Most patients with small-cell lung cancer (SCLC) respond to first-line chemotherapy, although acquired resistance is almost inevitable. Now, an analysis of blood samples from patients with limited-stage (LS)-SCLC or extensive-stage (ES)-SCLC demonstrate the feasibility of monitoring these cancers using changes in cell-free DNA (cfDNA).
Researchers analysed samples from 39 patients with LS-SCLC and 30 patients with ES-SCLC: tumour-related changes (copy-number alterations (CNAs) and/or somatic mutations) could be detected in samples from 94% and 100% of patients, respectively. Mutant TP53 variant allele frequency (VAF; >30 versus ≤30) and size of the largest VAF (Z-score >32,000 versus ≤32,000) were both associated with inferior outcomes (P = 0.0001 and P < 0.0001, respectively), and both parameters were also positively correlated with circulating tumour cell (CTC) number (P < 0.0001). However, no significant correlations were observed between CTC number and number of mutations detected or number of genes mutated in cfDNA (as detected using a 110-gene panel).
Among the 110 genes analysed in cfDNA, a total of 272 somatic mutations were identified, including driver alterations in 69% of samples of which 60% were deemed by the investigators to be potentially targetable.
The role of cfDNA in disease monitoring was explored in longitudinal samples from a subset of six patients. Four patients had baseline CNAs in cfDNA that became undetectable on completion of therapy, with a 10-fold reduction observed in a 5th patient, and no notable change in a 6th patient who had a partial response. CNAs were detectable at the time of relapse in 4 of 5 patients. The patient without detectable CNAs was found to have CNS-only relapse, with stable lung lesions.
These data confirm the potential of cfDNA in the management of SCLC. Data from prospective studies incorporating cfDNA-based approaches are eagerly awaited.
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Original article
Mohan, S. et al. Profiling of circulating free DNA using targeted and genome wide sequencing in patients with small cell lung cancer. J. Thorac. Oncol. https://doi.org/10.1016/j.jtho.2019.10.007 (2019)
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Sidaway, P. cfDNA monitoring is feasible in SCLC. Nat Rev Clin Oncol 17, 7 (2020). https://doi.org/10.1038/s41571-019-0300-7
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DOI: https://doi.org/10.1038/s41571-019-0300-7