Tsung-Mu Yang1
Nirmish Singla
Chung-Hsin Chen
Jer-Tsong Hsieh
Hsin-Chih Yeh- 1Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- 2Brady Urological Institute, School of Medicine, Johns Hopkins Medicine, Baltimore, MD, United States
- 3Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
- 4Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, United States
- 5Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
- 6Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- 7Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- 8Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Editorial on the Research Topic
Prognostic research and precision oncology in upper tract urothelial carcinoma-volume II
Upper tract urothelial carcinoma (UTUC) is an aggressive but rare urological cancer. Prognostic models in UTUC have largely been derived from clinical and pathological factors, although more recently, investigators have turned to the molecular landscape to gain prognostic information. Compared to UTUC, bladder urothelial carcinoma (UC) is more common. As UTUC shares many genomic alterations with bladder UC (1), studies of bladder UC have provided important reference for the management of UTUC. These studies have helped facilitate personalized management strategies. In this Research Topic, four articles, including two original articles, one case report, and one review article, explore the prognostic factors in UC with an emphasis towards advancing precision medicine.
The gold standard treatment of localized UTUC is radical nephroureterectomy (RNU) with bladder cuff resection. However, there can be various reasons for delayed surgery (2). The outbreak of coronavirus disease-19 (COVID-19) has significantly impacted medical practices globally, resulting in prolonged surgical wait times (SWT). In a multicenter retrospective cohort involving 1,251 Asian (mainly Taiwanese) patients, Wu et al. find that a SWT of more than 90 days is independently associated with worse overall survival (OS) and disease-free survival. This study is the first large-scale study of its kind in Asia, and the authors’ important findings emphasize the negative impact of prolonged SWT on survival.
In a study on >3,000 patients with high-grade bladder UC, Li et al. establish a prognostic nomogram by leveraging the SEER database (3). This nomogram includes six variables: T stage, positive lymph nodes, age, chemotherapy, regional lymph nodes examined, and primary tumor size. Both internal and external validation demonstrate the excellent discrimination and calibration ability of the nomogram. This nomogram may assist urologists in optimizing follow-up plans, determining subsequent treatment options, and improving outcomes in this group of patients.
Xu et al. demonstrate the application of precision medicine in the systemic treatment of UTUC. Platinum-based chemotherapy is considered the first-line therapy for locally advanced and metastatic UC, while immune checkpoint inhibitors (ICIs) are recommended for patients who are ineligible for cisplatin or have refractory disease after first-line chemotherapy. In order to optimize first-line treatment regimens, recent trials have focused on combining ICIs with chemotherapy, known as immunochemotherapy (ICT). However, the results of these trials were inconsistent (4–6). In their case report, Xu et al. present a case of highly aggressive UTUC. Through pathologic and molecular analyses, their patient’s tumor is classified as luminal-infiltrated subtype, characterized by TP53/MDM2 and ERBB2 mutations, non-mesenchymal state, and immune-infiltrated contexture, suggesting potential responsiveness to ICIs. Their patient receives ICT with gemcitabine, carboplatin, and the off-label PD-1 inhibitor sintilimab, followed by sintilimab maintenance monotherapy, leading to a sustained complete response over 2 years. This case highlights ICT as a promising option for first-line therapy in selected patients.
The final article explores the genetic predisposition of UC. CCAAT/enhancer-binding protein delta (CEBPD), a transcription factor, functions as a potent regulator for cell differentiation, proliferation, motility, growth arrest, and cell death. Notably, CEBPD overexpression is associated with a poor prognosis in UC, which has been found to have oncogenic functions in multiple regulation pathways. The review article by Chan et al. provides a comprehensive reappraisal of the regulatory mechanisms of CEBPD in UC progression and its characteristics in response to cisplatin treatment. CEBPD drives cancerization by influencing glycolytic metabolism shift and angiogenesis through multiple mechanisms involving MYC, hsa-miR-429, HK2, VEGFA, and MMP2. However, the role of upregulated CEBPD after cisplatin treatment remains uncertain. Two studies have proposed the potential association of CEBPD with cisplatin resistance (7, 8), while another study suggested its possible role in anti-tumorigenesis (9). Further investigations are needed to clarify this controversy. Lastly, their review sheds light on the involvement of CEBPD in the tumor microenvironment, underscoring the necessity for additional exploration in this field.
This Research Topic provides readers with novel insights into the prognostic factors of UTUC to help guide current clinical practice and serve as an essential juncture for future research.
Author contributions
TY: Writing – review & editing, Writing – original draft. NS: Writing – review & editing, Validation. CC: Validation, Writing – review & editing. JH: Validation, Writing – review & editing. HY: Validation, Writing – review & editing, Supervision.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. Sfakianos JP, Gul Z, Shariat SF, Matin SF, Daneshmand S, Plimack E, et al. Genetic differences between bladder and upper urinary tract carcinoma: Implications for therapy. Eur Urol Oncol (2021) 4(2):170–9. doi: 10.1016/j.euo.2020.12.007
2. Waldert M, Karakiewicz PI, Raman JD, Remzi M, Isbarn H, Lotan Y, et al. A delay in radical nephroureterectomy can lead to upstaging. BJU Int (2010) 105(6):812–7. doi: 10.1111/j.1464-410X.2009.08821.x
3. Hankey BF, Ries LA, Edwards BK. The surveillance, epidemiology, and end results program: A national resource. Cancer Epidemiol Biomarkers Prev (1999) 8(12):1117–21.
4. Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol (2021) 22(7):931–45. doi: 10.1016/s1470-2045(21)00152-2
5. Perez Valderrama B, Castellano Gauna D, Pinto Marin A, Mellado Gonzalez B, Puente J, Climent Duran MA, et al. LBA27 Phase II multicenter, randomized study to evaluate efficacy and safety of avelumab with gemcitabine/carboplatin (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy. Ann Oncol (2020) 31:S1158–S9. doi: 10.1016/j.annonc.2020.08.2256
6. Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet (2020) 395(10236):1547–57. doi: 10.1016/S0140-6736(20)30230-0
7. Hour TC, Lai YL, Kuan CI, Chou CK, Wang JM, Tu HY, et al. Transcriptional up-regulation of SOD1 by CEBPD: A potential target for cisplatin resistant human urothelial carcinoma cells. Biochem Pharmacol (2010) 80(3):325–34. doi: 10.1016/j.bcp.2010.04.007
8. Wang WJ, Li CF, Chu YY, Wang YH, Hour TC, Yen CJ, et al. Inhibition of the EGFR/STAT3/CEBPD axis reverses cisplatin cross-resistance with paclitaxel in the urothelial carcinoma of the urinary bladder. Clin Cancer Res (2017) 23(2):503–13. doi: 10.1158/1078-0432.Ccr-15-1169
Keywords: upper tract urothelial carcinoma, precision oncology, surgical wait time, nomogram, immunochemotherapy, CCAAT/enhancer-binding protein delta
Citation: Yang T-M, Singla N, Chen C-H, Hsieh J-T and Yeh H-C (2023) Editorial: Prognostic research and precision oncology in upper tract urothelial carcinoma-volume II. Front. Oncol. 13:1276718. doi: 10.3389/fonc.2023.1276718
Received: 12 August 2023; Accepted: 21 August 2023;
Published: 05 September 2023.
Edited and Reviewed by:
Dana Kristjansson, Norwegian Institute of Public Health (NIPH), NorwayCopyright © 2023 Yang, Singla, Chen, Hsieh and Yeh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hsin-Chih Yeh, patrick1201.tw@yahoo.com.tw