Relationship Among DNA Damage Response Gene Alterations, Molecular Subtypes, and Survival Outcomes in Patients With Metastatic Bladder Cancer Treated on CALGB 90601

Gopa Iyer ^1,2, Woonyoung Choi ³, Bin Luo ⁴

¹Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
²Weill Cornell Medical College, New York, NY.
³Department of Urology, Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD.
⁴Department of Biostatistics & Bioinformatics, Duke University School of Medicine, Durham, NC.
⁵Division of Urology, Brigham and Women's Hospital, Boston, MA.
⁶Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
⁷Institute of Pathology, University Hospital Frankfurt, Frankfurt, Germany.
⁸Wilmot Cancer Institute, University of Rochester, Rochester, NY.
⁹The Alliance Biobank at the Ohio State University, Columbus, OH.
¹⁰Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL.
¹¹Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
¹²Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
¹³University of Virginia Cancer Center, Charlottesville, VA.
¹⁴UCHealth University of Colorado Hospital, Aurora, CO.

⁰Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Jco Precision Oncology +

|

July 1, 2025

View abstract on PubMed

Summary

Basal/squamous molecular subtypes and DNA damage response (DDR) gene alterations did not predict chemotherapy benefit in metastatic urothelial carcinoma patients in the CALGB 90601 trial.

Area Of Science

Oncology
Genomics
Translational Research

Background

Prior studies suggested basal/squamous molecular subtypes and DNA damage response (DDR) gene alterations predict benefit from cisplatin-based chemotherapy in urothelial carcinoma.
The Cancer and Leukemia Group B (CALGB) 90601 trial investigated gemcitabine/cisplatin plus bevacizumab or placebo in metastatic bladder cancer.

Purpose Of The Study

To evaluate molecular subtypes and DDR gene alterations as predictive biomarkers in the CALGB 90601 trial.
To assess the association of these biomarkers with overall survival (OS) and progression-free survival (PFS).

Main Methods

Whole-transcriptome and exon capture DNA sequencing on pretreatment tumors (n=188-208).
Whole-exome sequencing (WES) on tumors from 22 patients with rapid progression or durable response.
Assignment of molecular subtypes using three classifiers and correlation with OS/PFS using proportional hazards models.

Main Results

Patients with basal tumors exhibited the shortest PFS and OS.
PFS was numerically longer in basal tumors treated with bevacizumab.
DDR gene alterations did not correlate with improved outcomes; the candidate biomarker *FRY* showed no chemosensitivity in functional studies.

Conclusions

Molecular subtype and DDR alterations did not predict improved outcomes in the CALGB 90601 trial.
Potential explanations include small cohort size, limited treatment effects, genomic heterogeneity, and differences in disease biology.