Transformation from NSCLC to SCLC: when did it happen? – Authors' reply

We read with great interest the Review by Matthew Oser and colleagues about the molecular drivers and cells of origin of transfor mation from non-small-cell lung cancer (NSCLC) to small-cell lung cancer (SCLC). Oser and colleagues described reported clinical cases of transformation from NSCLC to SCLC. Most of these cases followed a pattern whereby patients who initially had a favourable response to tyrosine kinase inhibitors (TKIs) had disease progression after a progressionfree survival of 10–38 months, after which transformation to SCLC could be confi rmed by repeated biopsy. However, the point at which the disease transformed from NSCLC to SCLC has not yet been established. We identifi ed one case that was not discussed in this Review that could provide some hints about the timing of this transformation. Zhang and colleagues reported a case of an 80-year-old man with lung adenocarcinoma (stage IB) who had an EGFR gene mutation (deletion of exon 19). Second-line treatment with EGFR-TKI failed, which was combined with increased concentrations of serum tumour markers. The patient’s disease progressed during 1 month of TKI therapy. Later, repeated biopsies of the metastatic and primary surgical lesions identifi ed a pathological transformation from adenocarcinoma to SCLC, which retained the same EGFR mutation. Combined with the fact that SCLC with mutation in the EGFR tends to have a poor response to TKIs, we suggest that, in this case, the transformation happened before the initial period of TKI treatment. By contrast, in most cases, patients have a long progression-free survival with TKI treatment, which supports the possibility that the transformation might happen during TKI treatment. This confl icting fi nding suggests the existence of other possible factors that might promote the transformation from EGFR-mutant adenocarcinoma to SCLC other than EGFR inhibition. Therapeutic strategies for SCLC and NSCLC diff er substantially. Therefore, identifi cation of a non-invasive way before repeated biopsy to detect potential disease transformation is crucial. In this case, in addition to the poor response to TKIs, the increased concentration of serum neuron-specifi c enolase, which rose from 17·9 ng/mL at the early stage of the disease to 211·40 ng/mL at the stage when progression was detected (reference range, <15 ng/mL) could be a preferable way to predict potential disease transformation. Evidence from another case report also supports the potential clinical signifi cance of the tumour marker neuron-specifi c enolase as an indicator of disease transformation. Furthermore, the pro-gastrinreleasing-peptide has also been recommended as a tumour marker for the early prediction of disease transformation from adenocarcinoma to SCLC. When and how this process started warrants further investigation, as does the predictive value of some specifi c tumour markers.