Targeted therapies have helped shift the treatment of non-small cell lung cancer (NSCLC) toward treatments guided by a tumor’s genetic changes. For eligible patients, median overall survival (OS) with targeted therapies has been reported at 18–38 months, compared with 8–12 months with supportive care and chemotherapy. [1] Therefore it is essential to identify the genetic changes that may guide treatment. The question is how to detect them reliably.

Tissue biopsy: the established starting point

Tissue biopsy-based next-generation sequencing (NGS) remains the standard approach for molecular profiling of solid tumors. It can identify multiple genetic changes while providing information on tumor histology and biomarkers such as PD-L1.

However, obtaining tissue may require an invasive procedure, with risks such as bleeding or pneumothorax. Samples may also be insufficient or unsuitable for comprehensive genomic profiling. One study found that approximately one in five tissue samples failed quality checks. [2]

Tumors can contain distinct populations of cancer cells with different genetic changes, and the primary tumor may differ genetically from metastases. [3,4] Since tissue biopsy captures only the sampled area, it may miss actionable alterations present elsewhere in the cancer.

These limitations have helped drive interest in liquid biopsy, which can assess tumor genetics without necessarily requiring another tissue procedure.

Table 1: Comparison of Tissue and Liquid Biopsy

Liquid biopsy: a complementary view

Liquid biopsy analyzes tumor-derived genetic material in body fluids. Material entering the bloodstream from different tumor sites may provide a broader view of a cancer’s genetic changes. Liquid biopsy can also be useful when tissue is insufficient or another biopsy is not feasible.

It may offer practical advantages too. In the LIQUIK study, mean turnaround time was 9.7 days for liquid biopsy compared with 21.7 days for tissue NGS. [5] Repeat blood sampling can also help track changes in tumor genetics over time without repeated invasive biopsies.

Cost is another advantage. A 2025 micro-costing analysis in advanced NSCLC found lower overall genotyping costs for liquid biopsy than tissue biopsy in the study setting. Automated sample preparation had a greater modeled effect on staff costs for liquid biopsy, reducing them by 33% compared with 10% for tissue testing.[6]

Despite these advantages, some biomarkers remain challenging to assess in blood. Tumor mutational burden (TMB), which measures the number of mutations detected in a tumor, can help inform treatment decisions in certain settings. Yet blood-based and tissue-based TMB results do not always agree. In one real-world study, more than one-third of matched cases were classified differently as TMB-high or TMB-low depending on whether the result came from blood or tissue. [7]

Sensitivity is another challenge. Some tumors release very little genetic material into the bloodstream, making their alterations harder to detect. Depending on the cancer and clinical question, other fluids may help address this gap. For example, cerebrospinal fluid (CSF) can help assess cancers involving the central nervous system, while urine can be informative for cancers that shed genetic material into the urinary tract.

Assay design can also improve detection. In LIQUIK, the evaluated amplicon-based liquid biopsy assay increased actionable biomarker yield by 15.6% relative to the evaluated hybridization-capture assay. [5] This finding applies to the specific assays compared and does not establish a general advantage of one technology over the other.

Adding circulating tumor RNA (ctRNA) analysis can provide further sensitivity, particularly for genetic rearrangements that may be difficult to detect using circulating tumor DNA (ctDNA) alone. At the 2026 World Conference on Lung Cancer, an analysis of 602 patients with NSCLC reported that combining ctDNA and ctRNA increased detection of actionable rearrangements by 38.7% compared with ctDNA alone. [8]

A complementary approach

The LIQUIK study also found that liquid biopsy results were 93%–100% concordant with tissue NGS across the individual biomarker categories evaluated. [5] Furthermore, liquid biopsy detected guideline-recommended biomarkers in 6 of 46 patients (13%) whose tissue NGS results were negative. [5]

Clinical guidelines support plasma ctDNA testing in selected situations, including when tissue is insufficient or a biopsy is not feasible. If plasma testing is negative, tissue testing may still be needed when clinically appropriate.[9]

When appropriate, concurrent tissue and liquid biopsy testing may broaden genomic assessment and help reduce delays. Neither method replaces the other. The best approach depends on the cancer, the clinical question and the biomarkers needed to guide treatment.

References

1. Chen R, Manochakian R, James L, et al. Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol. 2020;13(1):58.

2. Hung LJ, Huang CY, Tung KC, et al. Comprehensive genomic profiling in multiple cancer types: comparative analysis of National Biobank Consortium of Taiwan and clinical practice cohorts. J Formos Med Assoc. 2025;124(9):830-838.

3. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-892.

4. Russano M, Napolitano A, Ribelli G, et al. Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples. J Exp Clin Cancer Res. 2020;39(1):95.

5. Samol J, Ng D, Poh J, et al. Prospective multicenter study evaluating a combined circulating tumor DNA and circulating tumor RNA liquid biopsy in metastatic non-small cell lung cancer (LIQUIK). JCO Precis Oncol. 2025;9. doi:10.1200/PO-25-00181

6. O’Reilly D, Moloney C, O’Grady A, et al. Cost and resource utilisation for liquid biopsy vs tissue biopsy genotyping in advanced NSCLC: a micro-costing model. J Clin Oncol. 2025;43(16 suppl):1542. doi:10.1200/JCO.2025.43.16_suppl.1542

7. Sturgill EG, Misch A, Jones CC, et al. Discordance in tumor mutation burden from blood and tissue affects association with response to immune checkpoint inhibition in real-world settings. The Oncologist. 2022;27(3):175-182. doi:10.1093/oncolo/oyab064

8. Jani CT, Negret L, Dormady S, et al. Enhanced detection of actionable fusions in NSCLC using combined ctDNA and ctRNA analysis. Presented at: World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract MO11.05.

9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 9.2026. Accessed February 1, 2026. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf