Although the new standard of treatment for the extensive disease involves the integration of platinum, etoposide and immunotherapy considering the statistical gain in survival, this benefit is limited in unselected populations, emphasizing the need for predictive biomarkers
In preclinical studies, there is increasing evidence of transcriptional heterogeneity among small cell lung cancers (SCLC), but the impact of therapeutic benefit remains undefined. In this regard, a trial that molecularly characterized four subtypes of SCLC gene expression from 81 tumor samples was presented at the American Association for Cancer Research (AACR) Annual Meeting 2021. Three subtypes had already been defined by the differential expression of transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and POU2F3 (SCLC-P). Now, a fourth subtype with low expression of all three transcription factor signatures has been identified.
Using transcriptional and proteomic data from patient tumors and tumor-derived models, the researchers molecularly characterized each of the four identified subtypes. The latter, named SCLC’1 (Small Cell LungCancer Inflamed), showed high expression of non-neuroendocrine transcription factors (e.g., REST) and EMT (Epithelial-Mesenchymal Transition) markers.
Additionally, in relation to the “cold” immune microenvironment typical of SCLC, SCLC-I tumors have a markedly higher interferon-γ signature and immune checkpoints, including CD274 (gene encoding the PD-L1 protein). Infiltration of various types of immune cells (macrophages, T cells, NK cells, and dendritic cells) was observed to be significantly higher in SCLC-I tumors.
The researchers then hypothesized that the SCLC-I subtype might show a positively disproportionate benefit with immunotherapy. To test this, 276 tumors of treatment-naïve patients with extensive disease SCLC from the IMpower133 trial were analyzed.
The distribution of subtypes was as follows:
Although there was a trend of benefit in terms of overall survival with the addition of atezolizumab in each subtype, the benefit was numerically higher in SCLC-I. Specifically, median OS (atezolizumab versus placebo) in months was 18.2 versus 10.4 months for SCLC-I tumors, while median OS for the other three subtypes showed variations of 9.6 to 10.9 months with immunotherapy and from 6.0 to 10.6 months with placebo.
The authors conclude that transcriptional analyses identified four subtypes of SCLC with distinct immunological characteristics. Although all subtypes showed benefit with the addition of anti-PD-L1 to cisplatin plus etoposide as the first line of treatment, it is suggested that patients with SCLC-I experienced greater benefit.
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