Prognostic factors for relapse in patients with clinical stage I testicular cancer: protocol for a Danish nationwide cohort study

Wagner, Thomas; Toft, Birgitte Grønkær; Engvad, Birte; Lauritsen, Jakob; Kreiberg, Michael; Bandak, Mikkel; Rosenvilde, Josephine; Christensen, Ib Jarle; Pilt, Anette Pedersen; Berney, Daniel M.; Daugaard, Gedske

doi:10.1136/bmjopen-2019-033713

Cited by 8 publications

(7 citation statements)

References 49 publications

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“…Treatment guidelines differ for SE and NS patients and according to disease burden/stage [41]. The field of biomarkers for risk stratification of stage I disease is expanding, in an attempt to safely place patients on surveillance and avoid overtreatment, only selecting for adjuvant chemotherapy a subgroup of higher risk patients [42,43]. Although the currently available serum tumor markers are useful [44], they are dependent on histology and show important limitations [45].…”

Section: Discussionmentioning

confidence: 99%

Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors

et al. 2021

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Testicular germ cell tumors (TGCTs) are the most common cancers in men aged 15–39 years and are divided into two major groups, seminomas and nonseminomas. Novel treatment options are required for these patients, to limit side effects of chemotherapy. We hypothesized that promoter methylation of relevant homologous recombination (HR) genes might be predictive of response to poly‐ADP ribose polymerase inhibitors (PARPis) in TGCTs. We report a study pipeline combining in silico, in vitro, and clinical steps. By using several databases and in silico tools, we identified BRCA1, RAD51C, PALB2, RAD54B, and SYCP3 as the most relevant genes for further investigation and pinpointed specific CpG sites with pronounced negative correlation to gene expression. Nonseminomas displayed significantly higher methylation levels for all target genes, where increased methylation was observed in patients with more differentiated subtypes and higher disease burden. We independently performed second‐line targeted validation in tissue series from TGCT patients. A moderate and/or strong anti‐correlation between gene expression (assessed by RNA‐sequencing) and promoter methylation (assessed by 450k array) was found, for all of the targets. As a proof of concept, we demonstrated the sensitivity of TGCT cell lines to Olaparib, which associated with differential methylation levels of a subset of targets, namely BRCA1 and RAD51C. Our findings support the use of HR genes promoter methylation as a predictor of the therapeutic response to PARPis in patients with TGCT.

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Section: Discussionmentioning

confidence: 99%

Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors

et al. 2021

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“…A detailed description of the study cohort has been reported elsewhere. 19 In brief, we confirmed primary diagnosis by pathology review of the orchiectomy specimens. Clinical stage I disease at presentation was confirmed by medical record review.…”

Section: Methodsmentioning

confidence: 83%

A Validated Algorithm for Register-Based Identification of Patients with Relapse of Clinical Stage I Testicular Cancer

Wagner¹,

Lauritsen²,

Bandak³

et al. 2023

CLEP

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Purpose The Danish Testicular Cancer (DaTeCa) database aims to monitor and improve quality of care for testicular cancer patients. Relapse data registered in the DaTeCa database rely on manual registration. Currently, some safeguarding against missing registrations is attempted by a non-validated register-based algorithm. However, this algorithm is inaccurate and entails time-consuming medical record reviews. We aimed (1) to validate relapse data as registered in the DaTeCa database, and (2) to develop and validate an improved register-based algorithm identifying patients diagnosed with relapse of clinical stage I testicular cancer. Patients and Methods Patients registered in the DaTeCa database with clinical stage I testicular cancer from 2013 to 2018 were included. Medical record information on relapse data served as a gold standard. A pre-specified algorithm to identify relapse was tested and optimized on a random sample of 250 patients. Indicators of relapse were obtained from pathology codes in the Danish National Pathology Register and from diagnosis and procedure codes in the Danish National Patient Register. We applied the final algorithm to the remaining study population to validate its performance. Results Of the 1377 included patients, 284 patients relapsed according to the gold standard during a median follow-up time of 5.9 years. The completeness of relapse data registered in the DaTeCa database was 97.2% (95% confidence interval (CI): 95.2–99.1). The algorithm achieved a sensitivity of 99.6% (95% CI: 98.7–100), a specificity of 98.9% (95% CI: 98.2–99.6), and a positive predictive value of 95.9% (95% CI: 93.4–98.4) in the validation cohort (n = 1127, 233 relapses). Conclusion The registration of relapse data in the DaTeCa database is accurate, confirming the database as a reliable source for ongoing clinical quality assessments. Applying the provided algorithm to the DaTeCa database will optimize the accuracy of relapse data further, decrease time-consuming medical record review and contribute to important future clinical research.

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“…Detailed information about the study cohort and methods has been published previously. 20 In brief, we identified all patients with clinical stage I TC diagnosed in Denmark between January 1, 2013, and December 31, 2018, in the prospective Danish Testicular Cancer database. 21 By individual-level data linkage to the Danish National Pathology Registry, 22 using the civil registration number, 23 we collected the histologic slides from the orchiectomy specimens.…”

Section: Methodsmentioning

confidence: 99%

Prognostic Factors for Relapse in Patients With Clinical Stage I Testicular Seminoma: A Nationwide, Population-Based Cohort Study

Wagner,

Toft,

Lauritsen

et al. 2024

JCO

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PURPOSE Approximately 20% of patients with clinical stage I seminoma relapse. Tumor size and rete testis invasion have been identified as risk factors for relapse. However, the level of evidence supporting the use of these risk factors in clinical decision making is low. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We assessed prognostic factors for relapse in an unselected nationwide population-based setting with centralized pathology review. METHODS Patients with clinical stage I seminoma diagnosed from January 2013 to December 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histologic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified potential clinical and histopathologic prognostic factors and relapse was assessed by the use of Cox regression analysis. RESULTS Of 924 patients included, 148 (16%) patients relapsed during a median follow-up of 6.3 years. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated preorchiectomy levels of β-human chorionic gonadotropin and lactate dehydrogenase were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors to 62% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the prognostic model had an overall concordance statistic of 0.70. CONCLUSION The provided prognostic factors could replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies.

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Prognostic factors for relapse in patients with clinical stage I testicular cancer: protocol for a Danish nationwide cohort study

Cited by 8 publications

References 49 publications

Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors

Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors

A Validated Algorithm for Register-Based Identification of Patients with Relapse of Clinical Stage I Testicular Cancer

Prognostic Factors for Relapse in Patients With Clinical Stage I Testicular Seminoma: A Nationwide, Population-Based Cohort Study

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