Radical cystectomy (RC), surgical removal of the bladder, is among the most complicated and expensive cancer surgeries. This procedure is associated with major complications and life-altering conditions as permanent ostomy for urinary diversion. However, in spite of the aggressive nature of muscle-invasive bladder cancer (MIBC), 30-40% of patients undergoing neoadjuvant chemotherapy (NAC) will have pathologic complete response (pCR) - there is no cancer left in their bladder at the time of RC. These patients may be cured in absence of bladder removal, but currently, the only reliable way to determine if a patient has had a complete response after NAC is to remove the bladder and examine it pathologically. Thereby, NAC followed by RC is the current standard of care for such patients. Similarly, patients with urothelial cancers of the upper urinary tract (UTUC) undergo radical nephroureterectomy (RNU). The clinical grading and staging of UTUC are difficult due to the anatomy of the collecting system and the tiny instrumentation that is required to obtain tissue biopsy. Small pieces of tissue are obtained by the urologist and can often either be nondiagnostic or (worse) not representative of the entire tumor. This leads to understaging. These facts frame the most important questions to urologists performing RC and RNU: whether an individual patient’s response to NAC can be predicted a priori or identified post hoc and, if so, whether RC or RNU can be safely avoided in such chemoresponders.
Summary of the Invention
Prior attempts at bladder sparing using current clinical assessment tools such as cross-sectional imaging, urine cytology, and cystoscopic evaluation resulted in unacceptably high failure rates, as measured by any recurrence, muscle-invasive recurrence, metastasis, bladder cancer death, or salvage cystectomy. This high failure rate dictates organ removal for most urologists/patients to avoid leaving a cancerous bladder in situ.
Dr. Abbosh, a urologic oncologist and Assistant Professor in the Molecular Therapeutics Program at Fox Chase Cancer Center, developed a DNA-based urinary biomarker that discriminates patients achieving a pCR from patients having residual disease after NAC. The central premise of such a discriminatory test is that patients with no residual disease will have no source of somatic mutations to shed into body fluids. The mutation clearance from urinary DNA (uDNA) of patients with urothelial cancers who received NAC or other neoadjuvant therapies would associate with pCR, while those with mutation persistence would have residual disease. Under this premise, patients achieving pCR would be better candidates for cystectomy avoidance algorithms in the management of urothelial cancer of the bladder or upper tract.
In addition, because it is well-known that mutations of certain genes are enriched in high grade or high stage UTUC or in low-grade or low-stage UTUC, urinary DNA sequencing could be used to enhance clinical staging. For instance, UTUCs which, based on clinical staging tests are deemed to be low-grade or low-stage, are often found to be of higher grade or stage at the time of RNU. Enhanced clinical staging with a urine test would decrease some of the uncertainty in preoperative decision making.
A clinical test that permits identification of true complete responders is clearly needed by the urology community in order to safely avoid organ removal in chemoresponders. This would be a practice-changing breakthrough, completely avoiding perioperative morbidity and urinary diversion in a significant proportion of MIBC patients or sparing nephron removal of UTUC patients. In addition, UTUC biomarkers could be used for both dynamic response measurement and to enhance clinical staging and grading of disease.
Patent Status: A patent application has been filed
For Licensing/Partnering information, please contact:
Inna Khartchenko, MS, MBA
Director, Technology Transfer and New Ventures