Integration of Liquid Biopsy Assays for the Early Detection of Lung Cancer
Maximilian Diehn, MD, PhD
Stanford University
Stanford
Lung cancer is the number one cause of cancer-related deaths in the US because it is often found only after it has spread to other organs in the body, decreasing the likelihood of surviving at least 5 years after diagnosis. Only 21% of patients are diagnosed then their lung cancer is early stage, when it is most treatable. The goal of this project is to create a new way to screen for lung cancer using a blood sample that can find early stage disease when patients can still be treated and/or cured. In preliminary work, Dr. Diehn has developed a blood test that can identify tiny amounts of DNA from lung cancer cells and in this study he will improve this test and apply it to patients and healthy controls. If successful, Dr. Diehn’s work has the potential to significantly improve early detection of lung cancer and improve outcomes for patients.
Research Summary
Lung cancer is the number one cause of cancer-related deaths in the U.S. and can affect both smokers and non-smokers. Lung cancer is often deadly because it is usually found after it has spread to other organs like the brain, liver, or bones, at which point it is no longer possible to cure the disease in most patients. But if caught early when the cancer cells are still confined to the lung, it can often be cured with surgery or radiation. Screening for lung cancer in current or former smokers using CT scans has been proven to reduce the number of patients who die from lung cancer by catching the disease early. Although insurance covers it in the U.S., only about 15% of those who qualify actually get screened. Some reasons for this low rate of screening include worries about false positives from CT scans and difficulty accessing radiology facilities. Our goal is to create a new way to screen for lung cancer using a blood sample that can find early stage cancers when they can still be cured. Our method looks for tiny amounts of DNA in the blood that comes from lung cancer cells. We have completed initial tests that show our idea could work. Now, we plan to further improve our test and to apply it to several hundred lung cancer patients and healthy controls. If our experiments are successful, our blood test could eventually be used alongside CT scans to cut down on unnecessary follow-up tests or even replace CT scans as the main way to screen for lung cancer. If so, this work could contribute to saving lives of patients with lung cancer.
Technical Abstract
Lung cancer is the leading cause of cancer in the U.S., with over 238,000 new cases and more than 125,000 deaths expected in 2023. Early detection is crucial for improving prognosis, and low-dose computed tomography (LDCT) scans are recommended for high-risk populations. However, LDCT screening has limitations, including a significant false positive rate and low compliance. New approaches are therefore needed to enhance early detection in high-risk individuals. Liquid biopsy assays that can detect circulating tumor DNA (ctDNA) represent a promising alternative early detection approach. Our group has developed three state-of-the-art liquid biopsy techniques that each have the potential to detect lung cancer noninvasively, including a somatic mutation approach (Lung-CLiP), a methylation-based approach (meCAPP-Seq), and a fragmentomic-based approach (EPIC-Seq). We hypothesize that combining mutation-, methylation-, and fragmentomic-based ctDNA analysis will maximize sensitivity for detecting early stage lung cancers. Our proposal includes three specific aims. In the first aim, we will compare the clinical sensitivity and specificity of meCAPP- Seq, EPIC-Seq, and Lung-CLiP for early lung cancer detection. In the second aim, we will determine the analytical limits of detection for the three methods, which is important for future regulatory considerations. In the third aim, we will develop an integrated liquid biopsy assay that combines meCAPP-Seq, EPIC-Seq, and/or Lung-CLiP. We will test if combining two or all three assays can improve performance over the best- performing single assay. The deliverable of this project will be the identification of the combination of liquid biopsy assays that achieves the best performance for early lung cancer detection. If successful, our work has the potential to significantly improve early lung cancer detection which would lead to improved outcomes for lung cancer patients.
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