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by Dr. C.H. Weaver M.D. updated 4/2022

Most cancers result from abnormal genes or gene regulation. The cause of these changes can be environmental, spontaneous, or inherited. By identifying the genomic changes and knowing which genes are altered in a patient, cancer drugs that specifically attack that gene (or the later consequences of that gene) can be used to target the cancer and avoid the more general side effects of chemotherapy. 

Lung CancerConnect 490

Cancer causing genetic mutations can be detected in a biopsy or by measuring circulating tumor DNA (ctDNA), in the blood. Detection of ctDNA allows for personalized cancer treatment based on an individual’s unique set of tumor mutations.

Doctors identify cancer growth driving mutations by performing "next generation sequencing" (NGS) on the the biopsy that identified the lung cancer. Identifying the specific genomic alteration rather than relying on a simple broad classification of cancer solely based on its site of origin avoids the traditional  “one-size-fits-all” approach to cancer treatment and allows for the identification of a precision cancer medicine or immunotherapy to treat a specific cancer. 

Traditionally, the most common way to detect the presence of cancer has been through the use of imaging techniques like computerized tomography (CT) scan, magnetic resonance imaging (MRI), and positron emission tomography (PET). However, these imaging tools are limited in their ability to detect molecular residual disease (MRD), or very small traces of cancer in the body. ctDNA can be detected in the blood long before it appears on a CT or MRI scan.

Knowing if there are traces of cancer present in your body can help your oncologist decide:

  • Your best initial treatment
  • If you are responding to treatment
  • If further cancer treatment needs to be considered
  • If there are signs that the cancer has returned or progressed

What is circulating tumor DNA (ctDNA)?

Circulating tumor DNA (ctDNA) is 150–200-base-pair fragments of DNA, which originate from cancer cells and are present in the bloodstream or other body fluids. 

Tissue biopsy-based tests are invasive, can have serious complications, are time-consuming, and the specimens are often inadequate to test for all the relevant mutations.

A liquid biopsy test can be performed quicker and is performed on a blood sample avoiding the need to obtain a biopsy or tissue sample.

Looking for evidence of cancer in blood samples may also help detect early cancer recurrence before its evident on CT or MRI and help determine if cancer has already spread or will benefit from treatment.

Detection of MRD using ctDNA using can inform prognosis and guide treatment.

For patients with early-stage NSCLC, routine surveillance after treatment is performed using serial radiological imaging to detect macroscopic disease recurrence, with limited sensitivity. Biomarkers with high specificity and sensitivity for detection of minimal residual disease (MRD) are needed to better identify patients at risk of relapse, and those who could benefit most from additional adjuvant and/or maintenance therapy while avoiding over-treatment for patients who have been successfully cured.

ctDNA can be detected before treatment in 24% of patients with stage I disease, 77% of patients with stage II and 87% of patients with stage III disease with high specificity and precedes clinical detection of recurrence of the primary by a median of 212.5 days.

Liquid Biopsies - Changing Management of NSCLC

About 30 percent of NSCLC's can now be treated with precision cancer medicines yet many patients are not undergoing genomic-biomarker testing to determine their eligibility for treatment.

A liquid biopsy test that utilizes cell-free tumor DNA (cfDNA) in blood and can detect all guideline-recommended predictive biomarker mutations (EGFR, ALK, ROS1, BRAF, RET, MET, ERBB2) one prognostic biomarker mutation (KRAS), and new cancer driving mutations as they are being identified.  

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About The NILE Study

The NILE study was a prospective, multicenter clinical study that directly compared the Guardant360 liquid biopsy comprehensive cell-free DNA (cfDNA) analysis to standard tissue genotyping for identifying NSCLC biomarkers among 282 patients with previously untreated, non-squamous cell advanced NSCLC.

Patients underwent standard genotyping and provided a pretreatment blood sample for cfDNA analysis using Guardant360 (Guardant Health). The detection rate of guideline-recommended genomic biomarkers — including EGFR, ALK, ROS1, BRAF, RET, MET and ERBB2 — using standard-of-care tissue testing verses Guardant360 served as the study’s primary endpoint.

