Role of Ki-67, MRE11, and PD-L1 as Predictive Biomarkers for Recurrence Pattern in Muscle-invasive Bladder Cancer

Pelvic recurrences following radical cystectomy (RC) can occur in up to 40% of patients with muscle-invasive bladder cancer (MIBC) and can be a significant source of morbidity. Post-operative radiotherapy (PORT) to reduce local recurrence rates has a well-defined role in other malignancies but for bladder cancer, the criteria for selecting appropriate patients are not well defined, controversial, and only take into consideration pathological findings at the time of cystectomy.

To prevent the morbidity of local recurrence but also avoid unnecessary toxicity from radiotherapy in a patient who is either unlikely to recur or whom will recur distantly, it is critical that we identify a subset of patients who will benefit most from adjuvant treatment to the pelvis. Molecular classifiers have been shown to be useful in the upfront management of bladder cancer to help identify which patients may benefit from bladder preservation. Additionally, MIBC can be categorized based on transcriptional subtypes with response to chemotherapy and immunotherapy varying across subtypes.

Despite these advances, no genomic or transcriptomic features are routinely being used to guide local therapy for MIBC. Identifying reliable predictive biomarkers of recurrence risk and patterns (local vs. distant) following RC could inform clinical decision-making, including the use of PORT.

In the current study, we used immunofluorescence (IF) and immunohistochemistry (IHC) to evaluate biomarkers for predicting local only recurrence using bladder cancer cystectomy specimen available at our institution. We choose Ki-67, MRE11, and PD-L1 as candidate biomarkers because these have previously been shown to be prognostic and predictive of response to upfront treatment of MIBC using cystectomy or definitive chemoradiation. Additionally, IF and IHC techniques were used because they are quantitative and can be performed relatively easily.

We found notable differences in biomarker expression between tumor and normal bladder tissue, but we were unable to identify a protein expression signature associated with local recurrence. These findings agree with other recent studies that suggest that IHC/IF markers alone may be insufficient as predictive biomarkers in MIBC and as such we are continuing to improve upon the array- and IHC-based analyses, with whole transcriptome RNA-sequencing at our institution.

Written by: Croix C. Fossum, MD, Chief Resident, PGY-5, Radiation Oncology, Keck School of Medicine of USC, University of Southern California, Los Angeles, California

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