Clinical, Genomic, and Transcriptomic Characteristics of Patients with Metastatic Renal Cell Carcinoma Who Developed Thromboembolic Events
Main Article Content
Keywords
cancer, kidney, renal cell carcinoma, thromboembolic events
Abstract
Thromboembolic events (TE) are a common complication in patients with metastatic renal cell carcinoma (mRCC) and are associated with poorer clinical outcomes. However, the incidence of TE and clinical and genomic characteristics of patients with mRCC who develop this complication are poorly understood. Herein, we describe the incidence and clinical features of patients with mRCC with or without TE at our institution, and examine their association with the underlying genomic and transcriptomic characteristics of the tumor. This retrospective study included all consecutive cases of mRCC seen at our institution. A CLIA-certified lab performed tumor genomics and transcriptomics. Patients were classified based on the presence of a TE within the first year of diagnosis. Three hundred and seventy patients with mRCC were included in the study. TE was seen in 11% (42) of the patients. Patients with favorable International mRCC Database Consortium (IMDC) risk were less likely to develop a TE. In contrast, patients receiving combination treatment with a tyrosine kinase inhibitor (TKI) and an immune checkpoint inhibitor were more likely to develop a TE. No difference in overall survival among patients with or without TE was observed (52 vs. 55 months; HR 0.85, 95% CI 0.5574–1.293, p = 0.24). The most upregulated pathways in mRCC with TEs versus those without were the xenobiotic metabolism and mTORC1 signaling pathways. Our findings suggest potential biomarkers that, after external validation, could be used to better select patients who would benefit from prophylactic anticoagulation.
References
1. Mulder FI, Horváth-Puhó E, van Es N, van Laarhoven HWM, Pedersen L, Moik F, et al. Venous thromboembolism in cancer patients: A population-based cohort study. Blood. 2021;137(14):1959–69. 10.1182/blood.2020007338
2. Khorana AA, Mackman N, Falanga A, Pabinger I, Noble S, Ageno W, et al. Cancer-associated venous thromboembolism. Nature Rev Dis Primers. 2022;8(1):11. 10.1038/s41572-022-00336-y
3. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122(10):1712–23. 10.1182/blood-2013-04-460121
4. Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005;6(6):401–10. 10.1016/S1470-2045(05)70207-2
5. Tabibu S, Vinod PK, Jawahar C V. Pan-Renal Cell Carcinoma classification and survival prediction from histopathology images using deep learning. Scientific Rep. 2019;9(1):10509. 10.1038/s41598-019-46718-3
6. Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Int Med. 2006;166(4):458. 10.1001/archinte.166.4.458
7. Sheng IY, Gupta S, Reddy CA, Angelini D, Funchain P, Sussman TA, et al. Thromboembolism in patients with metastatic renal cell carcinoma treated with immunotherapy. Targeted Oncol. 2021;16(6):813–21. 10.1007/s11523-021-00852-z
8. Leiva O, Connors JM, Al-Samkari H. Impact of tumor genomic mutations on thrombotic risk in cancer patients. Cancers (Basel). 2020;12(7):1958. 10.3390/cancers12071958
9. Mantha S, Rak J. Cancer genetic alterations and risk of venous thromboembolism. Thromb Res. 2022;213:S29–34. 10.1016/j.thromres.2021.12.008
10. Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database hallmark gene set collection. Cell Syst. 2015;1(6):417–25. 10.1016/j.cels.2015.12.004
11. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 2005;102(43):15545–50. 10.1073/pnas.0506580102
12. Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood. 2017;130(13):1499–506. 10.1182/blood-2017-03-743211
13. Mahajan A, Brunson A, Adesina O, Keegan THM, Wun T. The incidence of cancer-associated thrombosis is increasing over time. Blood Adv. 2022;6(1):307–20. 10.1182/bloodadvances.2021005590
14. Connelly-Frost A, Shantakumar S, Kobayashi MG, Li H, Li L. Older renal cell cancer patients experience increased rates of venous thromboembolic events: A retrospective cohort study of SEER-Medicare data. BMC Cancer. 2013;13(1):209. 10.1186/1471-2407-13-209
