Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2023 Dec 15;29(24):5116-5127. doi: 10.1158/1078-0432.CCR-23-0792.
There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood.
We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of patients with MIBC homogeneously treated with TMT. Pretreatment tumors from 76 patients with MIBC underwent whole-exome sequencing; 67 underwent matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation.
With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS [HR, 0.15; 95% confidence interval (CI), 0.06-0.37; P = 0.030] and improved BI-EFS, an endpoint that includes all-cause mortality (HR, 0.33; 95% CI, 0.15-0.68; P = 0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wild-type cells.
Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts.
在保器官治疗中，急需寻找辐射反应的生物标志物。多模式治疗（TMT）包括经尿道肿瘤切除术，随后进行放化疗，可作为肌层浸润性膀胱癌（MIBC）的根治性膀胱切除术的替代方法，但反应的分子决定因素仍知之甚少。
我们对在一家机构接受 TMT 同质治疗的 MIBC 患者的队列中，与长期反应相关的基因组和转录组特征进行了描述。76 例 MIBC 患者的预处理肿瘤进行了全外显子测序；67 例进行了匹配的转录组谱分析。分子特征与临床结果相关，包括改良的膀胱完整无事件生存率（mBI-EFS），这是反映保留膀胱的长期癌症控制的综合终点。
在存活患者的中位随访时间为 74.6 个月时，37 例患者对 TMT 有良好的长期反应，而 39 例患者则无良好的长期反应。肿瘤突变负担与 TMT 后的结果无关。DNA 损伤反应基因改变与局部区域控制和 mBI-EFS 改善相关。在这些改变中，体细胞 ERCC2 突变明显与良好的长期结果相关；ERCC2 突变的患者 mBI-EFS 显著改善[HR，0.15；95%置信区间（CI），0.06-0.37；P=0.030]，且 BI-EFS 也得到改善，该终点包括全因死亡率（HR，0.33；95%CI，0.15-0.68；P=0.044）。体外 ERCC2 突变型膀胱癌细胞系对顺铂和放疗的敏感性明显高于同源 ERCC2 野生型细胞系。
我们的数据确定 ERCC2 突变为 MIBC 中与放化疗敏感性和长期反应相关的候选生物标志物。这些发现需要在独立队列中进行验证。
