miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

Approximately 20–30% of patients with metastatic renal cell carcinoma (mRCC) in first-line treatment with tyrosine kinase inhibitors (TKIs) do not respond due to primary resistance to this drug. At present, suitable robust biomarkers for prediction of a response are not available. Therefore, the aim of this study was to evaluate a panel of microRNAs (miRNAs) in nephrectomy specimens for use as predictive biomarkers for TKI resistance. Archived formalin-fixed, paraffin embedded nephrectomy samples from 60 mRCC patients treated with first-line TKIs (sunitinib, n = 51; pazopanib, n = 6; sorafenib, n = 3) were categorized into responders and non-responders. Using the standard Response Evaluation Criteria in Solid Tumors, patients with progressive disease within 3 months after the start of treatment with TKI were considered as non-responders and those patients with stable disease and complete or partial response under the TKI treatment for at least 6 months as responders. Based on a miRNA microarray expression profile in the two stratified groups of patients, seven differentially expressed miRNAs were validated using droplet digital reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assays in the two groups. Receiver operating characteristic curve analysis and binary logistic regression of response prediction were performed. MiR-9-5p and miR-489-3p were able to discriminate between the two groups. MiR-9-5p, as the most significant miRNA, improved the correct prediction of primary resistance against TKIs in comparison to that of conventional clinicopathological variables. The results of the decision curve analyses, Kaplan-Meier analyses and Cox regression analyses confirmed the potential of miR-9-5p in the prediction of response to TKIs and the prediction of progression-free survival after the initiation of TKI treatment.

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Antiangiogenic tyrosine kinase inhibitors and immunotherapy as first-line treatment for metastatic renal cell carcinoma: is there an increased risk of hypothyroidism?

Therapeutic Advances in Urology ◽

10.1177/17562872211029784 ◽

2021 ◽

Vol 13 ◽

pp. 175628722110297

Author(s):

Giandomenico Roviello ◽

Sebastiano Buti ◽

Carlo Cattrini ◽

Alessia Mennitto ◽

Carlo Messina ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tyrosine Kinase ◽

Cell Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Renal Cell ◽

Kinase Inhibitors ◽

Line Treatment ◽

First Line ◽

Increased Risk ◽

First Line Treatment

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Application of the American society of clinical oncology frameworks to compare tyrosine kinase inhibitors used in first line treatment of metastatic renal cell carcinoma: had we solved the mystery?

Expert Review of Anticancer Therapy ◽

10.1080/14737140.2017.1372197 ◽

2017 ◽

Vol 17 (11) ◽

pp. 1061-1070

Author(s):

Sherif Hassanien Ahmed ◽

Noha Elbaghdady ◽

Mohamed Alorabi

Keyword(s):

Renal Cell Carcinoma ◽

Tyrosine Kinase ◽

Cell Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Renal Cell ◽

Kinase Inhibitors ◽

Line Treatment ◽

First Line ◽

American Society ◽

First Line Treatment

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Role and relevance of quality indicators in the selection of first-line treatment of patients with metastatic renal cell carcinoma: a position paper of the MeetURO Group

Future Oncology ◽

10.2217/fon-2018-0857 ◽

2019 ◽

Vol 15 (22) ◽

pp. 2657-2666

Author(s):

Giuseppe Procopio ◽

Sandro Pignata ◽

Amelia Altavilla ◽

Laura Attademo ◽

Delia De Lisi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Line Treatment ◽

First Line ◽

Patient Reported ◽

Related Quality ◽

First Line Treatment

Tyrosine kinase inhibitors still play a very important role in the treatment of metastatic renal cell carcinoma despite a continuously changing scenario, in which immunotherapy and several combination-based approaches are also available. In this light, patient-reported outcomes and health-related quality of life are important factors in the selection of the best first-line treatment. This Review focuses on the existing evidence on patient-reported outcomes and health-related quality of life with several tyrosine kinase inhibitors (pazopanib, sunitinib, cabozantinib and tivozanib) used as first-line treatment for metastatic renal cell carcinoma.

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Neutrophil to lymphocyte ratio and response to tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.477 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 477-477 ◽

Cited By ~ 2

Author(s):

