Human · observationalMechanismReported positiveLimited evidenceTier 3 · early humann = 107
Science advances · Aug 2026 · Proteogenomic analysis of tumors and paired normal adjacent tissues from 107 patients; preclinical optimization and testing of recombinant IL-33 in mouse models and pharmacokinetics in cynomolgus monkeys
pulmonary large-cell neuroendocrine carcinomanon-small cell lung carcinoma
Researchers performed proteogenomic analysis on tumors and matched normal tissues from 107 patients with pulmonary large-cell neuroendocrine carcinoma and identified molecular features, mutational signatures, and three LCNEC subtypes. Interleukin-33 (IL-33) was identified as a biomarker associated with increased T cell infiltration and antitumor activity; the authors optimized recombinant IL-33 and developed a PEGylated form that showed prolonged circulation in cynomolgus monkeys and stronger immune agonist activity in mouse models.
Key findings
- Proteogenomic analysis was performed on tumors and paired normal adjacent tissues from 107 LCNEC patients (81 pure LCNEC and 26 combined LCNEC).
- APOBEC mutational signatures strongly correlate with processes of tumor initiation and immune suppression in LCNEC.
- KEAP1 mutations correlate with metabolic reprogramming in LCNEC combined with NSCLC.
- A conflicting relationship was observed between neuroendocrine and immune phenotypes.
- Three LCNEC subtypes were identified, each with distinct prognosis features, microenvironment dysregulation, genetic alterations, and potential therapeutic targets.
- Interleukin-33 (IL-33) emerged as a critical therapeutic biomarker associated with enhanced T cell infiltration and antitumor activity.
- Recombinant IL-33 was optimized via site-directed mutagenesis and PEGylation.
- PEGylated recombinant IL-33 demonstrated prolonged circulation time in cynomolgus monkeys and superior immune agonist activity in mouse models.
Limitations: Therapeutic optimization and activity of recombinant/PEGylated IL-33 were tested only in animal models (mice) and assessed for circulation in cynomolgus monkeys; no clinical (human interventional) data are reported.; Proteogenomic analyses are observational and associative; causality of identified correlations (e.g., APOBEC signatures, KEAP1 mutations) is not established in patients.; The human cohort, while sizable for a rare tumor, is limited to 107 patients and subgroup sizes (81 vs 26) may limit power for some subtype analyses.; The abstract does not report dosing, safety, or efficacy endpoints in humans, nor detailed statistical measures for the reported associations.; Translatability of mouse and nonhuman primate findings to human clinical benefit is not demonstrated in this study..
AI summary of the abstract, human-reviewed · Sep 2026. Describes what this study reported, not medical advice. View on PubMed · Full text
Human · observationalMechanismReported positiveLimited evidenceTier 3 · early humann = 216
International journal of molecular sciences · Mar 2026 · retrospective cohort
pulmonary large-cell neuroendocrine carcinomaLCNEC
Researchers performed targeted next-generation sequencing on 216 pulmonary LCNEC tumor samples from a retrospective Polish cohort to look for actionable gene variants. They found 46 variants in 46/216 samples (21.3%), with 28/216 (13%) harboring at least one potentially actionable alteration; most common were KRAS and PIK3CA (each 5%), and a novel TMEM79::NTRK1 fusion was found in one case (0.5%). Several typical NSCLC alterations (classical EGFR exon 18–21, ALK, FGFR1/2/3, ROS1) were not detected.
Reported effects: variant_count 46, n=216 · variant_positive_rate 21.3%, n=216 · +8 more
Key findings
- Overall, 46 variants were identified in 46/216 (21.3%) tumor samples.
- 28/216 (13%) LCNECs harbored at least one actionable molecular variant potentially targetable by registered or investigational agents.
- KRAS variants were present in 5% of tumors (including G12C at 2%).
- PIK3CA variants were present in 5% of tumors.
- RET single-nucleotide variants were observed in 3% of tumors.
- Uncommon EGFR variants were observed in 1% of tumors; BRAF class II and III variants were observed at <1%.
- A novel in-frame gene fusion (TMEM79::NTRK1) was identified in a single tumor sample (0.5%).
- No classical EGFR exon 18-21 mutations nor ALK, FGFR1/2/3, or ROS1 alterations (mutations or fusions) were detected.
