Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities

Abstract

Background: Combined small-cell lung cancer (C-SCLC) is composed of SCLC admixed with a non-small-cell cancer component. They currently receive the same treatment as SCLC. The recent evidence that SCLC may belong to either of two lineages, neuroendocrine (NE) or non-NE, with different vulnerability to specific cell death pathways such as ferroptosis, opens new therapeutic opportunities also for C-SCLC. Materials and methods: Thirteen C-SCLCs, including five with adenocarcinoma (CoADC), five with large-cell neuroendocrine carcinoma (CoLCNEC) and three with squamous cell carcinoma (CoSQC) components, were assessed for alterations in 409 genes and transcriptomic profiling of 20 815 genes. Results: All 13 cases harbored TP53 (12 cases) and/or RB1 (7 cases) inactivation, which was accompanied by mutated KRAS in 4 and PTEN in 3 cases. Potentially targetable alterations included two KRAS G12C, two PIK3CA and one EGFR mutations. Comparison of C-SCLC transcriptomes with those of 57 pure histology lung cancers (17 ADCs, 20 SQCs, 11 LCNECs, 9 SCLCs) showed that CoLCNEC and CoADC constituted a standalone group of NE tumors, while CoSQC transcriptional setup was overlapping that of pure SQC. Using transcriptional signatures of NE versus non-NE SCLC as classifier, CoLCNEC was clearly NE while CoSQC was strongly non-NE and CoADC exhibited a heterogeneous phenotype. Similarly, using ferroptosis sensitivity/resistance markers, CoSQC was classified as sensitive (as expected for non-NE), CoLCNEC as resistant (as expected for NE) and CoADC showed a heterogeneous pattern. Conclusions: These data support routine molecular profiling of C-SCLC to search for targetable driver alterations and to precisely classify them according to therapeutically relevant subgroups (e.g. NE versus non-NE).

Clinical Efficacy of Single-Port Thoracoscopic Lobectomy versus Three-Port Thoracoscopic Lobectomy for Lung Cancer

“…Currently, the three-port approach is the conventional choice for thoracoscopic radical pneumonectomy [ 9 ], but the continuous optimization of medical technology has also confirmed the effectiveness of the single-port approach. Prior literature has partially compared the therapeutic efficacy of the three-port approach with the single-port approach [ 10 ], albeit evidence was untenable given the small sample size and unidentified mechanism. Accordingly, this study was to investigate the clinical efficacy of conventional three-port thoracoscopic lobectomy versus single-port thoracoscopic lobectomy for the treatment of lung cancer by examining the impact of different approaches on patients' perioperative indices.…”

Prognostic significance of eighth edition TNM stage criteria in combined small-cell lung cancer

“…It was thought that surgery therapy is mostly suitable for the patients with early-stage C-SCLC ( 13 ). Our study showed the all-different-staged patients without surgery were significantly associated with a bigger HR and were referred to surgery.…”

Clinicopathological and Treatment Patterns of Combined Small-Cell Lung Carcinoma with Future Insight to Treatment: A Population-Based Study

“…A recent study by a Chinese group suggested that combined SCLC components are derived from the same pluripotent clonal stem cells and share initial driver mutations with subsequent genomic alterations [17]. However, pulmonary combined SCLC and combined large-cell neuroendocrine carcinoma (combined LCNEC) were noted to possess different interacting driver genes, as exemplified by the lower incidence of EGFR mutations in combined SCLC than in combined LCNEC (5% vs. 25.7%, p = 0.004) [18].…”

“…TP53 and RB1 were the most altered genes in 12 patients (83.3% and 66.7%, respectively). Another case series of 13 combined SCLC patients showed KRAS G12C (2/13), PI3KCA (2/13), and EGFR (1/13) alterations, which are potentially targetable [17]. Other frequently noted genes in combined SCLC are PTEN, TERT, ARID1B, SDHA, NF1, NOTCH2, NOTCH1, ALK, FGFR4, FGFR1, SOX2, NOTCH3, KMT2D, FAT1, and FAM135B [18,19].…”