ctDNA Sequencing for Accurate Staging of Invasive UTUC
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Solution Overview
Problem
Current clinical staging methods for upper tract urothelial carcinoma (UTUC) are suboptimal, limiting the use of neoadjuvant chemotherapy and affecting patient selection, as tumor biopsies often under-stage the disease, leading to missed opportunities for systemic therapy.
Innovation Solution
The use of circulating tumor DNA (ctDNA) analysis through next-generation sequencing to detect somatic mutations in specific genes, such as ABRAXAS1, TP53, and FGFR3, in liquid biopsies from blood, plasma, or urine, to accurately identify muscle-invasive UTUC and guide treatment decisions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional clinical staging methods are used for UTUC, then the staging process is simple and accessible, but the accuracy of staging is suboptimal leading to missed opportunities for neoadjuvant chemotherapy
Solution Approach 1:
The patent introduces ctDNA as an intermediary biomarker that mediates between the tumor and the diagnostic system. By detecting circulating tumor DNA in blood, the method provides an accessible window into tumor status without requiring complex surgical staging procedures, thus improving accuracy while maintaining clinical accessibility
Solution Approach 2:
The patent replaces traditional mechanical/surgical staging methods (ureteroscopy, biopsy) with a molecular detection approach. Instead of physically examining the tumor through invasive procedures, the system uses genetic sequencing to detect tumor DNA in circulation, substituting mechanical diagnosis with molecular analysis
2Measurement precision
If tumor biopsies are performed for staging, then tissue diagnosis is obtained, but the biopsies often under-stage the disease leading to inaccurate classification
Solution Approach 1:
The patent creates a molecular copy of the tumor through ctDNA detection. Instead of relying on the limited tissue sample from biopsy, the method detects and sequences circulating tumor DNA that reflects the comprehensive genetic profile of the tumor, providing a more accurate staging picture without requiring additional tissue invasion
Solution Approach 2:
The patent changes the detection parameter from morphological assessment (visual grading of tumor invasion) to molecular parameter detection (genetic mutations, copy number variations). This parameter transformation allows for more sensitive and accurate detection of tumor stage, as molecular changes occur earlier and more comprehensively than morphological changes
3Reliability
If neoadjuvant chemotherapy is administered to all high-risk patients, then treatment coverage is maximized, but patient selection accuracy is reduced due to suboptimal staging
Solution Approach 1:
The patent implements feedback through ctDNA-based staging that provides reliable information about tumor stage and chemotherapy benefit prediction. This feedback enables precise patient selection for neoadjuvant chemotherapy, ensuring that only patients who will benefit from treatment receive it, thereby improving both reliability of selection and efficiency of treatment delivery
Data Source
AI summary
Disclosed are compositions and methods for detecting, prognosing, grading, and treating a cancer such as, for example a bladder cancer including, but not limited to upper tract urothelial carcinoma (UTUC) using circulating tumor DNA (ctDNA).