For patients with non-small cell lung cancer (NSCLC), the 2022 NCCN guideline recommends tests for a mutation in PD-L1, a biomarker for immunotherapy, and EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping and RET mutations for targeted therapy so that patients can receive optimal customized treatment with a new targeted therapy.

To diagnose lung cancer in Korea, doctors generally use PCR-based sequential tests, which are relatively cheap and take less time. However, this makes it difficult to develop a comprehensive and fast diagnosis for many different types of mutations, as the NCCN guideline recommends.

The government recently made next-generation sequencing (NGS) testing reimbursable for cancer patients and reduced the co-pay percentage to 50 percent to lower the financial burden for patients.

Still, current NGS testing using tissue biopsy has limitations in taking samples and takes too long to get results.

Guardant360, developed by Guardant Health, is a blood-only NGS-based liquid biopsy. It obtained approval as a companion diagnostic (CDx) in the U.S. for third-generation EGFR TKI Tagrisso (osimertinib), the world's first antibody treatment targeting EGFR exon 20 insertion mutation Rybrevant (amivantamab), and the world's first KRAS inhibitor Lumakras (sotorasib).

Korea Biomedical Review sat down with Cho Byoung-chul, head of the Lung Cancer Center at Yonsei Cancer Center, and Lim Sun-min, a professor at Yonsei Cancer Center, to understand the limitations of lung cancer diagnosis in Korea, what makes NGS liquid biopsy different from tissue biopsy, and characteristics of liquid biopsy tool Guardant360.

Yonsei Cancer Center's Lung Cancer Center works on multiple clinical trials of liquid biopsies such as Guardant360.

KBR: Targeted therapies targeting various oncogenes have recently been launched in Korea, and NGS testing in lung cancer diagnosis is getting more important. How widely is NGS used in lung cancer patients in Korea, and what improvement has it made?

Cho: The NCCN, ESMO, and other major global guidelines recommend targeted therapy as a preferred option for patients with a mutation. As more targeted therapies in lung cancer are made available targeting EGFR, ALK, ROS1, MET, NTRK, or KRAS mutations, understanding individual patients' characteristics through biomarker testing is more important.

Now, more evidence shows early NGS testing is more cost-effective. Many patients do not have a mutation in EGFR, ALK, or ROS1. Globally, no more than 30 to 35 percent of patients are thought to have a mutation in either EGFR, ALK, or ROS1. It means 65 to 70 percent of patients need other biomarker diagnostic tests.

The problem is that tissues must have already been used up by that time for sequential testing with no tissue left for NGS. Besides, even NGS can take about four to six weeks in Korea before results come in if it leverages tissue biopsy. This calls for a new diagnostic test that can reduce the time to results.

Lim: The latest NCCN guideline recommends comprehensive genomic profiling (CGP) for cancer diagnosis, for which either tissue biopsy or liquid biopsy needs to be selected. Tissue biopsy has its limitations as its turnaround time (TAT) is at least one month, and the test itself cannot be properly conducted sometimes when the amount of tissue collected is insufficient. As for liquid biopsy, the TAT is only about two weeks, but patient access is limited as it is not yet reimbursable.

KBR: Are you saying liquid biopsy is better than tissue biopsy for NGS?

Cho: We have to understand liquid biopsy and tissue biopsy as mutually complementary, not exclusive. One of the benefits of tissue biopsy is high accuracy as the patient's tissues are collected and tested directly. However, this does not mean the sensitivity of liquid biopsy is always poor. Guardant360, despite being a liquid biopsy, is highly sensitive, quickly and accurately providing information required to treat a patient. In the case of tissue biopsy, the time to results can be quite long, and taking a tissue sample is an invasive procedure.

On the other hand, liquid biopsies like Guardant360 are not invasive. A blood sample of about 10cc is enough. This is a huge benefit for patients unsuitable for an invasive biopsy. Tissue biopsy in elderly patients or those on an anticoagulant due to cardiovascular disease is associated with the risk of bleeding.

Another benefit of liquid biopsy is reduced time to results. It typically takes about 10 days until results come in, which is very fast compared to tissue biopsy. That's why a liquid biopsy is recommended for urgent cancer patients visiting the center. For instance, one patient experienced shortness of breath for one or two months and did not know the exact cause. The patient visited the center only to find a 10cm-long cancerous tumor in the lung. Taking any more time for diagnosis could jeopardize that patient's life.

KBR: For which patients do you recommend liquid biopsy in clinical care?

Lim: We try liquid biopsy when the histological diagnosis is difficult or lung cancer is strongly suspected. Thus treatment is urgently needed. Liquid biopsy is also used for patients who developed resistance following targeted therapy. I believe there is no better diagnostic test than liquid biopsy for patients who have developed a resistance to their previous therapy. We cannot spend too long choosing a new therapy option for this patient population.

Cho: Firstly, liquid biopsy is done in patients strongly suspected of having stage-4 lung cancer but whose cardiovascular disease makes biopsy unsuitable. Liquid biopsy is also recommended for patients who are expected to be eligible for targeted therapy when a biopsy is done. Patients who have lung adenocarcinoma and do not or rarely smoke are typical examples.

In some cases, liquid biopsy and tissue biopsy are done simultaneously. That's because sometimes results are urgently needed, or tissue biopsy does not find any gene mutation.

As Professor Lim said, liquid biopsy is important in patients who developed a resistance to a targeted therapy. Unfortunately, contrary to the NCCN and ESMO guidelines, even if NGS finds a gene mutation in a patient who has already developed a resistance, targeted therapy for that mutation cannot be reimbursable in Korea. It is because NGS is not approved as a companion diagnostic (CDx). For instance, when a patient develops a resistance to gefitinib or afatinib, osimertinib and lazertinib are reimbursable only when a T790M mutation is confirmed through a certain diagnostic test (Cobas).

This is a very unfortunate situation, in my opinion. If the tumor burden potentially increased due to resistance, it would make even breathing difficult. Besides, an increase in tumor size makes necrosis inside tumor areas more likely, making it difficult to find a tumor cell through biopsy. We are forced to do another diagnostic test for reimbursement, even when the situation is extremely critical because it is not approved as CDx. Korea is not officially acknowledging diagnostics like Guardant360, which is already validated and approved by the FDA, and it is extremely frustrating.