Genomic and Clinical Prognostic Factors in Patients With Advanced Urothelial Carcinoma Receiving Immune Checkpoint Inhibitors

Chawla, Neal Shiv; Sayegh, Nicolas; Tripathi, Nishita; Govindarajan, Ameish; Zengin, Zeynep Büşra; Phillip, Errol J.; Dizman, Nazlı; Meza, Luís; Muddasani, Ramya; Chehrazi‐Raffle, Alex; Malhotra, Jasnoor; Hsu, JoAnn; Agarwal, Neeraj; Pal, Sumanta K.; Tripathi, Abhishek

doi:10.1016/j.clgc.2022.11.007

Cited by 4 publications

(5 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found 455 articles, of which nine [ 1 , 3 , 6 , 12 – 17 ] were selected for further analysis. Figure 1 depicts the search process (PRISMA flowchart).…”

Section: Resultsmentioning

confidence: 99%

“…The meta-analysis included eight studies with a total of 1,458 patients [ 1 , 6 , 12 – 17 ]. Figure 2 depicts the pooled results of overall survival.…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, TERT mutation improved PFS (HR 0.38, P = 0.012) and OS (HR 0.32, P = 0.037) in one study [ 16 ]. No difference was found between two groups regarding PFS and OS in Neal’s study [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of the TERT mutation on the prognosis of patients with urothelial carcinoma: a systematic review and meta-analysis

Shuai,

Duan,

Zhou

et al. 2023

BMC Urol

View full text Add to dashboard Cite

Background Telomerase reverse transcriptase (TERT) mutation represents the most prevalent genetic mutation found in urothelial carcinoma (UC) and holds potential as a prognostic indicator for tumor outcomes. However, the association between TERT mutation and prognosis in UC patients remains poorly elucidated due to conflicting findings in existing literature. Therefore, this study aimed to investigate the effect of the TERT mutation on the survival of UC patients. Methods We systematically searched the PubMed, Embase, and Cochrane Library databases for studies that investigated the relationship between the TERT mutation and the prognosis of UC patients. Endpoints included the 2-year and 5-year recurrence-free survival (RFS) and overall survival (OS). The Newcastle–Ottawa Scale (NOS) tool was used to assess the risk of bias in the included studies. Review Manager 5.3 was used for the meta-analysis. Results Nine studies with a total of 1,552 patients were included in the analysis. Two studies were prospective, and seven were retrospective. The TERT promoter mutation was associated with a lower 2-year OS (relative risk [RR] = 0.92, 95% confidence interval [CI] 0.86–0.98; P = 0.007) and a lower 5-year OS (RR = 0.80, 95% CI 0.68–0.94; P = 0.008) compared with the TERT wild type. However, no significantly differences were found between two groups in terms of HR for OS (hazard ratio [HR] = 1.29, 95% CI 0.80–2.08; P = 0.29). Furthermore, we investigated the differences in RFS and disease-specific survival (DSS) between the two groups. Conclusion The TERT mutation increases the risk of death and decreases the survival time of UC patients. TERT may be a valuable marker with individual prognostic value.

show abstract

“…We found 455 articles, of which nine [ 1 , 3 , 6 , 12 – 17 ] were selected for further analysis. Figure 1 depicts the search process (PRISMA flowchart).…”

Section: Resultsmentioning

confidence: 99%

“…The meta-analysis included eight studies with a total of 1,458 patients [ 1 , 6 , 12 – 17 ]. Figure 2 depicts the pooled results of overall survival.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Effect of the TERT mutation on the prognosis of patients with urothelial carcinoma: a systematic review and meta-analysis

Shuai,

Duan,

Zhou

et al. 2023

BMC Urol

View full text Add to dashboard Cite

show abstract

“…Additionally, the mutational status of specific genes may offer insights into the prognosis of UC patients undergoing immunotherapy. A retrospective analysis revealed that mUC patients receiving ICIs and harboring FGFR3 alterations had numerically higher progression events 59 . Consistently, our results demonstrated that mUC patients receiving immunotherapy with FGFR3 alterations had correspondingly worse PFS.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of circulating tumor DNA in urothelial carcinoma: a systematic review and meta-analysis

