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Using Cell Lines To Guide Neoadjuvant Therapy in Bladder Cancer: COXEN and SWOG S1314.

ABSTRACT: There are no predictive biomarkers in clinical use for the neoadjuvant treatment of bladder cancer. Here we report on a recent randomized phase 2 trial validating the identification of predictive biomarkers using cell lines in the absence of patient response data.

SUBMITTER: Dancik GM

PROVIDER: S-EPMC10112179 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Using Cell Lines To Guide Neoadjuvant Therapy in Bladder Cancer: COXEN and SWOG S1314.

Dancik Garrett M GM Theodorescu Dan D

European urology focus 20220323 3

There are no predictive biomarkers in clinical use for the neoadjuvant treatment of bladder cancer. Here we report on a recent randomized phase 2 trial validating the identification of predictive biomarkers using cell lines in the absence of patient response data. ...[more]

PMID: 35339415

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Project description:BackgroundThe COXEN gene expression model was evaluated for prediction of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC).ObjectiveTo conduct a secondary analysis of the association of each COXEN score with event-free survival (EFS) and overall survival (OS) and by treatment arm.Design, setting, and participantsThis was a randomized phase 2 trial of neoadjuvant gemcitabine-cisplatin (GC) or dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) in MIBC.InterventionPatients were randomized to ddMVAC (every 14 d) or GC (every 21 d), both for four cycles.Outcome measurements and statistical analysisEFS events were defined as progression or death before scheduled surgery, a decision to not undergo surgery, recurrence, or death due to any cause after surgery. Cox regression was used to evaluate the COXEN score or treatment arm association with EFS and OS.Results and limitationsA total of 167 evaluable patients were included in the COXEN analysis. The COXEN scores were not significantly prognostic for OS or EFS in the respective arms, but the GC COXEN score had a hazard ratio (HR) of 0.45 (95% confidence interval [CI] 0.20-0.99; p = 0.047) when the arms were pooled. In the intent-to-treat analysis (n = 227), there was no significant difference between ddMVAC and GC for OS (HR 0.87, 95% CI 0.54-1.40; p = 0.57) or EFS (HR 0.86, 95% CI 0.59-1.26; p = 0.45). Among the 192 patients who underwent surgery, pathologic response (pT0 vs downstaging vs no response) was strongly correlated with superior postsurgical survival (5-yr OS 90%, 89% and 52%, respectively).ConclusionsThe COXEN GC score has prognostic value for patients receiving cisplatin-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and EFS for GC and ddMVAC in this population. Pathologic response (<pT2) performed well as an intermediate endpoint in this modern cohort. For expediency in evaluating new regimens, pathologic response should continue to be used in phase 2 trials.Patient summaryIn this study, we evaluated a biomarker to predict the response to chemotherapy. The results did not meet the preset study parameters, but our study provides information on clinical outcomes with the use of chemotherapy before surgery for bladder cancer.

Project description:BackgroundNeoadjuvant 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.ObjectiveTo 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.Design, setting, and participantsSWOG 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.InterventionNo additional interventions besides plasma collection.Outcome measurements and statistical analysisDifferential 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.Results and limitationsUsing 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.ConclusionsOur study provides the proof of concept that cfDNA methylation can be used to generate classifiers of NAC response in bladder cancer patients.Patient summaryIn 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.

Dataset Information

Using Cell Lines To Guide Neoadjuvant Therapy in Bladder Cancer: COXEN and SWOG S1314.

Publications

Using Cell Lines To Guide Neoadjuvant Therapy in Bladder Cancer: COXEN and SWOG S1314.

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