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

Abstract

BackgroundFor 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.MethodsConsent 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.ResultsPostmortem 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.ConclusionsPost‐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.

Guideline-Adherent Clinical Validation of a Comprehensive 170-Gene DNA/RNA Panel for Determination of Small Variants, Copy Number Variations, Splice Variants, and Fusions on a Next-Generation Sequencing Platform in the CLIA Setting

“…This allows for the detection of rare and novel fusions. For example, an expected EML4-ALK fusion and an unexpected AGK-BRAF fusion was detected in a lung cancer sample harboring a known EML4-ALK fusion at Laboratory A during the TST170 validation and was confirmed by orthogonal testing with a different NGS assay ( Boyle et al, 2020 ).…”

Analytical validation and initial clinical testing of quantitative microscopic evaluation for PD-L1 and HLA I expression on circulating tumor cells from patients with non-small cell lung cancer

“…However, there is significant debate in the field whether a tumor biopsy represents the phenotype of all metastatic sites, and CTCs may provide the opportunity to evaluate cancer cells shed from all sites of disease. Heterogeneity in PD-L1 expression between metastatic sites has been observed with rapid autopsy studies of patients with metastatic prostate cancer [ 38 ] and in rapid post-mortem tissue donated from patients with NSCLC [ 39 ]. While some studies have shown correlation in the expression of PD-L1 on solid tissue biopsy compared to liquid biopsy [ 40 ], several publications have demonstrated discordance [ 41 – 43 ].…”

Acylglycerol Kinase-Targeted Therapies in Oncology

“…EGFR mutant non-small cell lung cancers are resistant to EGFR tyrosine kinase inhibitor (EGFR-TKI) (Westover et al, 2018), and BRAF fusion is one of the reasons for their resistance (Yu et al, 2013). Lung cancer patients show secondary resistance to EGFR TKIs due to acquired AGK/BRAF fusion (Vojnic et al, 2019;Boyle et al, 2020), which suggests that AGK is involved in some acquired tumor resistance, but the specific AGK mechanism in this context needs to be clarified.…”