Correlation of c-Met Expression and Outcome in Patients With Renal Cell Carcinoma Treated With Sunitinib

Peltola, Katriina; Penttilä, Patrick; Rautiola, Juhana; Joensuu, Heikki; Hänninen, Erkki; Ristimäki, Ari; Bono, Petri

doi:10.1016/j.clgc.2017.01.021

Cited by 19 publications

(16 citation statements)

References 22 publications

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“…In a descriptive analysis, we observed that patients in our cohort who were treated with VEGF-TT and had high c-Met expression had numerically worse clinical outcomes, in terms of reduced TTF and OS, compared to those patients treated with VEGF-TT who had low c-Met expression. While our small sample size limited formal statistical testing, our findings are consistent with other data showing that high c-Met expression portends worse clinical prognosis [ 5 , 7 , 9 , 14 , 15 ]. Furthermore, we observed that patients treated with VEGF-TT in between the resection of their primary RCC and subsequent metastasis had numerically higher c-Met expression in metastatic sites compared to those who did not receive systemic therapy before the resection of the metastases.…”

Section: Discussionsupporting

confidence: 90%

“…In RCC, high c-Met expression was reported to be an independent predictor of survival in 330 nephrectomy cases using quantitative immunofluorescence [ 6 ]. In the metastatic RCC (mRCC) setting, c- Met expression also appears to be associated with worse outcomes in a retrospective cohort of patients treated with sunitinib, an antiangiogenic agent against vascular endothelial growth factor receptor (VEGFR) [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression

Lalani

Gray

Albigès³

et al. 2017

Oncotarget

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In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0–300): intensity of c-Met staining (0–3) x % of positive cells (0–100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression

Lalani

Gray

Albigès³

et al. 2017

Oncotarget

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“…In RCC, many studies have suggested that c-Met expression is associated with significantly inferior clinicopathological features, such as tumor grade [ 27 , 28 – 31 , 36 , 38 ], primary tumor stage [ 30 , 31 , 36 ], lymphatic invasion [ 27 ], metastases [ 30 , 35 , 38 ], and worse progression-free survival [ 37 ] or OS [ 31 , 34 , 36 ]. However, the pathological or clinical impacts of c-Met expression are not consistent across the studies [ 33 , 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological impacts of high c-Met expression in renal cell carcinoma: a meta-analysis and review

Kim

2017

Oncotarget

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c-Met overexpression has been observed in renal cell carcinoma (RCC). However, its clinicopathological impacts remain uncertain. We performed this meta-analysis to evaluate the pathologic and prognostic impacts of high c-Met expression in patients with RCC. A systematic computerized search of the electronic databases PubMed and Embase was performed. From 12 studies, 1,724 patients with RCC were included in the meta-analysis. Compared with RCCs showing low c-Met expression, tumors with high c-Met expression showed significantly higher nuclear grade (odds ratio = 2.45 [95% CI: 1.43–4.19], P = 0.001) and pT stage (odds ratio = 2.18 [95% CI: 1.27–3.72], P = 0.005). In addition, patients with c-Met-high RCC showed significantly worse overall survival than those with c-Met-low tumor (hazard ratio = 1.32 [95% CI: 1.12–1.56], P = 0.0009). In conclusion, this meta-analysis demonstrates that high c-Met expression correlate with significantly worse pathological features and overall survival, indicating c-Met overexpression is a potential adverse prognostic marker for patients with RCC.

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“…1) [24,25]. Принципиальным отличием кабозантиниба от TKI 1-го поколения (сунитиниб, пазопаниб, сорафениб, акситиниб) является способность блокировать MET и AXL, гиперэкспрессия которых ассоциирована с плохим прогнозом и резистентностью к противоопухолевой терапии при раке почки [26,27]. В образцах рака почки, рефрактерного к сунитинибу, кабозантиниб ингибировал экспрессию AXL и MET [28].…”

Section: механизм действия кабозантинибаunclassified

Cabozantinib: from studies to clinical practice

2019

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Disseminated renal cell carcinoma is an immunogenic tumor in which cytokine immunotherapy is usually used as the second-line treatment. It is associated with a low frequency of objective responses and short progression-free survival. Modern studies resulted in more effective treatment regimens based on new high-affinity TKI multikinases (cabozantinib, lenvatinib), as well as immuno-oncological drugs that can specifically block intercellular transmission of anti-immunogenic signal (PD-1 inhibitors) (nivolumab, pembrolizumab) or its ligand type 1 (PD-L1) (avelumab), antigen type 4 associated with anticytotoxic T-lymphocyte (ipilimumab)). Cabozantinib is a 2nd generation multikinase inhibitor that blocks the receptors of growth factors MET, AXL, and VEGFR-2, which are involved in tumorigenesis and responsible for resistance to traditional antiangiogenic therapy in renal cell carcinoma. Registration studies have shown that cabozantinib together with combined targeted therapy is more effective in patients with favorable and intermediate prognosis, while the PD-1 inhibitor (nivolumab) – in patients with poor and intermediate prognosis.Objective: to analyze the results of cabozantinib studies and its possible use in the sequential treatment of disseminated renal cell carcinoma.

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Correlation of c-Met Expression and Outcome in Patients With Renal Cell Carcinoma Treated With Sunitinib

Abstract: High c-Met expression was associated with poor survival in patients with mRCC treated with sunitinib. Interestingly, the prognostic role may vary based on the location of metastases.

Cited by 19 publications

References 22 publications

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression

Clinicopathological impacts of high c-Met expression in renal cell carcinoma: a meta-analysis and review

Cabozantinib: from studies to clinical practice

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