15. Sheng IY, Gupta S, Reddy CA, Angelini D, Funchain P, Sussman TA, et al. Thromboembolism in patients with metastatic renal cell carcinoma treated with immunotherapy. Target Oncol. 2021;16(6):813–21. 10.1007/s11523-021-00852-z
16. Abdol Razak N, Jones G, Bhandari M, Berndt M, Metharom P. Cancer-associated thrombosis: An overview of mechanisms, risk factors, and treatment. Cancers. 2018;10(10):380. 10.3390/cancers10100380
17. Schuster J, Sheng IY, Reddy CA, Khorana AA, Nizam A, Gupta S, et al. Risk of thromboembolism in patients receiving immunotherapy-based combinations as front-line therapy for metastatic renal cell carcinoma. Clin Genitourin Cancer. 2024;22(2):92-97. 10.1016/j.clgc.2023.09.005
18. Kaptein FHJ, van der Hulle T, Braken SJE, van Gennep EJ, Buijs JT, Burgmans MC, et al. Prevalence, treatment, and prognosis of tumor thrombi in renal cell carcinoma. JACC: CardioOncology. 2022;4(4):522–31. 10.1016/j.jaccao.2022.07.011
19. Roopkumar J, Swaidani S, Kim AS, Thapa B, Gervaso L, Hobbs BP, et al. Increased incidence of venous thromboembolism with cancer immunotherapy. Med (N Y). 2021;2(4):423–434.e3. 10.1016/j.medj.2021.02.002
20. Moik F, Chan WSE, Wiedemann S, Hoeller C, Tuchmann F, Aretin MB, et al. Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood. 2021;137(12):1669–78. 10.1182/blood.2020007878
21. Li H, Sahu KK, Brundage J, Benson M, Swami U, Boucher KM, et al. Phase I trial of combination therapy with avelumab and cabozantinib in patients with newly diagnosed metastatic clear cell renal cell carcinoma. Oncologist. 2023;28(8):737–e693. 10.1093/oncolo/oyad019
22. Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): Long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7): 888–98. 10.1016/S1470-2045(22)00290-X
23. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New Engl J Med. 2019;380(12):1103–15. 10.1056/NEJMoa1816047
24. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New Engl J Med. 2019;380(12):1116–27. 10.1056/NEJMoa1816714
25. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. New Engl J Med. 2021;384(14):1289–300. 10.1056/NEJMoa2035716
26. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. New Engl J Med. 2018;378(14):1277–90. 10.1056/NEJMoa1712126
27. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. New Engl J Med. 2013;369(8):722–31. 10.1056/NEJMoa1303989
28. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New Engl J Med. 2007;356(2):115–24. 10.1056/NEJMoa065044
29. Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. New Engl J Med. 2018;379(5):417–27. 10.1056/NEJMoa1803675
30. Heck JE, Moore LE, Lee YCA, McKay JD, Hung RJ, Karami S, et al. Xenobiotic metabolizing gene variants and renal cell cancer: A multicenter study. Front Oncol. 2012;2:16. 10.3389/fonc.2012.00016
31. Li H, Li W, Dai S, Guo Y, Zheng J, Liu J, et al. Identification of metabolism-associated genes and pathways involved in different stages of clear cell renal cell carcinoma. Oncol Lett. 2018; 15(2):2316–22. 10.3892/ol.2017.7567
32. Qi Y, Wang L, Wang K, Peng Z, Ma Y, Zheng Z, et al. New mechanistic insights of clear cell renal cell carcinoma from integrated miRNA and mRNA expression profiling studies. Biomed Pharmacother. 2019;111:821–34. 10.1016/j.biopha.2018.12.099
33. Bui P, Imaizumi S, Beedanagari SR, Reddy ST, Hankinson O. Human CYP2S1 metabolizes cyclooxygenase-and lipoxygenase-derived eicosanoids. Drug Metab Dispos. 2011;39(2):180–90. 10.1124/dmd.110.035121
34. Wang B, Wu L, Chen J, Dong L, Chen C, Wen Z, et al. Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets. Signal Transduct Target Ther. 2021;6(1):94. 10.1038/s41392-020-00443-w
35. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. 10.1126/science.1260419
36. Zou Z, Tao T, Li H, Zhu X. mTOR signaling pathway and mTOR inhibitors in cancer: Progress and challenges. Cell Biosci. 2020;10(1):31. 10.1186/s13578-020-00396-1
37. Faes S, Demartines N, Dormond O. Mechanistic target of rapamycin inhibitors in renal cell carcinoma: Potential, limitations, and perspectives. Front Cell Develop Biol. 2021;9: 636037. 10.3389/fcell.2021.636037
