Research Spotlight: Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer

Sophia C. Kamran, MD, a physician investigator in the Mass General Cancer Center and an assistant professor of Radiation Oncology at Harvard Medical School, is the first author of a recently published paper in Clinical Cancer Research, Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer.

David Miyamoto, MD, PhD, a physician investigator in the Department of Radiation Oncology and an Assistant Professor of Radiation Oncology at Harvard Medical School and Jason Efstathiou, MD, DPhil, a physician investigator in the Department of Radiation Oncology and a Professor of Radiation Oncology at Harvard Medical School and Kent W. Mouw, MD, PhD, a physician investigator in the Department of Radiation Oncology at Dana-Farber Cancer Institute and an Assistant Professor of Radiation Oncology at Harvard Medical School are co-senior authors of the paper. 

What was the question you set out to answer with this study?

Can we identify candidate biomarkers for predicting successful outcomes after radiotherapy to improve patient selection?

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 (complete bladder removal) for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood

What Methods or Approach Did You Use?

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.

What Did You Find?

We performed whole exome sequencing in combination with gene expression profiling to identify potential biomarkers associated with clinical outcomes of chemoradiation therapy

Results: 37 out of 76 patients (49%) were characterized as having favorable long-term outcomes for modified bladder-intact event-free survival (mBI-EFS). There were 39 patients (51%) that had unfavorable long-term outcomes for modified bladder-intact event-free survival

It was found that having any DNA damage response and repair gene alteration as per genes defined in the Alliance A031701 (NCT03609216) and RETAIN BLADDER (NCT02710734) trials associated with improved locoregional control as well as mBI-EFS.

Of these, ERCC2 mutations stood out as being significantly associated with improved long-term clinical outcomes, with a trend towards improved overall survival.

What are the Implications?

These data require validation but demonstrate early promise in elucidating novel biomarkers to guide precision oncology for radiation-based management in MIBC patients.

 

Additional MGH authors: Keisuke Otani, Michael Drumm, Yukako Otani, Shulin Wu, Chin-Lee Wu, Adam S Feldman, Matthew Wszolek, Richard J Lee, Philip J Saylor, Jochen Lennerz, Henning Willers, Theodore S Hong, William U Shipley

Grants and funding

R01CA259007/Office of Extramural Research, National Institutes of Health (OER)

U01CA220714/Office of Extramural Research, National Institutes of Health (OER)

R0125737/Office of Extramural Research, National Institutes of Health (OER)

CA059267/Office of Extramural Research, National Institutes of Health (OER)

ROI2021-9151/Radiation Oncology Institute (ROI)

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.