Utility of Liquid Biopsy for Mutation Detection in NSCLC

In non-small lung cancer (NSCLC), genetic alterations in genes such as EGFR, ALK, ROS1, and BRAF have been validated as reliable targets, and molecular testing and genotype-driven targeted therapy is the standard of care for patients with advanced NSCLC harboring these alterations. However, tumor tissue may be difficult to obtain or yield inadequate samples to perform molecular testing. Furthermore, mutation status may change during the course of disease due to the development of acquired resistance. In recent years, molecular testing of patient plasma using next generation sequencing (NGS) or polymerase chain reaction (PCR) platforms has emerged as a potential alternative to tissue biopsy.

A prospective, single-center, cohort study sought to evaluate the accuracy and clinical implications of liquid biopsy as a tool for treatment selection in 323 patients with metastatic NSCLC. Plasma NGS testing was performed using a 73-gene commercial platform as part of routine clinical management. Among all patients, 128 had concurrent plasma and tissue NGS performed, while 195 patients had only plasma NGS, either because tissue NGS was not possible (N = 101) or because of patient/physician preference (N = 94).

Therapeutically targetable mutations were detected in 113 of 323 patients (35%), including mutations or alterations in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, or BRAF. Plasma testing alone identified therapeutically targetable mutations in 26.7% of the 101 patients for whom tissue biopsy was impossible and in 33.0% of the 94 patients who declined tissue biopsy.

In the 128 patients who had concurrent plasma and tissue testing, NGS of tissue alone detected targetable mutations in 47 patients (20.5%) and concurrent plasma NGS increased detection to 82 patients (35.8%). Among these 128 patients, 24 had targetable mutations detected in tissue or plasma, but not in both (81.3% concordance). The concordance rate for the 81 newly diagnosed patients was significantly higher than for 47 patients who had progressed on prior therapy (88.9% vs 70.2%; P = .008).

Sixty-seven patients (69.1%) with targetable mutations detected by plasma NGS received targeted therapy that yielded clinically significant disease control in 85.7%.

The investigators concluded that this large, prospective, real-world study indicates that plasma-based molecular profiling can increase mutation detection and delivery of personalized targeted therapy. In the accompanying editorial, the authors commented that, while liquid biopsy is an effective tool for patients without an available tissue sample, it should not be used as a replacement for tissue biopsy in all patients, particularly as tissue biopsy can sometimes reveal mutations missed in plasma samples.


JAMA Oncol. 2018 Oct 11. [Epub ahead of print].

JAMA Oncol. 2018 Oct 11. [Epub ahead of print].


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