Lung neuroendocrine tumors (lung NETs) make up 20-30% of all neuroendocrine cancers, yet their diversity and complexity have long puzzled researchers and clinicians. Now, thanks to cutting-edge research, we’re one step closer to precision medicine that tailors treatments specifically for each patient.
At NETRF, we’re excited to share recent findings that highlight a simple yet powerful tool for identifying unique subtypes of lung NETs using routine pathology techniques. This work is funded by a NETRF Mentored Research Award to Jules Derks, MD, PhD, of Erasmus Medical Center and published recently in the Journal of Thoracic Oncology. This tool, developed by Dr. Derks and his team, has the potential to revolutionize how we diagnose, treat, and understand these tumors.
The Problem: One Size Doesn’t Fit All
Historically, lung NETs have been divided into two categories, typical and atypical, based on how they look under the microscope. But this doesn’t capture the full biological story. Patients can have vastly different clinical outcomes, and until recently, doctors couldn’t explain why.
Dr. Derks and his team studied hundreds of tumor samples and matched them with molecular data to identify three distinct subgroups of lung NETs. The exciting finding is that these subgroups can now be identified using a simple test called immunohistochemistry (IHC) that looks at three key proteins: OTP, ASCL1, and HNF1A.
By measuring these markers, these tumors can be classified into:
- A1: Often found in older women with peripheral (outer lung) tumors. These tumors show low potential for spread but may express DLL3, a targetable protein.
- A2: More common in younger individuals with centrally located tumors. These tumors respond well to therapies that target SSTR2A, another druggable protein.
- B: A smaller group with higher recurrence rates and more aggressive behavior. Still, they show promise for therapies targeting SSTR2A.
About 88% of patients can be clearly classified using this panel, and for the remaining 12%, two additional markers (TTF1 and S100) help refine the diagnosis.
Why This Matters: Tailoring Therapies, Improving Lives
Identifying these subtypes isn’t just academic. Each group has unique vulnerabilities:
- A2 and B subgroups may benefit from therapies like peptide receptor radionuclide therapy (PRRT), thanks to high levels of SSTR2A.
- A1 tumors, while less aggressive, express DLL3—a target of emerging therapies like tarlatamab, a promising new drug already showing success in small cell lung cancer.
Even more reassuring, these biomarker patterns stay consistent as tumors spread, meaning doctors can use the same tests to guide treatment for both primary and metastatic tumors.
From Bench to Bedside: A Step Toward Precision Medicine
This study marks a major step toward precision medicine, customizing care based on the unique biology of a patient’s tumor. It’s a hopeful shift from the “one-size-fits-all” approach, and it’s especially critical for uncommon cancers like lung NETs, where treatment options are limited.
Looking Ahead: Research, Risk, and Personalized Care
This new IHC panel gives researchers and clinicians a vital tool to further explore:
- Why different subgroups arise
- Whether environmental or genetic risk factors influence them
- Which treatments work best for each group
It also opens the door for new clinical trials that target therapies based on a tumor’s molecular fingerprint.
Precision Medicine is a Pillar of NETRF’s Research Roadmap
At NETRF, we believe that no patient should be left behind due to a lack of tailored treatment. This work not only deepens our understanding of lung NETs, but it also shows that with the right tools, personalized treatment is within reach.
Dr. Derks says, “This work represents an important step toward personalized treatment for patients with lung NETs. By showing that a simple immunohistochemical panel—OTP, ASCL1, and HNF1A—can reliably reflect complex molecular profiles, we now have an accessible tool to stratify tumors into three biologically and clinically distinct subgroups. Each group shows unique clinical patterns and therapeutic vulnerabilities, from differences in somatostatin receptor and DLL3 expression to varying risks of recurrence. The next critical step is prospective validation in the clinic and incorporation into trials of targeted therapies and peptide-receptor radionuclide treatment.”
Precision medicine is a pillar of NETRF’s Research Roadmap, designed to move the needle more quickly on improved treatments and a cure. Stay tuned as we continue to support research that transforms lives through science. Ultimately, we believe that every NET patient deserves a treatment as unique as their tumor.