Although liquid biopsy is a non-invasive means of identifying the T790M resistance mutation in patients with non–small cell lung cancer (NSCLC), tissue biopsy is recommended for ruling out small-cell lung cancer (SCLC) transformation and other resistance mechanisms, according to a study published in Lung Cancer.1

A challenge in the management of patients with NSCLC receiving EGFR tyrosine kinase inhibitor (TKI) therapy is not only a high rate of relapse characterized by various resistance mechanisms (the T790M mutation accounts for approximately 50% to 60% of cases), but also the morbidity that accompanies repeated biopsy. Accurate identification of mutations is required to properly inform therapy, and liquid biopsy is a less invasive alternative.

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For this study, the authors evaluated the biopsies and outcomes of 5 patients with an EGFR-activating mutation who were initially treated with a first- or second-generation EGFR-TKI. T790M mutations were detected by liquid biopsy and patients were switched to osimertinib — a third-generation EGFR TKI indicated for patients with T790M — but all patients had disease progression.

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Tissue re-biopsy showed an SCLC component in all 5 patients. This finding, in addition to the noted osimertinib resistance, suggests that the SCLC component may have been present at the time of initial resistance and points out a possible heterogeneity of resistance mechanisms.

The patients also had a low ratio of T790M to activating mutation (less than 0.3) in the blood prior to initiating osimertinib. For 3 patients, EGFR mutation assessment with a low-sensitivity assay was negative but the same sample returned positive results when tested with a high-sensitivity method.

The authors concluded that “tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.”


  1. Minari R, Bordi P, Del Re M, et al. Primary resistance to osimertinib due to SCLC transformation: issue of T790M determination on liquid re-biopsy. Lung Canc. doi: 10.1016/j.lungcan.2017.11.011 [Epub ahead of print]