Bacon Jack V W, Müller David C, Ritch Elie, Annala Matti, Dugas Sarah G, Herberts Cameron, Vandekerkhove Gillian, Seifert Helge, Zellweger Tobias, Black Peter C, Bubendorf Lukas, Wyatt Alexander W, Rentsch Cyrill A
Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; Department of Urology, University Hospital Basel, University of Basel, Basel, Switzerland.
Eur Urol Oncol. 2022 Dec;5(6):677-686. doi: 10.1016/j.euo.2021.11.002. Epub 2021 Dec 8.
High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with bacillus Calmette-Guérin (BCG), but relapse is common. Improvement of patient outcomes requires better understanding of links between BCG resistance and genomic driver alterations.
To validate the prognostic impact of common genomic alterations in NMIBC pretreatment and define somatic changes present in post-BCG relapses.
DESIGN, SETTING, AND PARTICIPANTS: We retrieved tumour tissues and outcomes for 90 patients with BCG-naive NMIBC initiating BCG monotherapy. Post-BCG tissue was available from 34 patients. All tissues underwent targeted sequencing of tumour and matched normal.
Associations between clinical outcomes and genomics were determined using Cox proportional hazard models.
Of the patients, 58% were relapse free at data cut-off, 24% had NMIBC recurrence, and 18% experienced muscle-invasive progression. The risk of relapse was associated with ARID1A mutation (hazard ratio [HR] = 2.00; p = 0.04) and CCNE1 amplification (HR = 2.61; p = 0.02). Pre- and post-BCG tumours shared truncal driver alterations, with mutations in TERT and chromatin remodelling genes particularly conserved. However, shifts in somatic profiles were common and clinically relevant alterations in FGFR3, PIK3CA, TSC1, and TP53 were temporally variable, despite apparent clonal prevalence at one time point. Limitations include the difficulty of resolving the relative impact of BCG therapy versus surgery on genomics at relapse and biopsy bias.
Somatic hypermutation and alterations in CCNE1 and ARID1A should be incorporated into future models predicting NMIBC BCG outcomes. Changes in tumour genomics over time highlight the importance of recent biopsy when considering targeted therapies, and suggest that relapse after BCG is due to persisting and evolving precursor populations.
Changes in key cancer genes can predict bladder cancer relapse after treatment with bacillus Calmette-Guérin. Relapses after treatment can be driven by large-scale genetic changes within the cancer. These genetic changes help us understand how superficial bladder cancer can progress to be treatment resistant.
高危非肌层浸润性膀胱癌（NMIBC）采用卡介苗（BCG）治疗，但复发很常见。改善患者预后需要更好地理解卡介苗耐药性与基因组驱动改变之间的联系。
验证NMIBC预处理中常见基因组改变的预后影响，并确定卡介苗治疗后复发中存在的体细胞变化。
设计、设置和参与者：我们检索了90例初治NMIBC且开始接受卡介苗单药治疗患者的肿瘤组织及预后情况。34例患者有卡介苗治疗后的组织样本。所有组织均进行了肿瘤及配对正常组织的靶向测序。
使用Cox比例风险模型确定临床结局与基因组学之间的关联。
在数据截止时，58%的患者无复发，24%的患者出现NMIBC复发，18%的患者发生肌层浸润进展。复发风险与ARID1A突变（风险比[HR]=2.00；p=0.04）和CCNE1扩增（HR=2.61；p=0.02）相关。卡介苗治疗前后的肿瘤具有共同的主干驱动改变，TERT和染色质重塑基因的突变尤其保守。然而，体细胞图谱的变化很常见，FGFR3、PIK3CA、TSC1和TP53的临床相关改变在时间上是可变的，尽管在某一时间点有明显的克隆优势。局限性包括难以区分卡介苗治疗与手术对复发时基因组学的相对影响以及活检偏倚。
体细胞高突变以及CCNE1和ARID1A的改变应纳入未来预测NMIBC卡介苗治疗结局的模型中。肿瘤基因组学随时间的变化突出了在考虑靶向治疗时近期活检的重要性，并表明卡介苗治疗后的复发是由于持续存在且不断演变的前驱细胞群所致。
关键癌症基因的变化可以预测卡介苗治疗后膀胱癌的复发。治疗后的复发可能由癌症内部的大规模基因变化驱动。这些基因变化有助于我们理解浅表性膀胱癌如何进展为耐药性。