Limitations: Retrospective study design.; Targeted NGS panel limited to 17 genes, so alterations outside the panel would not be detected.; Single-country (Polish) cohort which may limit generalizability.; No clinical outcome or treatment-response data reported in the abstract to link variants to patient benefit..
AI summary of the abstract, human-reviewed · Jun 2026. Describes what this study reported, not medical advice. View on PubMed · Full text
Case reportMechanismReported positiveLimited evidenceTier 3 · early humann = 1
Tumori · Dec 2025 · case report
breast cancerlarge-cell neuroendocrine carcinoma
This is a case report of a 34-year-old woman initially treated for HR+/HER2- breast cancer in 2012 who developed a mediastinal large-cell neuroendocrine carcinoma (LCNEC) in 2021. Next-generation sequencing identified the same pathogenic PIK3CA variant in both the breast tumor and the LCNEC, suggesting a possible metastatic relationship. The LCNEC progressed on cisplatin/etoposide but had a remarkable and prolonged response to pembrolizumab until treatment was stopped for grade 3 immune-related colitis; the patient had no clinical evidence of disease as of November 2024.
Reported effects: PD-L1 expression 10%, n=1 · tumor mutational burden (TMB) 9.54, n=1 · +1 more
Key findings
- Next-generation sequencing identified shared tumor PIK3CA pathogenic variants in both breast cancer and LCNEC tissues, suggesting a potential relationship as primary tumor and metastasis.
- The mediastinal tumor was a high-grade LCNEC lacking breast-specific markers (GATA3-, HR-, HER2-, mammoglobin-, GCDFP15-).
- PD-L1 expression was 10% and tumor mutational burden (TMB) was 9.54 mut/MB in the LCNEC specimen.
- First-line chemotherapy (cisplatin plus etoposide) led to rapid disease progression; second-line pembrolizumab produced a remarkable and prolonged disease response.
- Treatment was discontinued in 2023 because of grade 3 immune-related colitis; patient had no clinical evidence of disease as of November 2024.
Limitations: Single-patient case report limits generalizability.; Shared PIK3CA mutation suggests but does not definitively prove clonal origin between the two tumors.; No control group or broader cohort for comparison; findings are observational and hypothesis-generating..
AI summary of the abstract, human-reviewed · Aug 2026. Describes what this study reported, not medical advice. View on PubMed
Case reportReported negativeLimited evidenceTier 3 · early humann = 1
BMJ case reports · Jun 2025 · case report
large-cell neuroendocrine carcinoma of the trachea
This case report describes a man in his 70s who presented with dyspnoea and was found to have a primary large-cell neuroendocrine carcinoma of the trachea. Bronchoscopic debulking immediately relieved his dyspnoea; PET suggested the trachea as the primary site. After an incidental COVID-19 infection delayed a second bronchoscopy for 1 month, regrowth of the tracheal lesion with multiple disseminated airway lesions was found; the patient is receiving chemotherapy. The authors note primary tracheal LCNEC is very rare and may be aggressive, and recommend systemic evaluation for metastases.
Reported effect: delay to second bronchoscopy 1, n=1
Key findings
- Patient: man in his 70s presenting with dyspnoea
- Imaging revealed an intratracheal tumour; a small lesion was also detected in the left main bronchus
- Bronchoscopic debulking of the intratracheal tumour resulted in immediate relief of dyspnoea
- Pathological diagnosis was large-cell neuroendocrine carcinoma (LCNEC)
- Positron emission tomography suggested the trachea was the primary site
- Incidental COVID-19 infection delayed the second bronchoscopy for 1 month
- Second bronchoscopy revealed regrowth of the residual tracheal lesion with multiple disseminated lesions in the airways
- The patient is currently undergoing chemotherapy
- Authors conclude primary tracheal LCNEC is very rare and may be aggressive; systemic evaluation for metastases should be considered
Limitations: Single-patient case report; results are not generalizable; No long-term follow-up or outcome data reported beyond initiation of chemotherapy; No controlled comparison or systematic data on frequency, prognosis, or optimal management; Timeline potentially confounded by incidental COVID-19 infection delaying care.
AI summary of the abstract, human-reviewed · Sep 2026. Describes what this study reported, not medical advice. View on PubMed