05 and 2.61 times higher, respectively, than in patients with less than 10% regression; in patients with RCC regression of 30% or more after sunitinib therapy, the levels of oncosuppressive microRNA-210 and microRNA-377 were 5.4 and 2.17 times lower, respectively, than in patients with less than 10% regression (p <0.05). By determining the coexpression of microRNA-99b/-377 and microRNA-210/-377, tumors were identified as sensitive to both sunitinib and pazopanib, sensitive to one of them, or not sensitive to either drug. Conclusions. The data obtained indicates the prospects of analyzing the concomitant expression of microRNA-99b/-377 and microRNA-210/-377 in RCC tissue for predictive evaluation of the effectiveness of systemic therapy based on its personalization. In the absence of tumor sensitivity to any tyrosine kinase inhibitors, immunotherapy is indicated.
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