Methods and systems for adjusting tumor mutational burden by tumor fraction and coverage
Inventors
QUINN, Katie Julia • HELMAN, Elena • Chudova, Darya
Assignees
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Publication Number
US-12291751-B2
Publication Date
2025-05-06
Expiration Date
Abstract
Provided herein are methods for detecting tumor mutational burden (TMB) in subjects. In one aspect, the methods include determining observed mutational counts from sequence information obtained from nucleic acids in samples from the subjects and determining a tumor fraction and/or a coverage of the nucleic acids to generate sequencing parameters. The methods also include determining an expected mutational fraction and/or an expected distribution of the expected mutational fraction given the sequencing parameters to generate an expected result, and adjusting the observed mutational count given the expected result to generate an adjusted result, thereby detecting the TMB in the subject. Other aspects are directed to methods of selecting customized therapies for treating cancer in subjects, and methods of treating cancer in subjects. Yet other aspects include related systems and computer readable media used to detect TMB in subjects.
Core Innovation
The invention relates to methods for treating a subject having cancer with an immunotherapeutic agent by determining whether the subject has Tumor Mutational Burden (TMB)-High status using cell-free DNA (cfDNA). A diagnostic assay determines an observed mutational count from sequence information obtained from nucleic acid molecules derived from the cfDNA and further determines a tumor fraction and a coverage of the nucleic acid molecules.
The method generates an expected result by determining an expected mutational fraction and/or an expected distribution of the expected mutational fraction. The expected distribution of expected MAFs is determined from expected distributions of relative MAFs obtained from a control sample dataset comprising at least 500 control samples by adjusting for tumor fraction in the sample, and the expected result includes calculating a probability of identifying a mutation in a given MAF using tumor fraction and the coverage across a distribution of expected MAFs.
Using the expected result, the method adjusts the observed mutational count to generate an adjusted mutational count. A TMB score is determined using the adjusted mutational count, and the subject is determined to have TMB-High status when the TMB score exceeds a threshold and to have TMB-Low status when the TMB score does not exceed the threshold. The immunotherapeutic agent is administered for treatment when the subject is determined to have the TMB-High status.
Claims Coverage
The partial content identifies one independent claim. The independent claim includes an immunotherapy treatment determination and a TMB-High classification pipeline with a tumor-fraction and coverage-based adjustment of an observed mutational count using an expected mutational fraction/distribution derived from a control sample dataset comprising at least 500 control samples.
TMB-based immunotherapy treatment using adjusted mutational counts from cfDNA
A method for treating a subject having cancer with an immunotherapeutic agent by determining whether the subject has TMB-High status using cfDNA, where the method determines an observed mutational count, determines tumor fraction and coverage, determines an expected mutational fraction and/or an expected distribution of the expected mutational fraction using an expected fraction of mutations called equation and a control-sample-derived distribution adjusted for tumor fraction, adjusts the observed mutational count given the expected result to generate an adjusted mutational count, determines a TMB score using the adjusted mutational count, assigns TMB-High when the TMB score exceeds a threshold and TMB-Low otherwise, and administers an immunotherapeutic agent when TMB-High status is determined.
Checkpoint inhibitors for TMB-High subjects
The immunotherapeutic agent is one or more checkpoint inhibitor selected from pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, and durvalumab, with administration determined by the subject having TMB-High status.
Overall, the claim coverage is centered on an immunotherapy decision workflow that converts an observed mutational count from cfDNA into an adjusted mutational count using expected mutational behavior conditioned on tumor fraction, coverage, and a control sample dataset-derived expected MAF distribution, followed by TMB score thresholding and administration of specified checkpoint inhibitors.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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