Methods for monitoring residual disease
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Publication Number
US-12319972-B2
Publication Date
2025-06-03
Expiration Date
Abstract
The present disclosure provides a method for monitoring residual disease in a subject. Generally, the method comprises determining a frequency of cancer mutations from a first sample obtained from a tumor biopsy from the subject; determining a frequency of the cancer mutations discovered in the first sample from a second sample comprising cell-free deoxyribonucleic acid (cfDNA) molecules that is obtained from the subject after the subject has undergone a course of treatment for cancer; and determining a presence or absence of cancer in the subject based on an analysis of the frequency of the cancer mutations from sequence data from the second sample.
Core Innovation
The disclosure provides methods for monitoring residual disease in a subject by analyzing cancer mutation frequencies in a tumor biopsy sample and a subsequent cell-free deoxyribonucleic acid (cfDNA) sample obtained after a course of treatment for cancer. A first set of sequence data is generated by sequencing genomic polynucleotides or amplicons from the tumor biopsy, and a frequency of cancer mutations is determined from the first set. A second set of sequence data is generated by sequencing cfDNA molecules or amplicons from the subject after treatment, and the frequency of the cancer mutations discovered in the first sample is determined from the second set.
Residual disease is monitored by determining a presence or absence of cancer in the subject based on an analysis of the frequency of the cancer mutations from the second set of sequence data. The approach supports cancer mutation frequency determination from cfDNA, including detection of rare mutations and cancer mutation frequency estimates that can be used for serial monitoring. The disclosure further connects the mutation-frequency analysis to monitoring after treatment, including the use of serial sampling and tumor burden estimates as part of the monitoring workflow.
To reduce sequencing artifacts and support rare-variant detection, sequencing reads are processed by grouping reads into families derived from tagged parent molecules, collapsing reads within each family into consensus sequences, and generating base calls at mappable base positions. The disclosure also includes analysis of copy number variation (CNV) from sequencing data and can infer discrete variant and CNV states using stochastic or probabilistic models, including Hidden Markov Models. The disclosure additionally includes molecule counting and barcode/tag strategies, including handling non-unique barcodes using start/stop read identity to define read families.
Claims Coverage
The independent claims are directed to a residual-disease monitoring method grounded on paired mutation-frequency analysis from a tumor biopsy and post-treatment cfDNA sequencing, yielding a presence-or-absence determination of cancer. The inventive features include selection of mutation types/length constraints and an analysis framework that connects two sample sources to residual disease monitoring through mutation frequency comparison.
Paired tumor biopsy and post-treatment cfDNA mutation-frequency monitoring
A method for monitoring residual disease in a subject by providing a first sample from a tumor biopsy and sequencing genomic polynucleotides or amplicons to determine a frequency of cancer mutations, providing a second sample comprising cfDNA after treatment and sequencing the cfDNA to determine the frequency of the cancer mutations discovered in the first sample, and determining a presence or absence of cancer in the subject based on analysis of the mutation frequency from the second set of sequence data.
Short cancer mutation frequency monitoring (≤5 nucleotides)
A method for monitoring residual disease in a subject using a tumor biopsy sequencing step to determine a frequency of cancer mutations that are at most 5 nucleotides in length, followed by sequencing cfDNA obtained after treatment to determine the frequency of the discovered cancer mutations, and determining a presence or absence of cancer based on analysis of the mutation frequency from the second set of sequence data.
Across the independent claims, the core coverage is residual disease monitoring using mutation-frequency determination from a tumor biopsy and a post-treatment cfDNA sample, with a presence-or-absence cancer determination driven by mutation-frequency analysis. One independent claim focuses on mutation frequency with single-base substitution mutations, while the other focuses on cancer mutations at most 5 nucleotides in length.
Stated Advantages
Allows monitoring residual disease by determining a presence or absence of cancer in the subject based on analysis of cancer mutation frequency from post-treatment cfDNA sequencing.
Enables high-sensitivity detection of cancer mutations from cfDNA, including rare mutations, through read-family processing and consensus base calling to reduce sequencing artifacts.
Supports serial monitoring by enabling residual disease tracking across time through repeated cfDNA-based mutation-frequency analysis.
Documented Applications
Monitoring residual disease in a subject after cancer treatment using cfDNA sequencing and mutation-frequency analysis to determine presence or absence of cancer.
Tumor burden estimation as part of residual disease monitoring, including serial sampling workflows.
Example analytical or pilot studies demonstrating rare-mutation sensitivity and concordance between tumor biopsy genomic sequencing profiles and cfDNA profiles.
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