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.
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