- Researchers at Fox Chase Cancer Center analyzed more than 49,000 lung cancer samples and identified a previously underrecognized subset of tumors with aggressive neuroendocrine-like biology.
- Although diagnosed as common forms of non-small cell lung cancer (NSCLC), these tumors were associated with shorter survival and increased spread to the brain and lymph nodes.
- The findings suggest advanced molecular testing may help identify patients who could benefit from more personalized treatment approaches, including therapies commonly explored in neuroendocrine cancers.
PHILADELPHIA (June 3, 2026) — A new study from researchers at Fox Chase Cancer Center and collaborators across multiple institutions has identified a hidden subset of lung cancers that behave more like aggressive neuroendocrine tumors than traditional non-small cell lung cancer (NSCLC).
The research, presented at the American Society of Clinical Oncology 2026 Annual Meeting in Chicago, used advanced transcriptomic profiling to uncover tumors with biological features resembling high-grade neuroendocrine carcinomas (HGNEC), including small-cell lung cancer and large-cell neuroendocrine carcinoma.
“These cancers are essentially hiding in plain sight,” said Parth Desai, MBBS, MD, Director of Clinical and Translational Research for the Thoracic and Head & Neck Service Lines at Fox Chase. “Under the microscope they may appear to be conventional lung cancers, but molecularly they behave much more aggressively.”
Looking Beyond Traditional Pathology
Most lung cancers are classified based on how tumor cells appear under a microscope. However, researchers say this approach may miss important biological differences that influence how cancers grow, spread, and respond to treatment.
To better understand these hidden differences, investigators analyzed DNA and RNA sequencing data from 49,144 tumor specimens using the Caris Life Sciences database. The team developed a transcriptomic “HGNEC activity score” to identify tumors with aggressive neuroendocrine-like biology, even when they had not been diagnosed as neuroendocrine cancers by pathologists.
The analysis identified a small but clinically meaningful subgroup of NSCLC tumors with aggressive HGNEC-like molecular features.
Key Findings
Compared with other non-squamous NSCLCs, HGNEC-like tumors (roughly about 3-6% estimated incidence) were:
- Associated with significantly shorter overall survival.
- More likely to spread to lymph nodes and the brain.
- More biologically aggressive and rapidly proliferating and resemble small cell lung cancers (SCLC).
- More likely to lack PD-L1 expression, a marker commonly associated with response to immunotherapy.
- More likely to express high levels of neuroendocrine markers such as DLL-3 that are now clinically targetable with highly effective drugs.
Researchers also found that these tumors carried molecular alterations commonly associated with neuroendocrine cancers such as SCLC, including abnormalities in TP53 and RB1, along with activation of neurodevelopmental pathways.
Importantly, the tumors demonstrated high expression of potentially targetable neuroendocrine markers, including DLL3, SEZ6, and SSTR2, suggesting some patients may benefit from therapies currently being explored in small-cell lung cancer and other neuroendocrine malignancies.
Why This Matters
Because these tumors may not be recognized using routine pathology alone, some patients could receive treatments that do not fully address the aggressive biology of their disease.
The findings suggest advanced molecular profiling may help physicians:
- Better identify high-risk tumors.
- Improve patient selection for clinical trials.
- Personalize treatment strategies based on tumor biology rather than appearance alone.
- Identify patients who may benefit from neuroendocrine-directed therapies.
“Our findings support a more biology-driven approach to lung cancer classification and treatment,” Desai said. “Understanding what these tumors are doing at the molecular level may ultimately help us deliver more precise therapies for patients.”
Study Details
The study, titled “Unmasking High-Grade Neuroendocrine Carcinoma (HGNEC) Biology Through Transcriptomic Profiling and Validation in Lung Cancer,” included investigators from Fox Chase Cancer Center, Caris Life Sciences, Moffitt Cancer Center, The Ohio State University Wexner Medical Center, National Cancer Institute, Georgetown University, and Montefiore Medical Center.