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Ultradeep Next-Generation Sequencing in Patients With Lung Cancer

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Key Points

  • Of the 91 patients in whom the tissue biopsy had found cancer-driving mutations, analysis of the liquid biopsy detected 68, giving a true positive rate of 75%.
  • Among the 19 patients without mutations detected in the tissue biopsy, the liquid biopsy also did not detect any mutations, meaning there were no false positives and giving a true negative rate of 100%.
  • The mutations detected by the tissue and liquid biopsies included alterations in the EGFRKRASALKROS1BRAFHER2RET, and MET genes.

A new method of determining the sequence of molecules in DNA can be used to detect small fragments of cancerous genetic material in blood samples from patients with lung cancer with a high degree of accuracy, according research published by Li et al in Annals of Oncology.

Liquid Biopsies and Ultradeep Sequencing

Results from analyses of liquid biopsies in patients with non–small cell lung cancer (NSCLC) show that it is possible to identify the genetic variants that are either driving the cancer or making disease treatment-resistant. This offers the potential for doctors to use liquid biopsies to help them choose the best treatment for patients based on the genetic make-up of their tumors.

Researchers in the Annals of Oncology study used a method of analyzing patient blood samples called ultradeep next-generation sequencing. This involves reading the DNA fragments that have been released by the tumors into the blood stream—known as cell-free DNA (cfDNA)—an average of 50,000 times to ensure the greatest accuracy in detecting variants from any of 37 genes commonly involved in lung cancer.

The proportion of cfDNA from tumors is very small compared to cfDNA from noncancerous cells in blood, and it is important to be able to distinguish the two types. To do this, patients’ white blood cells were also sequenced and used to filter out noncancer signals from the bone marrow, a process called clonal hematopoiesis filtering. The information from the ultradeep next-generation sequencing was fed into a newly-developed computer algorithm that used machine learning to sift the tumor-related cfDNA from the noncancerous cfDNA.

Study Methods

Researchers collected blood samples from 127 patients with newly diagnosed advanced NSCLC that had metastasized or who had recurrent metastases. There were 3 groups of patients: 91 who had genetic mutations driving their cancer or making it resistant to treatment that had been identified from a tissue biopsy; 19 in whom the tissue biopsy had not detected any such mutations; and 17 patients with no tissue biopsy available or a tissue biospy insufficient for analysis.

In order to compare the performance of the liquid biopsy with the tissue biopsy in an unbiased manner, the liquid biopsy was tested without knowledge of what the tissue biopsy had already found. This enabled the researchers to extrapolate the usefulness of the liquid biopsy to detect mutations accurately in patients without adequate tissue to test.

Findings

Bob T. Li, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center who led the research on behalf of the Actionable Genome Consortium, said, “We found that of the 91 patients in whom the tissue biopsy had found cancer-driving mutations, analysis of the liquid biopsy detected 68, giving a true positive rate of 75%. Among the 19 patients without mutations detected in the tissue biopsy, the liquid biopsy also did not detect any mutations, meaning there were no false positives and giving a true negative rate of 100%.”

He added that the true positive rate of 75% compared favorably with other digital methods for detecting lung cancer driver mutations.

Among the third group of 17 patients for whom no tissue biopsy was available, the cfDNA analysis detected cancer-driving mutations in 4 patients. In one patient, this was subsequently confirmed by a tissue biopsy, while the other three did not have subsequent tissue biopsies. Of the remaining 13 patients, subsequent tissue biopsies confirmed mutations in 2 of them, while the other 11 did not have subsequent biopsies.

The mutations detected by the tissue and liquid biopsies included alterations in the EGFRKRASALKROS1BRAFHER2RET, and MET genes, for which there are existing, targeted treatments as well as new drugs or drug combinations in development.

“Our results suggest that liquid biopsy can play a complementary role to tissue biopsy in the treatment of lung cancers. Due to its high specificity of 100%...liquid biopsy could be performed first and be used to guide treatment, especially when tissue biopsy may be inadequate or not feasible. The caveat is that owing to its modest true positive rate of 75%, if the liquid biopsy is negative, a tissue biopsy is still required,” said Dr. Li.

Previous research at Memorial Sloan Kettering Cancer Center has shown that liquid biopsy can be taken and analyzed in approximately 9 days, compared to 20 days for tissue biopsies.

Dr. Li concluded, “Liquid biopsy is a promising technology development that could help improve the care of patients. We are carrying out further research into this novel test, and these latest results are a step in the right direction for the field of liquid biopsy.”

Disclosure: The study authors' full disclosures can be found at academic.oup.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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