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.
European urology oncology. 2023 Apr 20 [Epub ahead of print]
Yi-Tsung Lu, Melissa Plets, Gareth Morrison, Alexander T Cunha, Steven Y Cen, Suhn K Rhie, Kimberly D Siegmund, Siamak Daneshmand, David I Quinn, Joshua J Meeks, Seth P Lerner, Daniel P Petrylak, David McConkey, Thomas W Flaig, Ian M Thompson, Amir Goldkorn
Division of Medical Oncology, Department of Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Department of Population and Public Health Science, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Departments of Urology, Biochemistry, and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Scott Department of Urology, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA., Smilow Cancer Center, Yale University, New Haven, CT, USA., Johns Hopkins School of Medicine, Baltimore, MD, USA., University of Colorado, School of Medicine, Aurora, CO, USA., CHRISTUS Medical Center Hospital, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Division of Medical Oncology, Department of Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37087309