当前位置: X-MOL 学术PLOS Med. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study.
PLOS Medicine ( IF 10.5 ) Pub Date : 2021-08-31 , DOI: 10.1371/journal.pmed.1003732
Pradeep S Chauhan 1 , Kevin Chen 1 , Ramandeep K Babbra 1 , Wenjia Feng 1 , Nadja Pejovic 1 , Armaan Nallicheri 1 , Peter K Harris 1 , Katherine Dienstbach 2, 3 , Andrew Atkocius 2, 3 , Lenon Maguire 2, 3 , Faridi Qaium 1 , Jeffrey J Szymanski 1 , Brian C Baumann 1, 3 , Li Ding 2, 3, 4, 5, 6 , Dengfeng Cao 7 , Melissa A Reimers 2, 3 , Eric H Kim 3, 8 , Zachary L Smith 3, 8 , Vivek K Arora 2, 3 , Aadel A Chaudhuri 1, 3, 4, 6, 9, 10
Affiliation  

BACKGROUND The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS AND FINDINGS We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. CONCLUSIONS utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

中文翻译:


尿液肿瘤 DNA 检测治疗根治性膀胱切除术治疗的肌层浸润性膀胱癌的微小残留病灶:一项队列研究。



背景 肌层浸润性膀胱癌(MIBC)的标准护理治疗是根治性膀胱切除术,通常先进行新辅助化疗。然而,无法无创评估微小残留病 (MRD) 限制了我们提供膀胱保留治疗的能力。在这里,我们试图通过尿液肿瘤 DNA (utDNA) 分析来开发液体活检解决方案。方法和结果 我们将深度测序尿液癌症个性化分析 (uCAPP-Seq)(一种用于检测 utDNA 的靶向下一代测序 (NGS) 方法)应用于 2019 年 4 月至 2020 年 11 月期间采集的尿液无细胞 DNA (cfDNA) 样本。对 42 名局限性膀胱癌患者进行根治性膀胱切除术的当天。患者平均年龄为69岁(范围:50至86岁),其中76%(32/42)为男性,64%(27/42)为吸烟者,76%(32/42)为确诊患者MIBC 的。在 MIBC 患者中,59% (19/32) 接受了新辅助化疗。 utDNA 变异检出是非侵入性进行的,无需事先对肿瘤组织进行测序。每个患者的总体 utDNA 水平由去除种系变异后具有最高变异等位基因分数的非沉默突变表示。对 15 名健康成年人的尿液进行了类似的分析。 utDNA 分析显示,健康成年人的 utDNA 中位水平为 0%,膀胱癌患者的中位 utDNA 水平为 2.4%。当患者被分类为在手术样本中检测到残留疾病的患者 (n = 16) 与实现病理完全缓解的患者 (pCR; n = 26) 相比,中位 utDNA 水平分别为 4.3% 和 0%( p = 0.002)。使用最佳 utDNA 阈值来定义 MRD 检测,utDNA MRD 检测阳性与 pCR 缺失高度相关 (p < 0.001),敏感性为 81%,特异性为 81%。在我们的队列中,基于 utDNA MRD 检测的留一交叉验证应用于预测病理反应,产生了 81% 的高度显着准确度 (p = 0.007)。此外,与 utDNA MRD 阴性患者相比,utDNA MRD 阳性患者的无进展生存期显着较差(PFS;HR = 7.4;95% CI:1.4-38.9;p = 0.02)。在 5 名 MIBC 患者中确定,尿液衍生突变和肿瘤衍生突变之间的一致性为 85%。 utDNA MRD 阳性患者的肿瘤突变负荷 (TMB) 是通过应用源自 409 个 MIBC 肿瘤的癌症基因组图谱 (TCGA) 全外显子组测序的线性关系,从尿液 cfDNA 中检测到的非沉默突变数量推断出来的。我们建议,大约 58% 的 TMB 高推断患者可能是早期免疫检查点阻断治疗的候选者。研究的局限性包括分析仅限于单核苷酸变异(SNV)、手术减少了生存差异,以及新辅助化疗后在 MRD 时间点检测到的 DNA 损伤反应(DRR)突变数量较少。结论 膀胱癌根治性膀胱切除术之前的 utDNA MRD 检测与病理反应显着相关,这可能有助于选择患者进行膀胱保留治疗。 utDNA MRD 检测也与 PFS 显着相关。此外,utDNA可用于非侵入性推断TMB,这有助于未来膀胱癌的个性化免疫治疗。
更新日期:2021-08-31
down
wechat
bug