医学
膀胱癌
肿瘤科
膀胱切除术
DNA甲基化
生物标志物
内科学
前瞻性队列研究
新辅助治疗
甲基化
预测标记
化疗
胎儿游离DNA
癌症
基因表达
基因
生物
乳腺癌
生物化学
怀孕
胎儿
遗传学
产前诊断
作者
Yi‐Tsung Lu,Melissa Plets,Gareth Morrison,Alexander Cunha,Steven Cen,Suhn Kyong Rhie,Kimberly D. Siegmund,Siamak Daneshmand,David I. Quinn,Joshua J. Meeks,Seth P. Lerner,Daniel P. Petrylak,David J. McConkey,Thomas W. Flaig,Ian M. Thompson,Amir Goldkorn
标识
DOI:10.1016/j.euo.2023.03.008
摘要
Neoadjuvant chemotherapy (NAC) is the standard of care in muscle-invasive bladder cancer (MIBC). However, treatment is intense, and the overall benefit is small, necessitating effective biomarkers to identify patients who will benefit most.To characterize cell-free DNA (cfDNA) methylation in patients receiving NAC in SWOG S1314, a prospective cooperative group trial, and to correlate the methylation signatures with pathologic response at radical cystectomy.SWOG S1314 is a prospective cooperative group trial for patients with MIBC (cT2-T4aN0M0, ≥5 mm of viable tumor), with a primary objective of evaluating the coexpression extrapolation (COXEN) gene expression signature as a predictor of NAC response, defined as achieving pT0N0 or ≤pT1N0 at radical cystectomy. For the current exploratory analysis, blood samples were collected prospectively from 72 patients in S1314 before and during NAC, and plasma cfDNA methylation was measured using the Infinium MethylationEPIC BeadChip array.No additional interventions besides plasma collection.Differential methylation between pathologic responders (≤pT1N0) and nonresponders was analyzed, and a classifier predictive of treatment response was generated using the Random Forest machine learning algorithm.Using prechemotherapy plasma cfDNA, we developed a methylation-based response score (mR-score) predictive of pathologic response. Plasma samples collected after the first cycle of NAC yielded mR-scores with similar predictive ability. Furthermore, we used cfDNA methylation data to calculate the circulating bladder DNA fraction, which had a modest but independent predictive ability for treatment response. In a model combining mR-score and circulating bladder DNA fraction, we correctly predicted pathologic response in 79% of patients based on their plasma collected at baseline and after one cycle of chemotherapy. Limitations of this study included a limited sample size and relatively low circulating bladder DNA levels.Our study provides the proof of concept that cfDNA methylation can be used to generate classifiers of NAC response in bladder cancer patients.In this exploratory analysis of S1314, we demonstrated that cell-free DNA methylation can be profiled to generate biomarker signatures associated with neoadjuvant chemotherapy response. With validation in additional cohorts, this minimally invasive approach may be used to predict chemotherapy response in locally advanced bladder cancer and perhaps also in metastatic disease.
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