38. Battelli C, Cho DC. mTOR inhibitors in renal cell carcinoma. Therapy. 2011;8(4):359–67. 10.2217/thy.11.32
39. Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruïne AP. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;221(2):125–38. 10.1002/path.2689
40. Yang J, Zhou X, Fan X, Xiao M, Yang D, Liang B, et al. mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation. Blood. 2016;128(5):615–24. 10.1182/blood-2015-10-672964
41. Wang L, Liu G, Wu N, Dai B, Han S, Liu Q, et al. mTOR regulates GPVI-mediated platelet activation. J Transl Med. 2021;19(1):201. 10.1186/s12967-021-02756-y
2. Khorana AA, Mackman N, Falanga A, Pabinger I, Noble S, Ageno W, et al. Cancer-associated venous thromboembolism. Nature Rev Dis Primers. 2022;8(1):11. 10.1038/s41572-022-00336-y
3. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122(10):1712–23. 10.1182/blood-2013-04-460121
4. Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005;6(6):401–10. 10.1016/S1470-2045(05)70207-2
5. Tabibu S, Vinod PK, Jawahar C V. Pan-Renal Cell Carcinoma classification and survival prediction from histopathology images using deep learning. Scientific Rep. 2019;9(1):10509. 10.1038/s41598-019-46718-3
6. Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Int Med. 2006;166(4):458. 10.1001/archinte.166.4.458
7. Sheng IY, Gupta S, Reddy CA, Angelini D, Funchain P, Sussman TA, et al. Thromboembolism in patients with metastatic renal cell carcinoma treated with immunotherapy. Targeted Oncol. 2021;16(6):813–21. 10.1007/s11523-021-00852-z
8. Leiva O, Connors JM, Al-Samkari H. Impact of tumor genomic mutations on thrombotic risk in cancer patients. Cancers (Basel). 2020;12(7):1958. 10.3390/cancers12071958
9. Mantha S, Rak J. Cancer genetic alterations and risk of venous thromboembolism. Thromb Res. 2022;213:S29–34. 10.1016/j.thromres.2021.12.008
10. Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database hallmark gene set collection. Cell Syst. 2015;1(6):417–25. 10.1016/j.cels.2015.12.004
11. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 2005;102(43):15545–50. 10.1073/pnas.0506580102
12. Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood. 2017;130(13):1499–506. 10.1182/blood-2017-03-743211
13. Mahajan A, Brunson A, Adesina O, Keegan THM, Wun T. The incidence of cancer-associated thrombosis is increasing over time. Blood Adv. 2022;6(1):307–20. 10.1182/bloodadvances.2021005590
14. Connelly-Frost A, Shantakumar S, Kobayashi MG, Li H, Li L. Older renal cell cancer patients experience increased rates of venous thromboembolic events: A retrospective cohort study of SEER-Medicare data. BMC Cancer. 2013;13(1):209. 10.1186/1471-2407-13-209
15. Sheng IY, Gupta S, Reddy CA, Angelini D, Funchain P, Sussman TA, et al. Thromboembolism in patients with metastatic renal cell carcinoma treated with immunotherapy. Target Oncol. 2021;16(6):813–21. 10.1007/s11523-021-00852-z
16. Abdol Razak N, Jones G, Bhandari M, Berndt M, Metharom P. Cancer-associated thrombosis: An overview of mechanisms, risk factors, and treatment. Cancers. 2018;10(10):380. 10.3390/cancers10100380
17. Schuster J, Sheng IY, Reddy CA, Khorana AA, Nizam A, Gupta S, et al. Risk of thromboembolism in patients receiving immunotherapy-based combinations as front-line therapy for metastatic renal cell carcinoma. Clin Genitourin Cancer. 2024;22(2):92-97. 10.1016/j.clgc.2023.09.005
18. Kaptein FHJ, van der Hulle T, Braken SJE, van Gennep EJ, Buijs JT, Burgmans MC, et al. Prevalence, treatment, and prognosis of tumor thrombi in renal cell carcinoma. JACC: CardioOncology. 2022;4(4):522–31. 10.1016/j.jaccao.2022.07.011
19. Roopkumar J, Swaidani S, Kim AS, Thapa B, Gervaso L, Hobbs BP, et al. Increased incidence of venous thromboembolism with cancer immunotherapy. Med (N Y). 2021;2(4):423–434.e3. 10.1016/j.medj.2021.02.002
20. Moik F, Chan WSE, Wiedemann S, Hoeller C, Tuchmann F, Aretin MB, et al. Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood. 2021;137(12):1669–78. 10.1182/blood.2020007878
