背景:目前,在非肌层浸润性膀胱癌患者中未发现丝裂霉素C应答的生物标志物.预测性生物标志物可以改善治疗结果并消除不必要治疗的不良事件。
目的:确定和验证丝裂霉素C化疗切除的预测生物标志物。
方法:确定一项随机对照试验的干预组进行分析。该研究于2018年1月至2019年6月在丹麦的两个主要泌尿科进行。患者有低级别/高级别疾病的病史,并在复发时纳入。干预组(58例患者)接受丝裂霉素C化学切除术。通过全外显子组测序分析来自先前肿瘤的肿瘤和参考种系DNA。预测性生物标志物在来自UROMOL研究的Ta低度肿瘤的背景下进行了验证。
方法:测量对化疗的反应(来自随机对照试验的干预组)和无复发生存期(UROMOL队列)。使用Fisher精确检验和Wilcoxon秩和检验比较各组。
结论:化疗反应与SPTAN1、APC、和FGFR3,以及APOBEC签名贡献水平(分别为p=0.035,p=0.034,p=0.055和p=0.035)。主要限制包括在化学切除之前没有活检生物标志物的发现和不匹配的验证队列。
结论:APC的突变状态,SPTAN1和FGFR3以及来自APOBEC相关特征的突变贡献水平被鉴定为非肌肉浸润性膀胱癌患者中丝裂霉素C化学切除术的潜在预测性生物标志物。然而,需要进行前瞻性验证研究。
结果:我们研究了非侵入性膀胱肿瘤的DNA,以预测化疗后的治疗反应。四种生物标志物显示了有希望的结果,这应该在未来的研究中进行测试。
BACKGROUND: Currently, no biomarkers of response to mitomycin C have been identified in non-muscle-invasive bladder cancer patients. Predictive biomarkers could improve the treatment outcome and eliminate adverse events from unnecessary treatment.
OBJECTIVE: To identify and validate predictive biomarkers of chemoresection with mitomycin C.
METHODS: The intervention group of a randomised controlled trial was identified for analyses. The study was conducted between January 2018 and June 2019 in two major urological departments in Denmark. Patients had a history of Ta low-grade/high-grade disease and were included upon recurrence. The intervention group (58 patients) received chemoresection with mitomycin C. Tumour and reference germline DNA from prior tumours were analysed by whole exome sequencing. Predictive biomarkers were validated in the context of Ta low-grade tumours from the UROMOL study.
METHODS: Response to chemotherapy (intervention group from the randomised controlled trial) and recurrence-free survival (UROMOL cohort) were measured. Groups were compared using Fisher\'s exact test and Wilcoxon rank sum test.
CONCLUSIONS: Chemoresponse was associated with the mutation status of SPTAN1, APC, and FGFR3, and the level of APOBEC signature contribution (p = 0.035, p = 0.034, p = 0.055, and p = 0.035, respectively). The main limitations include no biopsy for biomarker discovery immediately prior to chemoresection and the unmatched validation cohort.
CONCLUSIONS: Mutation status of APC, SPTAN1, and FGFR3 and the level of mutational contribution from APOBEC-related signatures were identified as potential predictive biomarkers for chemoresection with mitomycin C in non-muscle-invasive bladder cancer patients. A prospective validation study is however needed.
RESULTS: We investigated DNA from noninvasive bladder tumours in order to predict treatment response to chemotherapy. Four biomarkers showed promising results, which should be tested in future studies.