Standard tissue biopsy identified a guideline-recommended biomarker in 60 patients, whereas cfDNA detected a biomarker in 77 patients. At least one of the guideline-recommended biomarkers was detected in 60 patients using tissue-based tests alone. By adding Guardant360, the rate of detection increased by 48 percent, from 60 patients to 89 patients, which included those whose samples were negative by tissue (7), not tested (16), or did not have enough material (6) for the tissue-based tests.

The NILE study also found that the cfDNA test results of four biomarkers (EGFR, ALK, ROS1, BRAF), for which there are U.S. Food and Drug Administration-approved drugs, were concordant with the tissue-based test results, with a positive-predictive value of 100 percent.

Genomic biomarker testing performed on a blood sample will allow patients to be more easily and thoroughly evaluated to determine whether they are eligible to be treated with newer precision cancer medicines.

Role of Liquid Biopsy in Recurrent NSCLC

Upon cancer recurrence doctors can reassess the molecular profile of the cancer with a liquid biopsy which allows the doctor to get an assessment of what's going on at all cancer sites throughout the body that are shedding their DNA into thee circulation. This can help identify any new mutations that might require treatment. 

Liquid Biopsy Accurately Detects MSI-High and Can Be Used to Identify Patients Treatable With PD-L1 Checkpoint Inhibitors

In the largest comparison of blood-based microsatellite instability (MSI) testing to traditional tissue methods across multiple solid tumor types, researchers demonstrated that a “liquid biopsy” can accurately detect MSI, an important biomarker used to identify patients that can benefit from treatment with checkpoint inhibitor precision immunotherapy treatment.3

About MSI

Microsatellite instability (MSI) is the condition of genetic hypermutability or a predisposition to mutations in cells that results from impaired DNA mismatch repair (MMR). DNA MMR corrects errors that spontaneously occur during DNA replication such as single base mismatches or short insertions and deletions. The proteins involved in MMR correct polymerase errors by forming a complex that binds to the mismatched section of DNA, excises the error, and inserts the correct sequence in its place.4-11

Cells with abnormally functioning MMR are unable to correct errors that occur during DNA replication and consequently accumulate errors. This causes the creation of novel microsatellite fragments. The presence of MSI represents evidence that MMR is not functioning normally, and specific tests can be used to detect for the presence of MSI. 5-7

High levels of microsatellite instability (MSI-high) occur in about 10% to 15% of colorectal cancers as well as non-colorectal cancers, and research has demonstrated that ~ 50% of MSI-high patients with mCRC respond to treatment with Keytruda resulting in a one-year survival rate of about 50%, which is significantly better than chemotherapy. 11

To validate Guardant 360’s MSI detection, researchers compared the results of 1,145 Guardant 360 samples taken from blood to MSI status determined using standard-of-care tissue testing results taken from medical records. The results from Guardant 360 were the same as the standard-of-care tissue test in 98.4% of cases.

Lung Newsletter 490


  1. Guardant360 Performance Matches Standard-of-Care Tissue Testing in First-Line, Advanced Non-Small Cell Lung Cancer, NILE Study Shows, Meeting Primary Endpoint
  2. GUARDANT360
  3. Largest Study of its Kind Finds Guardant360 MSI Highly Concordant to Tissue
  4. Ramalingam S. Abstract CT078. Presented at American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
  5. Schrock AB, et al. Ann Oncol. 2019; doi:10.1093/annonc/mdz134.
  6. Alexandrov LB et al. Nature. 2013; 500: 415-421.
  7. Yuan J et al. J lmmunother Cancer. 2016; 4:3.
  8. Schumacher TN, Schreiber RD. Science. 2015;348(6230):69-74.
  9. Le DT, Uram JN, Wang H. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
  10. Janjigian YY, Sanchez-Vega F, Jonsson P, et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 2018;8(1):49-58.
  11. Yaeger R, Chatila WK, Lipsyc MD, et al. [Clinical sequencing defines the genomic landscape of metastatic colorectal cancer]( Cancer Cell. 2018;33(1):125-136.
  12. Gale D, Heider K, Ruiz-Valdepenas A, et al. Residual ctDNA after treatment predicts early relapse in patients with early-stage nonsmall cell lung cancer. Annals of Oncology; Published online 16 March 2022. DOI: