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Updated: Jan 3, 2026
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
A community-based lung cancer rapid tissue donation protocol provides high-quality drug-resistant specimens for
Theresa A Boyle1,2,3, Gwendolyn P Quinn4, Matthew B Schabath1,3,5
1Department of Oncologic Science, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
Background:
For the advancement of cancer research, the collection of tissue specimens from drug-resistant tumors after targeted therapy is crucial. Although patients with lung cancer are often provided targeted therapy, post-therapy specimens are not routinely collected due to the risks of collection, limiting the study of targeted therapy resistance mechanisms. Posthumous rapid tissue donation (RTD) is an expedient collection process that provides an opportunity to understand treatment-resistant lung cancers.
Methods:
Consent to participate in the thoracic RTD protocol was obtained during patient care. When death occurred, tumor and paired non-tumor, cytology, and blood specimens were collected within 48 hours and preserved as formalin-fixed and frozen specimens. Tissue sections were evaluated with hematoxylin and eosin staining and immunohistochemistry (IHC) against multiple biomarkers, including various programmed death ligand 1 (PD-L1) clones. Next-generation sequencing was performed on 13 specimens from 5 patients.
Results:
Postmortem specimens (N = 180) were well preserved from 9 patients with lung cancer. PD-L1 IHC revealed heterogeneity within and between tumors. An AGK-BRAF fusion was newly identified in tumor from a donor with a known echinoderm microtubule-associated protein-like 4 to anaplastic lymphoma kinase (EML4-ALK) fusion and history of anaplastic lymphoma kinase (ALK) inhibitor therapy. RNA expression analysis revealed a clonal genetic origin of metastatic cancer cells.
Conclusions:
Post-therapy specimens demonstrated PD-L1 heterogeneity and an acyl glycerol kinase to B-rapidly accelerated fibrosarcoma (AGK-BRAF) fusion in a patient with an EML4-ALK-positive lung adenocarcinoma as a potential resistance mechanism to ALK inhibitor therapy. Rapid tissue donation collection of postmortem tissue from lung cancer patients is a novel approach to cancer research that enables studies of molecular evolution and drug resistance.
Insights
Rapid tissue donation (RTD) enables collection of post-therapy lung cancer specimens. This approach revealed programmed death ligand 1 (PD-L1) heterogeneity and a novel AGK-BRAF fusion, offering insights into targeted therapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pathology
Background:
- Collecting post-targeted therapy tumor specimens is vital for cancer research but often limited by collection risks.
- Understanding targeted therapy resistance mechanisms in lung cancer requires post-therapy tissue samples.
- Posthumous rapid tissue donation (RTD) offers a viable method for obtaining these crucial specimens.
Purpose of the Study:
- To evaluate the feasibility and utility of posthumous rapid tissue donation (RTD) for collecting post-therapy lung cancer specimens.
- To investigate molecular characteristics, including programmed death ligand 1 (PD-L1) expression and genetic alterations, in these collected specimens.
- To identify potential mechanisms of resistance to targeted therapies in lung cancer.
Main Methods:
- Obtained consent for thoracic RTD protocol during patient care.
- Collected tumor, non-tumor, cytology, and blood specimens within 48 hours of death.
- Preserved specimens as formalin-fixed and frozen, followed by hematoxylin and eosin staining, immunohistochemistry (IHC) for biomarkers (including PD-L1 clones), and next-generation sequencing.
Main Results:
- Successfully collected 180 postmortem specimens from 9 lung cancer patients.
- PD-L1 IHC revealed significant heterogeneity in programmed death ligand 1 expression within and between tumors.
- Identified a novel acyl glycerol kinase to B-rapidly accelerated fibrosarcoma (AGK-BRAF) fusion in a patient with an echinoderm microtubule-associated protein-like 4 to anaplastic lymphoma kinase (EML4-ALK) fusion, suggesting a potential resistance mechanism to ALK inhibitor therapy.
Conclusions:
- Post-therapy specimens obtained via RTD demonstrate PD-L1 heterogeneity and novel genetic fusions (e.g., AGK-BRAF) as potential lung cancer drug resistance mechanisms.
- RTD is a novel approach for collecting postmortem lung cancer tissue, enabling studies on molecular evolution and treatment resistance.
- This method facilitates research into understanding and overcoming targeted therapy resistance in lung cancer.
