Search Results (918)

Epidermal growth factor receptor (EGFR)-targeted therapy represents one of the earliest and most established examples of precision oncology in non-small-cell lung cancer (NSCLC), with more than 10 approved agents, including tyrosine kinase inhibitors, bispecific antibodies and antibody–drug conjugates. Over the past two decades, the diagnostic and therapeutic landscape of EGFR-mutant NSCLC has evolved from empiric treatment to mutation subtype-guided strategies, from advanced disease to earlier-stage interventions, and from monotherapy to rational combination regimens. Somatic EGFR mutations remain key predictive biomarkers guiding treatment selection, therapeutic intensification, resistance mechanism-directed treatment, and disease monitoring through plasma circulating tumor DNA burden. In parallel, germline EGFR alterations are increasingly recognized as contributors to inherited lung cancer susceptibility, particularly among never-smokers and familial clusters. Germline EGFR T790M is the best-characterized pathogenic variant, creating a permissive background for multifocal lung nodules and lung adenocarcinoma development, often following acquisition of a second somatic EGFR driver mutation. Recent familial, regional, and paired tumor–normal sequencing studies have expanded the evidence beyond isolated case reports and support an emerging hereditary lung cancer predisposition phenotype. Clinically, germline EGFR should be suspected when EGFR T790M is detected prior to TKI exposure, particularly at variant allele fractions near 50%, or in patients with multifocal ground-glass nodules, multiple primary lung adenocarcinomas, early-onset disease, never/light smoking history, or family history of lung cancer. Confirmation requires germline testing and genetic counseling. This review highlights the current knowledge, recent advances, and future directions in somatic and germline EGFR-mutant NSCLC, emphasizing translational relevance for clinicians and researchers. Full article

Urothelial carcinoma (UC) is a biologically and clinically heterogeneous disease arising from the bladder and upper urinary tract. Immune checkpoint inhibitors (ICIs) have transformed treatment of advanced UC, yet durable responses remain limited to a minority of patients, underscoring the need to better understand the tumor immune microenvironment (TME). This narrative review examines the UC immune phenotype across disease stages and anatomical sites, integrating evidence from bulk and single-cell transcriptomics, spatial profiling, and translational studies. We describe the principal immune cell populations of the UC TME—including cytotoxic and regulatory T cells, macrophages, myeloid-derived suppressor cells, natural killer cells, B cells, and dendritic cells—and their relationship to established molecular subtypes. We review how this immune landscape evolves from non-muscle-invasive to metastatic disease, including the distinct contexture of upper tract UC and variant histology. We critically evaluate established ICI biomarkers (PD-L1, FGFR3, tumor mutational burden, mismatch repair deficiency) alongside emerging candidates—tumor-infiltrating lymphocyte density, HLA class I expression, tertiary lymphoid structures, and multiparameter transcriptomic scores—noting that most remain investigational and require prospective validation before clinical use. Finally, we address key biological, technical, and clinical barriers to this research and outline future directions in AI-assisted digital pathology and multimodal biomarker integration. A comprehensive characterization of UC immune phenotype is essential to guide rational, biomarker-driven patient selection and optimize next-generation immunotherapy strategies. Full article

Background/Aim: Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase involved in cell growth, proliferation, and angiogenesis. While FGFR1–3 are well studied in cancer, FGFR4 remains relatively understudied, and the distribution of its mutations across cancers and patient populations is not well defined. Materials and Methods: A retrospective pan-cancer analysis was performed using the AACR Project GENIE v12 database via cBioPortal. Tumors with somatic FGFR4 mutations were included, excluding copy number alterations and structural variants. Mutations were grouped by hotspot (amino acid 401) and major protein domains. Comparative analyses assessed cancer type distribution, demographics, mutation burden, and co-occurring genomic alterations using chi-square testing with multiple comparison correction. Results: A total of 4565 tumor samples (4283 patients) were analyzed. FGFR4 alterations were observed across diverse malignancies, most commonly non-small cell lung cancer, colorectal cancer, and melanoma. Mutations clustered primarily in the tyrosine kinase and immunoglobulin I-set domains, with no significant variation in distribution across cancer types. Sex was not associated with the mutation group, while race and ethnicity showed significant differences. The FGFR4 hotspot 401 group demonstrated a higher mutation burden, driven by a subset of hypermutated tumors, and showed enrichment for co-occurring alterations in chromatin remodeling, DNA repair, tumor suppressor, and receptor tyrosine kinase genes; however, sensitivity analyses indicated this association was largely attributable to mutation burden rather than a mutation-specific effect. Domain-based mutation groups had lower mutation burdens and fewer co-alterations. Conclusions: FGFR4 alterations occur across a broad range of cancers with consistent domain-level patterns. The hotspot 401 mutation shows a higher mutation burden and co-alteration frequency driven largely by a subset of hypermutated tumors, rather than acting as an isolated driver. Full article

