A community‐based lung cancer rapid tissue donation protocol provides high‐quality drug‐resistant specimens for proteogenomic analyses

• Published in: Cancer medicine (Malden, MA) Vol. 9; no. 1; pp. 225 - 237
• Main Authors: Boyle, Theresa A., Quinn, Gwendolyn P., Schabath, Matthew B., Muñoz‐Antonia, Teresita, Saller, James J., Duarte, Luisa F., Hair, Laura S., Teer, Jamie K., Chiang, Derek Y., Leary, Rebecca, Wong, Connie C., Savchenko, Alexander, Singh, Angad P., Charette, LaSalette, Mendell, Kate, Gorgun, Gullu, Antonia, Scott J., Chiappori, Alberto A., Creelan, Benjamin C., Gray, Jhanelle E., Haura, Eric B.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2020; John Wiley and Sons Inc; Wiley
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - mortality; Adenocarcinoma of Lung - pathology; Aged; Apoptosis; Autopsy; B7-H1 Antigen - genetics; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Brain research; Clinical Cancer Research; Community-Based Participatory Research - methods; Consent; Cytology; Deoxyribonucleic acid; DNA; donation; Donations; Drug resistance; Drug Resistance, Neoplasm - genetics; Enzyme inhibitors; Evolution, Molecular; Female; Fibrosarcoma; Florida; Genetic analysis; Genetic Heterogeneity; Genomes; Glycerol; Glycerol kinase; heterogeneity; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Immunotherapy; Library collections; Lung - pathology; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Medical research; Metastases; Metastasis; Middle Aged; Molecular evolution; Oncogene Proteins, Fusion - genetics; Original Research; Patients; PD-L1 protein; PD‐L1; Phosphotransferases (Alcohol Group Acceptor) - genetics; Principal components analysis; Protein-tyrosine kinase; Proto-Oncogene Proteins B-raf - genetics; Quality; rapid autopsy; resistance mutation; Ribonucleic acid; RNA; specimen quality; Studies; Thorax; Tissue and Organ Procurement - methods; Treatment resistance; Tumors; Florida; lung cancer; rapid autopsy; specimen quality; PD-L1; donation; resistance mutation; heterogeneity
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.2670

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. We collected high‐quality primary and metastatic lung cancer specimens from donors after death by rapid collection in the community. Protein analysis of this tissue revealed discordant programmed death ligand 1 (PD‐L1) results at different cancer sites from the same patient; genetic analysis identified anaplastic lymphoma kinase (ALK) and B‐rapidly accelerated fibrosarcoma (BRAF) gene fusions in a patient with a history of ALK inhibitor therapy and a clonal genetic origin of metastatic cancer cells.