Novel Biomarkers May Inform Prognosis in SCLC

Three molecular subtypes of small cell lung cancer (SCLC) and specific gene mutations that may impact prognosis were identified in a study published in Scientific Reports.1

While the prognosis for SCLC remains poor, with just one-third of cases considered curable, immune checkpoint inhibitors have given hope for the future of treatment. Current immunotherapy options for patients with SCLC include atezolizumab (Tecentriq; Genentech) for extensive-stage SCLC (ES-SCLC), durvalumab (Imfinzi; AstraZeneca) for ES-SCLC and, most recently, for limited-stage SCLC.2-4

“Currently, the most urgent need is to identify stable prognostic molecular markers and develop therapeutic strategies for patients most likely to respond to treatment, thereby enabling more patients to benefit from antitumor immunotherapy,” the researchers wrote.

The group analyzed over 500 samples of SCLC—200 using whole-exome sequencing and 313 using targeted sequencing.

The study identified several molecular markers related to SCLC prognosis by integrating somatic mutation profiles, mRNA transcriptome data, and clinical information. | Image credit: vitstudio - stock.adobe.com

Five mutational signatures were identified, but when deploying a clustering analysis, the maximum slope of the straight line occurred when there were 3 clusters. Among the 3 clusters, the smoking-related SBS4 mutational signature showed the worst prognosis, even when adjusting for other confounding factors (HR, 1.63; 95% CI, 1.01-2.36; P = .029). Notably, this cluster had the lowest tumor mutational burden (TMB) compared with the other subtypes (Wilcoxon rank-sum test P < .001), suggesting that this subtype may be resistant to immunotherapy.

Meanwhile, patients with an SBS13 signature may have a better response to immunotherapy, suggested findings. The SBS13 signature identified by the researchers was associated with a more favorable prognosis and higher TMB. This signature has previously been linked to better response to anti-programmed death 1 treatment in other tumors.

The researchers noted that while they accounted for various confounding patient and disease factors, such as age, gender, stage of disease, and sample type, they were unable to account for other potential confounders. For example, the combinations of treatment with chemotherapy, radiotherapy, and immunotherapy that patients receive will vary. There may be certain comutations or genetic alterations not yet detected that impact tumor biology and response to treatment for patients. The group also highlighted potential influence of lifestyle factors, such as different smoking habits or exposure to carcinogens.

Looking deeper, specific mutations associated with prognosis, the researchers found that among 38 high-frequency mutations, just 1 was associated with favorable prognosis. The survival benefit observed with UNC13A mutations was due to activated immune microenvironment and immune response pathways.

"Recent studies have demonstrated close relationships of single-gene mutations with high immunogenicity and immunotherapy efficacy, such as FAT1, TP53, MUC16, and POLE," the authors wrote. "Therefore, UNC13A mutations may serve as a potential indicator of response to immunotherapy in SCLC. Prospective cohorts are needed to confirm these findings."

Across the other mutations, TP53 splice mutations were associated with worse prognosis, even when accounting for confounders (HR, 4.20; 95% CI, 1.08-16.30; P = .043). TP53 is a known driver of SCLC, and mutations of the gene have previously been identified as an indicator of inferior survival for these patients.

"In summary, this study identified several molecular markers related to SCLC prognosis by integrating somatic mutation profiles, mRNA transcriptome data, and clinical information," the authors wrote. "At the same time, we clarified underlying molecular immunological characteristics and provided clues for the development of SCLC clinical trials and the updating of treatment methods."

References

1. Li Y, Song C, Wang H, et al. Novel prognostic biomarkers in small cell lung cancer reveal mutational signatures, genomic mutations, and immune implications. Sci Rep. Published online May 4, 2025. doi:10.1038/s41598-025-00222-z
2. FDA approved atezolizumab for extensive-stage small cell lung cancer. News release. FDA. March 19, 2019. Accessed May 30, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancer
3. FDA approved durvalumab for extensive-stage small cell lung cancer. FDA. Last updated March 30, 2020. Accessed May 30, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-extensive-stage-small-cell-lung-cancer
4. Imfinzi approved in the US as first and only immunotherapy regimen for patients with limited-stage small cell lung cancer. News release. AstaZeneca. December 5, 2024. Accessed May 30, 2025. https://www.astrazeneca.com/media-centre/press-releases/2024/imfinzi-approved-in-us-for-limited-stage-sclc.html