Soft tissue sarcomas (STSs) are rare and heterogeneous mesenchymal malignancies characterized by diverse molecular profiles and immune landscapes. Although immunotherapy has revolutionized the treatment of specific solid tumors, its efficacy in STSs remains limited and variable across histotypes. This review explores the panorama of biomarkers of immunotherapy sensitiveness in STSs, with particular emphasis on tumor-intrinsic features and on tumor microenvironment (TME) signatures. Current evidence highlights low tumor mutational burden, rare microsatellite instability, heterogeneous antigen expression, and epigenetic suppression of antigen presentation as hallmarks of the immune resistance that is characteristic of many STSs. However, growing evidence underlines TME composition as a major determinant of response to different types of immunotherapy. Indeed, the presence of B-cell-rich tertiary lymphoid structures and certain traits of adaptive immune responses are provenly associated with enhanced sensitivity to immunotherapy and enhanced outcomes. We further discuss emerging strategies aimed at enhancing STS immunogenicity, either by increasing intrinsic tumor immunogenicity or remodeling TME composition and functional profile. Collectively, the available data support a paradigm shift from a sarcoma cell-centered approach toward a multi-compartment TME-including strategy, providing a framework for the development of more effective and personalized immunotherapeutic strategies in STS. Full article

Background/Objectives: Breast cancer (BC) remains the most frequently diagnosed malignancy among women worldwide, and patient outcome is strongly influenced by disease stage at diagnosis. Although imaging-based screening has improved early detection, its performance may be reduced in dense breast tissue and is associated with false-positive findings. In addition, tissue biopsy is invasive and unsuitable for longitudinal disease monitoring. Liquid biopsy (LB) has emerged as a minimally invasive approach for detecting tumor-derived material in peripheral blood. However, early-stage tumors typically exhibit low tumor burden and limited biomarker shedding, generating weak systemic signals that challenge reliable detection. This review examines current and emerging LB biomarkers for early BC detection. Methods: A comprehensive review of recent literature was conducted focusing on circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNAs, proteins, and other blood-based biomarkers associated with early BC. Studies addressing biomarker biology, detection technologies, clinical applications, and methodological limitations were critically evaluated. Results: ctDNA, CTCs, EVs, circulating RNAs, proteins, and additional blood-based biomarkers capture distinct aspects of tumor biology and disease evolution. ctDNA enables the analysis of tumor-specific mutations, methylation patterns, and fragmentation profiles, whereas CTCs provide direct cellular and phenotypic information despite their rarity and marked epithelial–mesenchymal plasticity. EVs offer increased molecular stability and actively participate in tumor progression, immune modulation, and metastatic niche formation. Nevertheless, low biomarker abundance, biological heterogeneity, technical variability, and background biological noise continue to limit analytical performance, particularly in early-stage disease. Current evidence further suggests that no single biomarker consistently provides sufficient sensitivity and specificity for reliable early BC detection. Conclusions: LB represents a promising strategy for non-invasive early BC detection. Future clinical implementation will likely depend on integrated multi-analyte approaches that combine complementary genomic, transcriptomic, proteomic, and cellular information, supported by multi-omics technologies and artificial intelligence-based analytical frameworks. Full article

Liver transplantation (LT) has re-emerged as a potentially curative treatment for carefully selected patients with unresectable, liver-only colorectal liver metastases (CRLM). Prospective trials (SECA-I/II) demonstrated 5-year overall survival (OS) rates of 60–83% in selected patients, findings recently corroborated by the randomized TransMet trial, which showed superior 5-year OS with LT compared with chemotherapy alone. Favorable outcomes depend on rigorous patient selection integrating clinical risk stratification (Oslo Score), tumor burden assessed by metabolic tumor volume on FDG-PET-CT, and molecular profiling, while excluding high-risk features such as BRAF V600E and RAS/TP53 co-mutations. Broader implementation raises ethical challenges related to organ allocation, driving interest in alternative strategies including living-donor LT and innovative procedures such as RAPID. This narrative review summarizes evolving evidence supporting LT for CRLM, current approaches to patient selection, oncological outcomes, and practical considerations for implementing LT into contemporary HPB and transplant practice. Full article

