Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Patients and Methods
2.1. Study Design and Patients
2.2. Immunohistochemistry in Tumor Samples
2.3. Analysis of Circulating Cytokines/Chemokines in Blood
2.4. Single Nucleotide Polymorphisms (SNPs) in Whole Blood Samples
2.5. Bioinformatic and Statistical Analysis
3. Results
Patient Characteristics and Treatment Efficiency
4. Biomarkers in Relation to Efficiency Endpoints
4.1. c-Met Protein Expression in Tumors
4.2. Circulating Cytokines, Chemokines and Growth Factors
4.3. Cox Proportional-Hazards Model and Prognostic Index for Risk Stratification
4.4. Circulating HGF Levels Strongly Correlate with CXCL11, CXCL10 and IL-6 Levels
4.5. Genetic Polymorphism rs1176221 in the MET Gene
5. Biomarkers in Relation to Toxicity
6. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Corhort (n = 60) | |
---|---|
Gender | n (%) |
Male | 46 (76.7) |
Female | 14 (23.3) |
Age at diagnosis (primary tumor) | |
<65 | 31 (51.7) |
≥65 | 29 (48.3) |
Age at metastasis | |
<65 | 30 (50) |
≥65 | 30 (50) |
Time between diagnosis and metastasis | |
Metastasis at diagnosis | 23 (38.3) |
≤1 years | 15 (25) |
≤5 years | 14 (23.3) |
>5 years | 8 (13.3) |
Metastatic disease at study enrollment | 60 (100) |
Number of metastatic sites | |
1 | 22 (36.7) |
2 | 30 (50) |
3 | 4 (6.7) |
4 | 4 (6.7) |
Risk factor (MSKCC *) | |
Good | 9 (15) |
Intermediate | 42 (70 ) |
Bad | 9 (15) |
Therapy | |
Sunitinib | 51 (85) |
Pazopanib | 4 (6.7) |
Sunitib + Pazopanib | 5 (8.3) |
Toxicity | Sunitinib n (%) | Pazopanib n (%) | Sunitinib/Pazopanib n (%) | Total | p |
---|---|---|---|---|---|
Asthenia | 33 (64.7) | 3 (75.0) | 2 (40) | 38 (63.3) | 0.495 |
Neutropenia | 6 (11.8) | - | - | 6 (10) | 0.356 |
Hand-foot syndrome | 14 (27.5) | - | 1 (20) | 15 (25.0) | 0.282 |
Hypertension | 17 (33.3) | 2 (50.0) | 1 (20.0) | 20 (33.3) | 0.635 |
Hypothyroidism | 5 (9.8) | - | - | 5 (8.3) | 0.427 |
Cardiotoxicity | 1 (2.0) | - | - | 1 (1.7) | 0.849 |
Mucositis | 27 (52.9) | 1 (25) | 5 (100) | 33 (55.0) | 0.023 |
Diarrhea | 18 (35.3) | 3 (75.0) | 2 (40.0) | 23 (38.3) | 0.297 |
Leukopenia | 7 (13.7) | - | - | 7 (11.7) | 0.297 |
Anemia | 14 (27.5) | - | - | 14 (23.3) | 0.073 |
Thrombocytope-nia | 15 (29.4) | 1 (25) | 2 (40.0) | 18 (30.0) | 0.864 |
Cytokine/Chemokine | Univariable Cox Hazards Model (PFS) | Multivariable Cox Hazards Model (PFS) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Cohort | Progression | ||||||||||
N | N | Person-Years | Crude HR | 95% CI | p | HR | 95% CI | p | LR | p | |
HGF | 55 | 28 | 22.3 | 0.0002 | |||||||
Low | 27 | 10 | 0.24 | 1 | 0.001 | 1 | 0.005 | ||||
High | 28 | 18 | 0.44 | 3.85 | (1.74–8.47) | 3.31 | (1.43–7.65) | ||||
IL-6 | 55 | ||||||||||
Low | 27 | 14 | 0.34 | 1 | 0.144 | 1 | 0.531 | ||||
High | 28 | 14 | 0.34 | 1.73 | (0.82–3.64) | 1.28 | (0.58–2.79) | ||||
CXCL-10 | 55 | ||||||||||
Low | 27 | 10 | 0.24 | 1 | 0.026 | 1 | 0.852 | ||||
High | 28 | 18 | 0.44 | 2.33 | (1.10–4.94) | 1.08 | (0.46–2.52) | ||||
CXCL-11 | 55 | ||||||||||
Low | 27 | 8 | 0.19 | 1 | 0.001 | 1 | 0.005 | ||||
High | 28 | 20 | 0.48 | 3.86 | (1.75–8.50) | 3.23 | (1.42–7.37) | ||||
Prognostic Index (PI) | 55 | ||||||||||
Low | 27 | 9 | 0.22 | 1 | <0.0001 | ||||||
High | 28 | 19 | 0.46 | 5.28 | (2.32–12.0) |
Cytokine/Chemokine | Univariable Cox Hazards Model (OS) | Multivariable Cox Hazards Model (OS) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Cohort | Exitus | ||||||||||
N | N | Person-Years | Crude HR | 95% CI | p | HR | 95% CI | p | LR | p | |
HGF | 55 | 28 | 19.29 | 0.0007 | |||||||
Low | 27 | 8 | 0.16 | 1 | 0.005 | 1 | 0.081 | ||||
High | 28 | 20 | 0.39 | 3.15 | (1.40–7.07) | 2.18 | (0.90–5.23) | ||||
IL-6 | 55 | ||||||||||
Low | 27 | 11 | 0.22 | 1 | 0.069 | 1 | 0.715 | ||||
High | 28 | 17 | 0.34 | 1.99 | (0.94–4.20) | 1.16 | (0.51–2.64) | ||||
CXCL-10 | 55 | ||||||||||
Low | 27 | 10 | 0.20 | 1 | 0.062 | 1 | 0.942 | ||||
High | 28 | 18 | 0.35 | 2.07 | (0.96–4.46) | 1.22 | (0.39–2.37) | ||||
CXCL-11 | 55 | ||||||||||
Low | 27 | 4 | 0.08 | 1 | 0.001 | 1 | 0.005 | ||||
High | 28 | 22 | 0.43 | 5.38 | (2.04–14.1) | 4.24 | (1.53–11.7 ) | ||||
Prognostic Index (PI) | 55 | ||||||||||
Low | 27 | 7 | 0.14 | 1 | <0.0001 | ||||||
High | 28 | 21 | 0.41 | 4.82 | (2.03–11.42) |
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Esteban, E.; Exposito, F.; Crespo, G.; Lambea, J.; Pinto, A.; Puente, J.; Arranz, J.A.; Redrado, M.; Rodriguez-Antona, C.; de Andrea, C.; et al. Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy. Cancers 2021, 13, 2849. https://doi.org/10.3390/cancers13112849
Esteban E, Exposito F, Crespo G, Lambea J, Pinto A, Puente J, Arranz JA, Redrado M, Rodriguez-Antona C, de Andrea C, et al. Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy. Cancers. 2021; 13(11):2849. https://doi.org/10.3390/cancers13112849
Chicago/Turabian StyleEsteban, Emilio, Francisco Exposito, Guillermo Crespo, Julio Lambea, Alvaro Pinto, Javier Puente, Jose A. Arranz, Miriam Redrado, Cristina Rodriguez-Antona, Carlos de Andrea, and et al. 2021. "Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy" Cancers 13, no. 11: 2849. https://doi.org/10.3390/cancers13112849