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Publication Number
US-11535895-B2
Publication Date
2022-12-27
Expiration Date
2038-04-05
Abstract
The present invention provides a method of predicting whether a pulmonary nodule in a subject is benign or non-small cell lung cancer, comprising obtaining the results of an assay that measures an expression level of miR205-5p in a plasma sample from the subject; obtaining the results of an assay that measures an expression level of miR126 in a plasma sample from the subject; obtaining the results of an assay that provides a size of the pulmonary nodule in the subject; and calculating a probability value based on the combination of the expression levels of miR205-5p and miR126, and the size of the pulmonary nodule, wherein if the probability value exceeds a specified threshold, the pulmonary nodule is predicted as non-small cell lung cancer.
Core Innovation
The invention provides methods for predicting whether a pulmonary nodule in a subject is benign or non-small cell lung cancer (NSCLC) by combining molecular biomarkers in plasma with radiological characteristics. Specifically, it involves obtaining assay results measuring expression levels of miR205-5p and miR126 in a plasma sample from the subject, obtaining the size of the pulmonary nodule, and calculating a probability value based on these combined factors. If this probability exceeds a specified threshold, the pulmonary nodule is predicted as NSCLC.
Additionally, the invention provides methods for predicting presence of lung cancer using a combination of plasma biomarkers miR-210, FUT8, and the long non-coding RNA SNHG1. These markers are measured in plasma samples and the probability value calculated based on their combined expression levels. This approach supports non-invasive early detection, diagnosis, prognostication, and monitoring of lung cancer, including determining treatment efficacy, by generating receiver operating characteristic (ROC) curves and calculating areas under the curve (AUCs).
The problem addressed by the invention arises from current lung cancer screening methods such as low-dose CT (LDCT), which, while reducing mortality, suffer from drawbacks including over-diagnosis, excessive cost, radiation exposure, and the detection of many indeterminate pulmonary nodules, most of which are benign. Traditional plasma biomarkers including circulating cell-free DNA, methylated genes, proteins, and metabolites exhibit low sensitivity and specificity, limiting clinical acceptance. MicroRNAs and long non-coding RNAs, though promising and stable in plasma, have produced inconsistent diagnostic results or insufficient sensitivity and specificity. There is a significant need for non-invasive, cost-effective, and accurate biomarkers and methods that improve early detection and diagnosis of lung cancer, particularly in distinguishing malignant from benign pulmonary nodules.
Claims Coverage
The patent contains one independent claim focusing on a method for targeting treatment of non-small cell lung cancer in a subject with a pulmonary nodule. The main inventive features involve assays measuring plasma expression levels of miR205-5p and miR126, determining pulmonary nodule size, calculating a probability value based on these data, and using this to guide treatment decisions.
Method of assessing lung nodule malignancy by integrating plasma miRNA levels and nodule size
The method comprises performing assays to measure miR205-5p and miR126 expression levels in a plasma sample, obtaining the size of the pulmonary nodule, and calculating a probability value combining these factors to predict non-small cell lung cancer.
Use of a probability threshold to classify pulmonary nodules and guide treatment
If the calculated probability value falls below a specified threshold, the nodule is considered benign and the subject is so notified; if the probability meets or exceeds the threshold, the subject is administered treatment for non-small cell lung cancer, which includes therapeutic agents, surgery, radiofrequency ablation, radiation, or their combinations.
Calculation of lung cancer probability via ROC curve analysis
The probability calculation involves generating a receiver operating characteristic (ROC) curve and calculating an area under the ROC curve (AUC) which provides the probability of lung cancer in the subject.
Detection of miR205-5p and miR126 without requiring internal controls
Expression levels of miR205-5p and/or miR126 may be detected using quantitative RT-PCR or droplet digital PCR methods that do not require an internal control gene for normalization.
Target subject populations
The methods apply to subjects who are current or former smokers, including those with specified smoking histories (at least 15 pack-years up to at least 65 pack-years), and aged between 55 and 80 years.
Assaying plasma samples for contaminating miRNAs
The plasma samples may be assayed for contaminating miRNAs such as RBC-related miR-451, myeloid-related miR-223, or lymphoid-associated miR-150 to reduce false positives related to blood cell contamination.
The independent claim presents a method integrating plasma miRNA biomarker expression measurements and pulmonary nodule size to calculate a probability value, which informs diagnosis and treatment decisions for non-small cell lung cancer, with detection and analysis methods designed for accurate and non-invasive clinical use.
Stated Advantages
Improved sensitivity and specificity for early detection and diagnosis of non-small cell lung cancer compared to existing methods.
Non-invasive and cost-effective assay relying on plasma biomarkers combined with radiological characteristics.
Reduction of false positives from indeterminate pulmonary nodules detected by low-dose CT screening.
Potential to spare patients with benign pulmonary nodules from invasive and expensive procedures.
Ability to assess treatment efficacy non-invasively by monitoring biomarker levels and pulmonary nodule size over time.
Documented Applications
Early detection and differential diagnosis of pulmonary nodules as benign or non-small cell lung cancer in subjects, such as smokers.
Non-invasive prognosis and monitoring of lung cancer progression through repeated biomarker and nodule size measurements.
Assessing the efficacy of therapeutic treatments for non-small cell lung cancer by measuring changes in biomarker expression and nodule size.
Development of diagnostic kits comprising reagents to detect miR205-5p, miR126, miR210, FUT8, and SNHG1 in plasma samples.
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