Background/Objectives: Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has undergone rapid therapeutic evolution. However, heterogeneous outcomes persist, driven by mutations, central nervous system (CNS) involvement, and dynamic tumor burden reflected in part by circulating tumor DNA (ctDNA). As such, this review aims to summarize the most recent risk stratification frameworks in treating EGFR-mutant NSCLC, evaluate evidence supporting treatment intensification strategies and managing adverse effects, and explore the evolving role of ctDNA in guiding personalized therapy. Methods: A comprehensive literature search was conducted using major medical databases with a focus on key relevant studies on the workup and management of EGFR-mutant NSCLC. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Molecular co-alterations, such as TP53 and RB1, as well as central nervous system (CNS) involvement, are consistently associated with inferior outcomes, supporting consideration of upfront treatment intensification. Combination strategies, including osimertinib plus chemotherapy or amivantamab-based regimens, demonstrate improved progression-free survival and delayed CNS progression when compared against osimertinib monotherapy. Intensification, however, is associated with a higher risk of increased toxicity, including dermatologic adverse events and infusion-related reactions. Finally, the utilization of circulating tumor DNA (ctDNA) has emerged as a strong prognostic marker, with ongoing trials investigating its predictive role for both escalation and de-escalation of therapy. Conclusions: The treatment paradigm for EGFR-mutant NSCLC is gradually evolving beyond first-line osimertinib to include a more integrated approach that considers molecular features, CNS involvement, and early ctDNA response. Although intensified regimens offer meaningful efficacy gains for high-risk patients, proactive toxicity management is essential to preserving quality of life. ctDNA-guided strategies represent a new and promising frontier for escalation and de-escalation of therapy, with results from ongoing trials poised to further refine personalized treatment algorithms. Full article

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma and is characterized by pronounced molecular heterogeneity that is not always fully captured by standard histopathological assessment. Circulating tumor DNA (ctDNA) is increasingly regarded as a promising liquid-biopsy biomarker that enables non-invasive molecular tumor profiling, assessment of tumor burden, dynamic monitoring of treatment response, and detection of measurable/minimal residual disease (MRD). Modern analytical platforms, ranging from PCR-based assays to next-generation sequencing approaches, including CAPP-Seq and PhasED-Seq, have substantially expanded the possibilities of molecular monitoring in DLBCL. This review summarizes current data on the biological characteristics of ctDNA, contemporary methods for its analysis, concordance between ctDNA and tumor-tissue mutational profiles, and the clinical significance of baseline ctDNA levels, early molecular response, post-treatment MRD status, and molecular surveillance during remission. Special attention is given to ctDNA monitoring in patients receiving novel immunotherapies, including CAR-T cell therapy, bispecific antibodies, and antibody–drug conjugates. Emerging multi-omic approaches integrating genomic, epigenomic, and fragmentomic data are discussed as promising future directions. Key limitations of clinical implementation include insufficient standardization of preanalytical and analytical workflows, the confounding effect of clonal hematopoiesis of indeterminate potential, variability across technological platforms, and the lack of completed prospective randomized interventional studies demonstrating improved outcomes when therapy is modified according to ctDNA status. Overall, ctDNA is currently a highly informative prognostic biomarker in DLBCL; however, its full implementation as a predictive tool for treatment selection requires further harmonization, prospective validation, and confirmation in interventional clinical trials. Full article

