Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study.
Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study.
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DOI：
10.1371/journal.pmed.1003732
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发表时间：
2021-08
期刊：
影响因子：
15.8
通讯作者：
Chaudhuri AA
中科院分区：
文献类型：
--
作者：
Chauhan PS;Chen K;Babbra RK;Feng W;Pejovic N;Nallicheri A;Harris PK;Dienstbach K;Atkocius A;Maguire L;Qaium F;Szymanski JJ;Baumann BC;Ding L;Cao D;Reimers MA;Kim EH;Smith ZL;Arora VK;Chaudhuri AA
肌肉浸润性膀胱癌(MIBC)的标准护理治疗是根治性膀胱切除术，通常在此之前进行新辅助化疗。然而，无法无创地评估微小残留病(MRD)限制了我们提供保留膀胱的治疗的能力。在这里，我们试图开发一种通过尿液肿瘤DNA(UtDNA)分析的液体活检液。我们应用尿癌个性化深度测序(uCAPP-Seq)，一种有针对性的下一代测序(NGS)方法检测utDNA，应用于2019年4月至2020年11月治疗意向根治性膀胱癌切除术当天采集的42例局限性膀胱癌患者的尿液无细胞DNA(CfDNA)样本。患者年龄50~86岁，平均69岁，男性占76%(32/42)，吸烟者占%(27/42)，确诊病例占76%(32/42)。在MIBC患者中，59%(19/32)接受了新辅助化疗。UtDNA变异体调用是在没有肿瘤组织事先测序的情况下非侵入性地执行的。每个患者的总体utDNA水平由去除生殖系变异后具有最高变异等位基因比例的非沉默突变表示。对15名健康成年人的尿液进行了类似的分析。UtDNA分析显示，健康成人的utDNA中位数为0%，膀胱癌患者的utDNA中位数为2.4%。当患者被归类为手术标本中检测到残留疾病的患者(n=16)和病理完全应答的患者(n=26)时，utDNA水平的中位数分别为4.3%和0%(p=0.002)。使用最佳utDNA阈值定义MRD检测，utDNA MRD检测阳性与无聚合酶链式反应高度相关(p<；0.001)，灵敏度和特异度分别为81%和81%。将留一法交叉验证应用于我们队列中基于utDNA MRD检测的病理反应的预测，得到了81%的高度显著的准确性(p=0.007)。此外，utDNA MRD阳性患者的无进展生存率显著低于utDNA MRD阴性患者(PFS；HR=7.4；95%CI：1.4-38.9；p=0.02)。在5名MIBC患者中，尿液和肿瘤来源的突变之间的符合率为85%。根据409例MIBC肿瘤的肿瘤基因组图谱(TCGA)全外显子组测序的线性关系，从尿cfDNA中检测到的非沉默突变的数量来推断utDNA MRD阳性患者的肿瘤突变负担(TMB)。我们认为，这些高推断TMB的患者中，约58%可能是早期免疫检查点阻断治疗的候选对象。研究的局限性包括仅限于单核苷酸变异(SNV)的分析，手术缩小的存活率差异，以及在MRD时间点新辅助化疗后检测到的DNA损伤反应(DRR)突变数量较少。膀胱癌根治性切除术前的utDNA MRD检测与病理反应显著相关，这可能有助于选择患者进行膀胱保留治疗。UtDNA MRD的检测也与PFS显著相关。此外，utDNA可用于无创性推断TMB，这将有助于未来膀胱癌的个性化免疫治疗。PraDeep S.Chauhan及其同事通过尿液肿瘤DNA(UtDNA)分析研究了一种液体活检液，以评估肌肉浸润性膀胱癌患者的微小残留病变。肌肉浸润性膀胱癌(MIBC)的治疗标准是先进行新辅助化疗，然后进行根治性膀胱切除术，这会显著影响患者的生活质量。无法无创地评估微小残留病(MRD)限制了我们提供保留膀胱的治疗的能力。我们确定在根治性膀胱切除术前检测尿液肿瘤DNA(UtDNA)是否可以预测病理完全应答(PCR)和生存结果的差异。我们确定utDNA分析是否可以确定哪些患者是早期免疫检查点阻断的候选患者。我们对42例局限性膀胱癌患者行根治性膀胱癌根治术当天的尿液游离DNA(CfDNA)标本进行了尿癌深度测序(uCAPP-Seq)。UtDNAMRD检测阳性与无聚合酶链式反应高度相关(p<；0.001)，其敏感性和特异性分别为81%和81%。UtDNA MRD阳性患者的无进展生存期(PFS)明显低于utDNA MRD阴性患者(HR=7.4；95%CI：1.4~38.9；P=0.02)。从尿液中推断出高TMB的患者可能是早期应用免疫检查点阻断治疗的对象。膀胱癌根治性切除术前的utDNA MRD检测与病理反应显著相关，这可能有助于选择患者进行膀胱保留治疗。UtDNA可用于无创性推断TMB，为未来膀胱癌患者的个体化免疫治疗提供便利。
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. 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. 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. Pradeep S. Chauhan and colleagues, investigate a liquid biopsy solution via urine tumor DNA (utDNA) analysis to assess minimal residual disease in patients with muscle-invasive bladder cancer. The standard of care for muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy, which significantly impacts quality of life. The inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. We determine if urine tumor DNA (utDNA) detection just prior to radical cystectomy can predict pathologic complete response (pCR) and differences in survival outcomes. We determine if utDNA analysis can identify patients who are candidates for early immune checkpoint blockade. We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq) to urine cell-free DNA (cfDNA) samples acquired on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. Positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. utDNA MRD–positive patients exhibited significantly worse progression-free survival (PFS) compared to utDNA MRD–negative patients (HR = 7.4; 95% CI: 1.4–38.9; p = 0.02). Patients with high TMB inferred from urine might have been candidates for early treatment with immune checkpoint blockade. 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 can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer patients in the future.
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DOI：
10.3233/blc-170129
发表时间：
2018-01-20
期刊：
Bladder cancer (Amsterdam, Netherlands)
影响因子：
--
作者：
Abbosh PH;Plimack ER
通讯作者：
Plimack ER
影响因子：
158.5
作者：
Grossman, HB;Natale, RB;Crawford, ED
通讯作者：
Crawford, ED
影响因子：
78.8
作者：
Abbosh, Christopher;Birkbak, Nicolai J.;Swanton, Charles
通讯作者：
Swanton, Charles
DOI：
10.1158/1078-0432.ccr-19-4162
发表时间：
2020-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Galsky MD;Saci A;Szabo PM;Han GC;Grossfeld G;Collette S;Siefker-Radtke A;Necchi A;Sharma P
通讯作者：
Sharma P
影响因子：
1.1
作者：
Jeeta, Ruhana R.;Gordon, Naheema S.;Ward, Douglas G.
通讯作者：
Ward, Douglas G.