cfDNA Sequencing for Non-Invasive Tumor Mutational Burden Prediction
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Solution Overview
Problem
Current methods for predicting and monitoring treatment response to immunotherapy in cancer patients are invasive and inefficient, relying on tissue biopsies that are not feasible for all patients, and lack accurate, non-invasive alternatives for assessing biomarkers like tumor mutational burden (TMB), tumoral heterogeneity (TH), and tumor fraction (TF).
Innovation Solution
A method utilizing cell-free DNA (cfDNA) sequencing to predict TMB, TH, and TF from blood samples, employing machine learning models to generate feature matrices from sequence data, and determining treatment response based on these biomarkers, allowing for non-invasive monitoring and adjustment of treatment plans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If tissue biopsies are used to assess biomarkers, then measurement precision is improved, but ease of operation deteriorates due to invasive procedures
Solution Approach 1:
The patent uses cell-free DNA (cfDNA) in blood plasma as an intermediary substance that carries tumor-derived genetic information. This intermediary allows indirect measurement of tumor biomarkers without direct tissue sampling, resolving the contradiction between measurement precision and ease of operation by providing accurate biomarker assessment through a non-invasive blood draw rather than invasive tissue biopsy
Solution Approach 2:
The patent creates a genetic copy of tumor information that exists in cfDNA molecules circulating in blood plasma. By sequencing and analyzing these cfDNA copies, the system reproduces the biomarker information that would otherwise require direct tissue sampling, enabling accurate measurement without invasive procedures
2Reliability
If tissue biopsies are performed frequently for monitoring, then reliability of treatment response assessment is improved, but loss of time increases due to procedural constraints
Solution Approach 1:
The patent enables continuous monitoring of treatment response by repeatedly sampling cfDNA from blood plasma at multiple time points throughout treatment. This continuous action allows dynamic tracking of biomarker changes and treatment efficacy without the time losses associated with repeated invasive biopsies, maintaining reliability while minimizing time loss
Solution Approach 2:
The patient's own blood plasma continuously provides tumor-derived cfDNA that serves as the monitoring material. The system uses the patient's readily accessible blood supply to repeatedly obtain biomarker information without requiring external tissue sampling procedures, enabling frequent monitoring with minimal time investment
3Productivity
If comprehensive biomarker analysis is performed, then productivity of treatment decision-making is improved, but device complexity increases
Solution Approach 1:
The patent extracts and analyzes only the specific cfDNA fragments and genetic markers that are most relevant for treatment response prediction. By focusing on extracting and sequencing only the necessary genomic regions rather than performing whole-genome sequencing, the system achieves comprehensive biomarker analysis for clinical decision-making while reducing sequencing system complexity and cost
Data Source
AI summary
Methods and systems for determining a subject's likelihood of responding to a treatment by assessing the subject's cell-free DNA (cfDNA) sample include receiving sequence data gathered from sequencing the cfDNA sample, generating a feature matrix of values that correspond to synonymous and nonsynonymous mutations detected in the sequence data, and predicting, based on analysis of the feature matrix at a TMB prediction model, a tumor mutational burden (TMB) for a tissue of interest at the subject. The predicted TMB is evaluated to determine whether a set of criteria indicating a likely response to treatment is met. The set of criteria can include criterion(s) that are met when the predicted TMB is high, when the predicted TMB corresponds to a predicted tumoral heterogeneity indicative of homogeneous tissue, when the predicted TMB corresponds to a tumor fraction indicative of a positive responder, or any combination thereof.