Liu,

Chen,

Huang

et al. 2024

International Journal of Surgery

View full text Add to dashboard Cite

Background: Circulating tumor DNA (ctDNA) has emerged as a non-invasive technique that provides valuable insights into molecular profiles and tumor disease management. This study aimed to evaluate the prognostic significance of circulating tumor DNA (ctDNA) in urothelial carcinoma (UC) through a systematic review and meta-analysis. Methods: A comprehensive search was conducted in MEDLINE, EMBASE, and the Cochrane Library from the inception to December 2023. Studies investigating the prognostic value of ctDNA in UC were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted. Overall meta-analysis and subgroup exploration stratified by metastatic status, ctDNA sampling time, treatment type, and detection method was performed using the R software (version 4.2.2). Results: A total of sixteen studies with 1725 patients were included. Fourteen studies assessed the association between baseline ctDNA status and patient outcomes. Patients with elevated ctDNA levels exhibited significantly worse DFS (HR=6.26; 95% CI, 3.71-10.58, P<0.001) and OS (HR=4.23; 95% CI, 2.72-6.57, P<0.001) regardless of metastatic status, ctDNA sampling time, treatment type and detection methods. Six studies evaluated the prognostic value of ctDNA dynamics in UC. Patients who showed a decrease or clearance in ctDNA levels during treatment or observation demonstrated more favorable DFS (HR=0.26, 95% CI, 0.17–0.41, P<0.001) and OS (HR=0.21, 95% CI, 0.11–0.38, P<0.001) compared to those who did not. The association remained consistent across the subgroup analysis based on metastatic status and detection methods. In the immune checkpoint inhibitor-treated setting, both lower baseline ctDNA level and ctDNA decrease during the treatment were significantly associated with more favorable oncologic outcomes. Furthermore, specific gene mutations such as FGFR3 identified in ctDNA also demonstrated predictive value in UC patients. Conclusion: This meta-analysis demonstrates a strong association of ctDNA status and its dynamic change with survival outcomes in UC, suggesting substantial clinical utility of ctDNA testing in prognosis prediction and decision making in this setting.

show abstract

“…The other common alterations, in addition to TP53 , present in our dataset included TERT promoter , CDKN2A/CDKN2B , and KDM6A , consistent with what has previously been reported. For patients with UC, the presence of TERT promoter alterations is associated with improved outcomes to ICI treatment ( 38 ), although another recent study did not replicate these results ( 39 ). On the other hand, CDKN2A/B alterations have been associated with increased resistance to ICI and chemotherapy ( 40 – 42 ).…”

Section: Discussionmentioning

confidence: 99%

Somatic alterations of TP53 and MDM2 associated with response to enfortumab vedotin in patients with advanced urothelial cancer

et al. 2023

View full text Add to dashboard Cite

BackgroundEnfortumab vedotin (EV) is an antibody-drug conjugate approved for patients with treatment-refractory advanced urothelial carcinoma (aUC), however data on biomarkers of response is lacking.MethodsWe retrospectively identified all aUC patients at our institution who received EV monotherapy and had next-generation sequencing (NGS) data available. Patients were considered responders if they had a complete response or partial response on restaging scans during treatment. Observed response rate (ORR) was evaluated by local investigator and compared between responders and non-responders using Chi-squared test. A univariable analysis was conducted using the Cox proportional hazard test to assess for associations between baseline characteristics and most common somatic alterations (in ≥10% of patients) with patient survival outcomes [progression-free survival (PFS) and overall survival (OS)]. Somatic alterations were then individually evaluated in separate multivariate models while accounting for patient and clinical characteristics using Cox regression models.ResultsAmong 29 patients treated with EV monotherapy, 27 had available NGS data. Median age was 70, 24 (83%) were men, 19 (62%) were Caucasian, 15 (52%) had pure urothelial histology and 22 (76%) had primary tumor in the bladder. ORR was 41%, and PFS and OS for the overall cohort were 5.1 months and 10.2 months. Responders were enriched among patients with TP53, KDM6A and MDM2 alterations. Patients with these alterations, as well as those with composite TP53/MDM2 alterations (alterations in either TP53 or MDM2), also had increased ORR with EV treatment compared to patients without these alterations. In the univariable analysis, baseline albumin level ≥ 3.0g/dL and presence of composite TP53/MDM2 alterations were associated with a prolonged OS. Baseline ECOG 0/1, TP53 alterations and TP53/MDM2 alterations were associated with a prolonged PFS. In the multivariable analysis, TP53 and TP53/MDM2 alterations were genomic markers predictive of improved PFS after accounting for the relevant clinical characteristics.ConclusionIn this single-center retrospective analysis of aUC patients treated with EV, presence of TP53 or MDM2 somatic alterations, lower ECOG PS scores (ECOG 0 or 1) and higher albumin levels (≥3 g/dL) were associated with improved outcomes with EV treatment. Prospective and external validation of these findings in larger cohorts is warranted.

show abstract

Genomic and Clinical Prognostic Factors in Patients With Advanced Urothelial Carcinoma Receiving Immune Checkpoint Inhibitors

Cited by 4 publications

References 34 publications

Effect of the TERT mutation on the prognosis of patients with urothelial carcinoma: a systematic review and meta-analysis

Effect of the TERT mutation on the prognosis of patients with urothelial carcinoma: a systematic review and meta-analysis

Prognostic significance of circulating tumor DNA in urothelial carcinoma: a systematic review and meta-analysis

Somatic alterations of TP53 and MDM2 associated with response to enfortumab vedotin in patients with advanced urothelial cancer

Contact Info

Product

Resources

About