Arnoud J. Templeton ◽

Eitan Amir ◽

Priya Aneja ◽

Francisco Emilio Vera-Badillo ◽

Thomas Hermanns ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitor ◽

Multivariable Analysis ◽

Line Treatment ◽

First Line ◽

Lymphocyte Ratio ◽

Tki Treatment ◽

First Line Treatment

477 Background: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are markers of host inflammation and have prognostic value in many solid tumors. Here we aimed to explore the association of NLR and PLR with response to tyrosine kinase inhibitor (TKI) treatment in metastatic renal cell carcinoma (mRCC). Methods: Data from patients with mRCC treated at the Princess Margaret Cancer Centrein Toronto with a TKI as first-line treatment were retrospectively collected. The association of several variables with response to treatment (complete response [CR] or partial response [PR] vs. stable disease > 3 months [SD] or progressive disease [PD]) was assessed by binary logistic regression. Significant variables were dichotomized and cut-offs selected by the area under the receiver operating characteristic (AUC) curve. Results: Data from 157 patients treated between 11/2004 and 09/2012 were analyzed. Median age at start of TKI treatment was 61 years and first-line treatment was sunitinib, sorafenib, and other in 49%, 43%, and 8% of patients, respectively. Best response was CR/PR, SD, and PD in 27%, 55%, and 18% patients. On multivariable analysis NLR > 2.5 and Karnofsky Performance Status (KPS) < 90% were associated with a lower likelihood of response and each allocated a score of 1 unit. Response rates for a score of 0, 1, or 2 were 45% (29-61%), 28% (17-38%), 10% (1-19%), respectively. PLR did not retain association with response in multivariable analysis. Conclusions: NLR and KPS are associated with response to TKI treatment in mRCC. Data from an external validation set will also be presented.

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Outcomes of immunotherapy (ICI) alone vs tyrosine kinase inhibitors (TKI) alone versus ICI and TKI combined in renal cell carcinoma brain metastasis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2030 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2030-2030

Author(s):

Patrick Joseph O'Shea ◽

Vineeth Tatineni ◽

Yasmeen Rauf ◽

Xuefei Jia ◽

Erin Sennett Murphy ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Brain Metastasis ◽

Cell Carcinoma ◽

Combination Treatment ◽

Renal Cell ◽

Kinase Inhibitors ◽

Age At Diagnosis ◽

Line Treatment ◽

First Line ◽

First Line Treatment

2030 Background: Renal cancer is the fourth most common cause of metastatic tumors to the brain. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and other receptors, such as sunitinib, pazopanib, etc., have been used as first line for renal cell carcinoma brain metastasis (RCCBM). Immune Checkpoint Inhibitors (ICIs) targeting PD-L1 and CTLA-4 interactions, such as nivolumab and ipilimumab respectively, have also been used as first line treatment for RCCBM. However, the efficacy of TKIs alone, ICIs alone, or TKIs and ICIs combined as first line treatment has emerged as a topic of interest. Methods: Patients with RCCBM treated with either TKIs, ICIs, or both at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from initiation of either TKI or ICI therapy to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS. Results: 218 patients with RCCBM were included. Of these, 32 were treated with ICIs alone, 112 were treated with TKIs alone, and 76 were treated with a combination of ICIs and TKIs. For ICI treatment alone the median age at diagnosis was 61 years (Interquartile range (IQR) 38-82), 72% of the patients were male, and 97% were white. For TKI treatment alone the median age at diagnosis was 58 years (IQR 37-82), 70% of the patients were male, and 92% were white. For the combination cohort the median age at diagnosis was 63 years (IQR 45-79), 69% of the patients were male, and 97% were white. OS for patients receiving ICI, TKI, and combination treatment had a median of 69.1, 42.7, and 126.0 months and a 2-year rate of 77%, 69%, and 93%, respectively. With ICI treatment as a reference, TKI treated patients had an OS hazard ratio of 1.32 (95% CI = 0.78 - 2.21, p = 0.30) and ICI/TKI combination had an OS hazard ratio of 0.52 (95% CI = 0.30 - 0.92, p = 0.024). Conclusions: A combination treatment of ICIs and TKIs was associated with an increase in OS when compared to treatment with either TKIs or ICIs alone in patients with RCCBM. These results should be interpreted cautiously due to treatment selection bias. Further studies need to be done to control for other patient variables such as performance status, number of intracranial lesions, and extra-cranial metastasis.[Table: see text]

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Determinants of treatment for first-line immune-based combinations in metastatic renal cell carcinoma: a critical overview of recent evidence

Immunotherapy ◽

10.2217/imt-2020-0323 ◽

2021 ◽

Author(s):

Alessandro Rizzo ◽

Matteo Rosellini ◽

Andrea Marchetti ◽

Veronica Mollica ◽

Francesco Massari

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Line Treatment ◽

First Line ◽

Critical Overview ◽

First Line Treatment

The last three decades have witnessed a revolution in the therapeutic scenario of metastatic renal cell carcinoma (mRCC), due to the advent of novel agents including tyrosine kinase inhibitors, immune checkpoint inhibitors and the combination of both treatments. These strategies have reported unprecedented response rates, thus improving the clinical outcomes of mRCC patients, and current international guidelines support the use of immune-based combinations as first-line treatment in patients with metastatic disease. However, more data are awaited to help clinicians in the decision-making process. Herein, we provide an overview of recently published results regarding immune-based combinations as first-line treatment in mRCC patients, critically discussing available data that could help in suggesting determinants of treatment in this setting.

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