To date hereditary risk factors for non-small cell lung cancer (NSCLC) are poorly understood. While most cases are considered sporadic, rare monogenic germline alterations in EGFR and TP53 have been reported to be associated with increased risk of NSCLC. While identification and accurate functional characterization of such variants are essential for improving risk assessment and personalized therapeutic strategies, they remain limited. Germline whole genome sequencing (WGS) was performed to identify potential hereditary causes of NSCLC within Task Force 5 of the German National Network for Genomic Medicine. Detected EGFR variants were further investigated using in silico structural modeling and in vitro functional characterization in Ba/F3 cell models to investigate their oncogenic potential and sensitivity to tyrosine kinase inhibitors (TKIs). We identified two different EGFR germline variants (NM_005228.5:c.2155G>A, p.(Gly719Ser); NM_005228.5: c.2327G>A, p.(Arg776His)) in three patients with NSCLC, each harboring a different somatic compound variants (p.(Gly719Ser)+p.(Ser768Ile), p.(Gly719Ala)+p.(Arg776His), p.(Arg776His)+p.(Leu861Gln) (liver metastasis) and p.(Arg776His)+p.(Gly719Ser)). In silico analyses predict that p.(Gly719Ser) and p.(Gly719Ala) stabilize the active EGFR kinase conformation, whereas p.(Ser768Ile), p.(Arg776His) and p.(Leu861Gln) destabilize the inactive conformation. Consistent with these predictions, cis co-expression of the compound variants in the Ba/F3 assay demonstrated oncogenic activity and sensitivity to afatinib. Clinically two individuals achieved a partial response to afatinib treatment. These findings highlight the clinical relevance of germline EGFR variants in NSCLC and support the value of in-silico and in-vitro analyses for variant interpretation and response prediction. Broadening germline testing and functional variant characterization may enhance risk prediction and targeted therapy for individuals with NSCLC.

Capillary leak syndrome (CLS) is a rare but potentially life-threatening condition characterized by generalized edema, hypotension, and hypoalbuminemia. Amivantamab has recently been approved for the management of metastatic NSCLC. Although peripheral edema has been reported with amivantamab, CLS has not previously been described in association with this treatment. Herein, we report a case of CLS attributed to amivantamab that resolved after drug discontinuation and a short course of high-dose intravenous immunoglobulin administration. The anti-inflammatory, neutralizing, and antibody clearance-accelerating effects of intravenous immunoglobulin may explain their potential efficacy in treating amivantamab-induced CLS. As therapeutic antibodies become increasingly used, CLS may be encountered more frequently. A better understanding of its pathophysiologic characteristics is therefore essential to develop effective treatments and preventive strategies, ultimately minimizing its consequences on patient outcomes.

In its 20-year history, the Journal of Thoracic Oncology (JTO) has published many major articles that have had a profound impact on the pathology of thoracic malignancies. One reason JTO has had such a great influence on thoracic oncology is the visionary leadership of the International Association for the Study of Lung Cancer (IASLC), which emphasizes an international, multidisciplinary approach across all its endeavors. JTO is one of the most important initiatives of the IASLC, and its global scope, encompassing all specialties, has enabled many pathologists to play a important role in the journal. This is reflected in the participation of multiple pathologists on the editorial board and in the prioritization of publishing impactful articles led by pathologists. This has been a good investment for JTO and IASLC, because eight of the top 20 most cited articles in the journal in the past 20 years were led by pathologists. This article reviews the many advances published in JTO, most of which concern lung cancer, mesothelioma, thymic tumors, and cardiac tumors. During this period, many breakthroughs occurred in surgical pathology, small biopsy and cytology, management of lung cancer after neoadjuvant therapy, molecular genetics, and biomarker testing. Many of these advances have had a direct impact on patient care, providing new ways to stratify patients for therapeutic management decisions.