21. Li H, Sahu KK, Brundage J, Benson M, Swami U, Boucher KM, et al. Phase I trial of combination therapy with avelumab and cabozantinib in patients with newly diagnosed metastatic clear cell renal cell carcinoma. Oncologist. 2023;28(8):737–e693. 10.1093/oncolo/oyad019
22. Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): Long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7): 888–98. 10.1016/S1470-2045(22)00290-X
23. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New Engl J Med. 2019;380(12):1103–15. 10.1056/NEJMoa1816047
24. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New Engl J Med. 2019;380(12):1116–27. 10.1056/NEJMoa1816714
25. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. New Engl J Med. 2021;384(14):1289–300. 10.1056/NEJMoa2035716
26. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. New Engl J Med. 2018;378(14):1277–90. 10.1056/NEJMoa1712126
27. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. New Engl J Med. 2013;369(8):722–31. 10.1056/NEJMoa1303989
28. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New Engl J Med. 2007;356(2):115–24. 10.1056/NEJMoa065044
29. Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. New Engl J Med. 2018;379(5):417–27. 10.1056/NEJMoa1803675
30. Heck JE, Moore LE, Lee YCA, McKay JD, Hung RJ, Karami S, et al. Xenobiotic metabolizing gene variants and renal cell cancer: A multicenter study. Front Oncol. 2012;2:16. 10.3389/fonc.2012.00016
31. Li H, Li W, Dai S, Guo Y, Zheng J, Liu J, et al. Identification of metabolism-associated genes and pathways involved in different stages of clear cell renal cell carcinoma. Oncol Lett. 2018; 15(2):2316–22. 10.3892/ol.2017.7567
32. Qi Y, Wang L, Wang K, Peng Z, Ma Y, Zheng Z, et al. New mechanistic insights of clear cell renal cell carcinoma from integrated miRNA and mRNA expression profiling studies. Biomed Pharmacother. 2019;111:821–34. 10.1016/j.biopha.2018.12.099
33. Bui P, Imaizumi S, Beedanagari SR, Reddy ST, Hankinson O. Human CYP2S1 metabolizes cyclooxygenase-and lipoxygenase-derived eicosanoids. Drug Metab Dispos. 2011;39(2):180–90. 10.1124/dmd.110.035121
34. Wang B, Wu L, Chen J, Dong L, Chen C, Wen Z, et al. Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets. Signal Transduct Target Ther. 2021;6(1):94. 10.1038/s41392-020-00443-w
35. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. 10.1126/science.1260419
36. Zou Z, Tao T, Li H, Zhu X. mTOR signaling pathway and mTOR inhibitors in cancer: Progress and challenges. Cell Biosci. 2020;10(1):31. 10.1186/s13578-020-00396-1
37. Faes S, Demartines N, Dormond O. Mechanistic target of rapamycin inhibitors in renal cell carcinoma: Potential, limitations, and perspectives. Front Cell Develop Biol. 2021;9: 636037. 10.3389/fcell.2021.636037
38. Battelli C, Cho DC. mTOR inhibitors in renal cell carcinoma. Therapy. 2011;8(4):359–67. 10.2217/thy.11.32
39. Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruïne AP. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;221(2):125–38. 10.1002/path.2689
40. Yang J, Zhou X, Fan X, Xiao M, Yang D, Liang B, et al. mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation. Blood. 2016;128(5):615–24. 10.1182/blood-2015-10-672964
41. Wang L, Liu G, Wu N, Dai B, Han S, Liu Q, et al. mTOR regulates GPVI-mediated platelet activation. J Transl Med. 2021;19(1):201. 10.1186/s12967-021-02756-y
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Jul 31, 2024
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Clinical, Genomic, and Transcriptomic Characteristics of Patients with Metastatic Renal Cell Carcinoma Who Developed Thromboembolic Events. (2024). Journal of Kidney Cancer, 11(3), 13-22. https://doi.org/10.15586/jkcvhl.v11i3.319
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Kidney Cancer: Original Articles
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How to Cite
Clinical, Genomic, and Transcriptomic Characteristics of Patients with Metastatic Renal Cell Carcinoma Who Developed Thromboembolic Events. (2024). Journal of Kidney Cancer, 11(3), 13-22. https://doi.org/10.15586/jkcvhl.v11i3.319