H. Lee Moffitt Cancer Center, Tampa, Florida.
NRG Oncology Statistics and Data Management Center/ACR, Philadelphia, Pennsylvania.
JAMA Netw Open. 2022 Nov 1;5(11):e2242378. doi: 10.1001/jamanetworkopen.2022.42378.
Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches.
To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis.
DESIGN, SETTING, AND PARTICIPANTS: This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020.
Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy.
MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio.
Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44).
Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.
膀胱保留的三联疗法可以作为根治性膀胱切除术治疗肌层浸润性膀胱癌（MIBC）的有效替代方法，但需要生物标志物来指导最佳患者选择。DNA 修复蛋白 MRE11 是一种候选的反应生物标志物，尚未在使用标准化测量方法的前瞻性队列中得到验证。
使用自动化定量图像分析评估 MIBC 患者接受三联疗法时 MRE11 表达作为预后生物标志物。
设计、地点和参与者：本预后研究分析了 1988 年至 2007 年间北美 37 个参与机构的 6 项前瞻性 I/II 期、II 期或 III 期三联疗法（放射治疗肿瘤学组 [RTOG] 8802、8903、9506、9706、9906 和 0233）中 MIBC 患者的多组学数据。合格的患者患有非转移性 MIBC，并被纳入 6 项三联疗法临床试验之一。分析于 2020 年 8 月完成。
经尿道膀胱肿瘤切除术和基于顺铂的放化疗联合治疗。
MRE11 表达与疾病特异性（膀胱癌）死亡率（DSM）的关联，定义为死于膀胱癌。在预处理的肿瘤组织上进行了抗 MRE11 抗体的免疫荧光，并使用自动化定量图像分析进行了分析，以根据核质（NC）信号比计算 MRE11 的归一化评分。
在 6 项试验的 465 名患者中，有 168 名患者有可用组织，其中 135 名可用于 MRE11 表达分析（中位年龄 65 岁[最小-最大，34-90 岁]；111[82.2%]名男性）。存活患者的中位（最小-最大）随访时间为 5.0（0.6-11.7）年。中位（Q1-Q3）MRE11 NC 信号比为 2.41（1.49-3.34）。MRE11 NC 比值高于 1.49（即高于四分位距第 1 四分位数）的患者，DSM 显著降低（HR，0.50；95%CI，0.26-0.93；P=0.03）。MRE11 NC 信号比为 1.49 或更低的患者的 4 年 DSM 为 41.0%（95%CI，23.2%-58.0%），而比值高于 1.49 的患者为 21.0%（95%CI，13.4%-29.8%）。MRE11 NC 信号比与总生存期无显著相关性（HR，0.84；95%CI，0.49-1.44）。
更高的 MRE11 NC 信号比与三联疗法后更好的 DSM 相关。较低的 MRE11 NC 信号比确定了预后较差的亚组，可能受益于治疗强化。
