A multi-institution study of 590 patients diagnosed with pulmonary large cell neuroendocrine carcinoma (LCNEC), a rare, aggressive lung tumor marked by significant molecular heterogeneity, offers new insights into the comparative effects of existing therapies and potential targets for future treatment.
LCNEC accounts for approximately 3% of al lung cancers. Patients diagnosed with late stahe (stage IV) LCNEC often have a high incidence of brain metastases, while KRAS mutations are common. The median survival of patients diagnosed with advanced disease is typically between 7 and 12 months [1]
The study was published in the August 19, 2025 edition of Nature Communication. [2]
“This work represents one of the largest collaborative efforts to date in large cell neuroendocrine carcinoma. By bringing together data from nearly 600 patients worldwide, we have created a foundation that can help accelerate the development of biomarker-driven and more effective therapies,” explained first author Amin Nassar, MD, a medical oncology-hematology fellow at Yale Cancer Center.
Comprehensive analysis of the real-world patient data revealed no significant difference in overall survival (OS) related to treatment of large cell neuroendocrine carcinomas (LCNEC) with chemotherapy, chemoimmunotherapy, or immunotherapy.
Tumor-infiltrating lymphocytes
The limited success of immunotherapies could be related to the study findings of significantly lower incidence of tumor-infiltrating lymphocytes (TILs) in LCNEC tumors compared to other lung cancers.
While no clear best treatment option was discovered, the close analysis of patient data found that in nearly 6% of cases there were genetic changes in the tumors that could be targeted with existing drugs for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
Yale researchers also determined a transcriptomic classifier that reclassified more than 70% of “unclassified” tumors into biologically meaningful SCLC-like or NSCLC-like subtypes.
Additionally, “this study shows how cooperation between institutions and integrating clinical and molecular insights can identify potential therapeutic targets” noted Anne Chiang, senior author. Specifically, the close analysis revealed that some LCNEC subtypes showed specific markers, including FGL-1 and SPINK1 in NSCLC-like tumors and DLL3 in SCLC-like tumors, pointing to possible targets for treatment.
The Yale-led study, which included several dozen researchers from the US, Norway, Spain, Belgium, Germany, Italy, and England, concluded that prospective clinical trials tailored to the genetic profiles of different LCNEC tumor types are critically important to evaluating the efficacy of new therapies.
Reference
[1] Naidoo J, Santos-Zabala ML, Iyriboz T, Woo KM, Sima CS, Fiore JJ, Kris MG, Riely GJ, Lito P, Iqbal A, Veach S, Smith-Marrone S, Sarkaria IS, Krug LM, Rudin CM, Travis WD, Rekhtman N, Pietanza MC. Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes. Clin Lung Cancer. 2016 Sep;17(5):e121-e129. doi: 10.1016/j.cllc.2016.01.003. Epub 2016 Jan 21. PMID: 26898325; PMCID: PMC5474315.
[2] Nassar AH, Kim C, Adeyelu T, Bou Farhat E, Abushukair H, Rakaee M, Matteson K, Lau SF, Takabe Y, Ocejo A, Ardeshir-Larijani F, Leal T, Ramalingam S, Alam S, Gray JE, Hicks J, Kaldas D, Baena J, Berjaga MZ, Nana FA, Grohe C, Leuders H, Citarella F, Cortellini A, Mingo EC, Pancirer D, Das M, Ellis-Caleo TJ, Cheung JM, Lin JJ, Watson AS, Camidge DR, Sridhar A, Parikh K, Crowley F, Marron TU, Aggarwal V, Ahmed M, Sankar K, Kawtharany H, Zhang J, Owen DH, Li M, Nagasaka M, Pinato DJ, Awosika N, Alhamad K, Puri S, Zaman U, Gupta DM, Lau C, Khan H, Liauw J, Velazquez AI, Brown T, Moliner L, Mosteiro M, Rocha P, Evans M, Vanderwalde A, Elliott A, Nieva J, Lopes G, Ma PC, Borghaei H, Lee M, Young L, Aljumaily R, Mirza H, Kwiatkowski DJ, Herbst RS, Flavell RA, Naqash AR, Chiang AC. Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma. Nat Commun. 2025 Aug 19;16(1):7717. doi: 10.1038/s41467-025-63091-0. PMID: 40830141; PMCID: PMC12365225.
Featured image: © 2016 – 2025 Fotolia/Adobe. Used with permission
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