DNA 损伤反应改变预测肌层浸润性膀胱癌新辅助化疗敏感性：SWOG S1314 试验的相关性分析。
DNA Damage Response Alterations Predict for Neoadjuvant Chemotherapy Sensitivity in Muscle-Invasive Bladder Cancer: A Correlative Analysis of the SWOG S1314 Trial.
机构信息
Memorial Sloan Kettering Cancer Center, New York, NY.
Weill Cornell Medical College, New York, NY.
出版信息
JCO Precis Oncol. 2024 Nov;8:e2400287. doi: 10.1200/PO.24.00287. Epub 2024 Nov 5.
PURPOSE
Alterations in DNA damage response (DDR) genes, including , have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response.
METHODS
Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in , and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to <pT2) using logistic regression, adjusting for clinical stage and performance status.
RESULTS
Deleterious DDR alterations were detected in 41 (23%) of 179 patients. Of the 151 patients evaluable for pathologic response, patients with deleterious DDR alterations (n = 39) demonstrated a higher pathologic response rate than those without (odds ratio [OR], 3.24 [95% CI, 1.51 to 6.94]; = .003). In 24 -mutant patients, the OR for pT0 was 3.33 (95% CI, 1.35 to 8.22; = .009) and for <pT2 was 2.33 (95% CI, 0.92 to 5.89; = .073). The association between deleterious DDR alterations and PFS provided an estimate of hazard ratio, 0.54 (95% CI, 0.29 to 1.01; = .053).
CONCLUSION
Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.
目的
在肌层浸润性膀胱癌（MIBC）患者中，DNA 损伤反应（DDR）基因的改变，包括 ，与新辅助顺铂为基础的化疗（NAC）的反应相关。SWOG 1314（S1314）试验纳入了接受两种 NAC 方案之一治疗后行根治性膀胱切除术的 MIBC 患者。我们检测了 NAC 应答者和无应答者中 DDR 改变的发生率，并将 DDR 改变状态与反应相关联。
方法
179 例可评估患者的预处理肿瘤标本进行了下一代测序（纪念斯隆凯特琳综合可操作癌症靶点突变分析）。使用 Cox 回归确定了九个预先定义的 DDR 基因中任何或仅有害改变，或 中的任何改变与无进展生存期（PFS）和总生存期之间的关联，在可评估患者的亚组中，使用逻辑回归确定与病理反应（完全缓解，pT0 或降期至 <pT2）的关联，调整临床分期和表现状态。
结果
179 例患者中有 41 例（23%）检测到有害 DDR 改变。在 151 例可评估病理反应的患者中，有有害 DDR 改变的患者（n=39）的病理反应率高于无改变的患者（比值比[OR]，3.24[95%CI，1.51 至 6.94]；=0.003）。在 24 个 突变患者中，pT0 的 OR 为 3.33（95%CI，1.35 至 8.22；=0.009），pT2 的 OR 为 2.33（95%CI，0.92 至 5.89；=0.073）。有害 DDR 改变与 PFS 之间的关联提供了风险比的估计值，为 0.54（95%CI，0.29 至 1.01；=0.053）。
结论
在 S1314 中，有害 DDR 改变与 NAC 后的病理反应相关。正在对 和其他 DDR 改变进行功能验证，以帮助将这些改变作为膀胱癌 NAC 生物标志物进行精细化。
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