- Researchers are examining prognostic and predictive biomarkers that could provide guidance for choosing between radical cystectomy and trimodality therapy for patients with muscle-invasive bladder cancer (MIBC)
- Examples of biomarkers currently under study are enzymes and proteins involved in DNA repair, receptor tyrosine kinases and factors in the angiogenesis signaling axis
- Biomarkers might also be used to select which patients with MIBC will benefit from a combination of immunotherapy and radiation
Now that bladder-preserving trimodality therapy (TMT) is considered a standard option for treating muscle-invasive bladder cancer (MIBC), physicians need to know what factors predict good outcomes. Clinicopathologic factors have not proven precise enough to guide therapy choice for these patients.
Thanks to next-generation sequencing and gene expression profiling, scientists have identified potential prognostic and predictive biomarkers in MIBC. Prognostic biomarkers are those associated with clinical outcomes based on the biology of the cancer and the patient, and they help identify which patients are good candidates for specific therapies.
In Lancet Oncology, Massachusetts General Hospital Cancer Center researchers David T. Miyamoto, MD, PhD, radiation oncologist, and Jason A. Efstathiou, MD, DPhil, director of the Genitourinary Program in the Department of Radiation Oncology, and colleagues recently reviewed what's currently known about biomarkers for MIBC, with a focus on TMT.
DNA Repair Pathway Alterations
Several emerging lines of evidence show that bladder tumors often have alterations in DNA repair pathway genes. Functional DNA repair deficiency can contribute to genomic instability and drive bladder tumor evolution and response to treatment.
One of the first DNA repair biomarkers to be investigated in patients with MIBC was MRE11, a DNA nuclease. In pooled data on 135 patients from six Radiation Therapy Oncology Group (RTOG) trials of TMT, low expression of MRE11 was associated with greater risk of disease-specific mortality.
ERCC1 is a key member of a DNA repair pathway that repairs intrastrand lesions created by genotoxins such as platinum drugs. In a clinical trial of patients undergoing TMT for MIBC, high expression of both ERCC1 and XRCC1, a protein involved in repair of single-strand DNA breaks, was associated with improved disease-specific survival.
Alterations in Signal Transduction Pathways
The ErbB family of receptor tyrosine kinases is altered by mutation, amplification or overexpression in more than 30% of bladder tumors. One of these, epithelial growth factor receptor (EGFR), seems to be associated with favorable prognosis after TMT for MIBC. Among 73 patients enrolled in four RTOG trials of TMT, positivity for EGFR was significantly associated with improved disease-specific survival.
Overexpression of human epidermal growth factor receptor 2 (HER2) has been associated with resistance to chemoradiation among patients with MIBC. In the aforementioned cohort of 73 patients, HER2 was significantly associated with reduced rates of complete response to chemoradiation. In a separate study of TMT in 119 patients, HER2 independently predicted pathologic incomplete response and greater risk of disease-specific mortality.
As in many other solid tumors, vascular endothelial growth factor (VEGF), a key angiogenesis signaling molecule, has been related to increased disease recurrence and metastasis in MIBC. In a study of 247 patients treated with TMT, elevated co-expression of VEGF-C and its transmembrane glycoprotein receptor, neuropilin-2, was associated with substantially shorter overall survival.
Increased expression of angiogenesis factors in the VEGF signaling axis might identify patients who are more likely to benefit from early cytotoxic therapy or anti-VEGF targeted therapies such as ramucirumab.
Because of the potential synergy between radiation and immunotherapy, the combination of TMT with an immune checkpoint inhibitor is a promising therapeutic approach. Not all bladder cancers respond to checkpoint inhibitors, though, so identification of predictive biomarkers is crucial.
One of the most promising genomic markers of sensitivity to checkpoint inhibitors is tumor DNA repair deficiency. This link has been best characterized in tumors that have a defect in the mismatch repair pathway, which is frequently associated with microsatellite instability.
Combining genomic and clinical data from TMT studies will provide further important insights; immune and stromal expression signatures may also be useful as predictive biomarkers for TMT and for predicting who will benefit from adding immunotherapy to TMT.
Toward Clinical Implementation
None of the biomarkers discussed have been validated in a prospective clinical trial. However, molecular biomarkers and genomic analyses have been incorporated into the design of several planned or ongoing clinical trials of TMT for MIBC.
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