Background: Bone and soft-tissue sarcomas are rare, heterogeneous malignancies whose surveillance remains dominated by imaging despite substantial molecular diversity and variable patterns of relapse. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) offer minimally invasive approaches for monitoring tumor biology, but their performance in sarcoma depends strongly on subtype, disease burden, assay design, and biological shedding. Methods: This narrative review synthesizes evidence published from 2015 to 2026 on ctDNA and CTCs for baseline risk assessment, treatment-response monitoring, minimal residual disease (MRD) detection, molecular relapse, and integration with imaging-based surveillance in bone and soft-tissue sarcomas. Results: Current evidence supports a genomics-guided framework in which liquid-biopsy strategy is selected according to sarcoma subtype, molecular architecture, and clinical purpose. ctDNA is the most mature analyte, with best-supported evidence in osteosarcoma, where tumor-informed assays predict postoperative relapse, and in translocation-associated sarcomas, where breakpoint-guided assays enable highly specific longitudinal monitoring. Copy-number-based approaches are relevant for complex-karyotype tumors, while mutation-, methylation-, fragmentomic-, and RNA-based strategies may be useful in selected contexts. However, detection rates vary, false-negative results occur in low-shedding or low-volume disease, and clinical utility for changing treatment remains incompletely established. CTCs provide complementary cellular and prognostic information, particularly in osteosarcoma, but remain limited by platform heterogeneity and incomplete standardization. Conclusion: Liquid biopsy may refine risk stratification, support treatment-response assessment, clarify indeterminate imaging findings, and identify molecular relapse in selected sarcoma patients. At present, it should be interpreted as an adjunct to imaging and specialist multidisciplinary care rather than as a replacement for standard radiologic surveillance. Full article

Background: Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has improved outcomes in non-small cell lung cancer (NSCLC), although reliable biomarkers for predicting benefit are still limited. Methods: In this exploratory study, we conducted a longitudinal analysis of the peripheral T-cell receptor (TCR) β repertoire in 28 patients with unresectable stage IIIb non-small cell lung cancer (NSCLC) who received anti-PD-L1 immunotherapy following chemoradiotherapy. Blood samples were collected at baseline and three months after treatment initiation. Results: At the cohort level, global TCR repertoire features such as diversity and richness did not change significantly over time. However, when looking at individual patients, more specific patterns became evident. Patients could be broadly separated based on changes in clonotype richness, with reductions generally accompanied by lower diversity and decreased convergent TCR frequency. We also observed differences in TRBV gene usage in relation to clinical outcome, with higher TRBV20-1 and lower TRBV28 frequencies tending to associate with improved survival and delayed disease progression. Interestingly, the disappearance of dominant clonotypes from the peripheral blood during treatment was linked to longer progression-free survival (PFS). In addition, patients with higher baseline blood plasma tumor mutational burden (bTMB) showed greater clonotype richness and were more likely to exhibit this clonotype loss. The combination of high bTMB and clonotype disappearance identified a subgroup of patients with particularly favorable outcomes. Conclusions: Overall, these results suggest that early responses to PD-L1 blockade may be reflected less in global TCR repertoire shifts, including clonality and diversity measures, and more in subtle changes in clonotype composition and dynamics, since the frequencies of certain TRBV genes and the disappearance of dominant clonotypes following ICB were associated with clinical outcomes integrating TCR profiling with bTMB and could therefore help refine patient stratification and improve the understanding of immune responses in NSCLC. Nevertheless, due to the small number of recruited patients, our study is exploratory and hypothesis-generating, and further validation in larger patient cohorts is warranted. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies widely used for the treatment of colorectal cancers. However, due to various mechanisms of resistance to these targeted therapies, the patients’ responses vary. These resistances remain a major obstacle in treatment and overcoming them has become a key emphasis of current therapeutic strategies. Intrinsic and acquired resistance often lead to reactivation of downstream signaling pathways, mainly the RAS-RAF-MEK-ERK (MAPK pathway) and PI3K-AKT axes. Prior existing mutations in KRAS, NRAS, and BRAF result in primary resistance by constantly activating the signals, irrespective of EGFR inhibition. That said, acquired resistance manifests under therapeutic burden through the process of clonal evolution via KRAS and BRAF alterations, restoring MAPK pathway activity despite EGFR inhibition. In addition to those mutations, tumor cells exploit mechanisms independent of EGFR, such as the pathway bypass, which includes amplification of ERBB family receptors like HER2 (ERBB2) and activation of MET signaling. To overcome these resistances, novel strategies have emerged, which target multiple nodes within the oncogenic networks. Such methods include vertical pathway inhibition, multi-kinase inhibition, liquid-biopsy-guided therapy, and anti-EGFR rechallenge. Reactivation driven by secondary mutation can be prevented by targeting multiple nodes within the MAPK cascade simultaneously, which is referred to as the vertical pathway inhibition. Overall, this review underscores that overcoming therapeutic resistance requires a multidimensional approach that integrates molecular profiling, rational combination therapies, and adaptive treatment. Finally, these advances underscore the shift toward precision oncology, where therapy is tailored to tumor evolution, leading to improved response and patient outcome. Full article

Background: Early recurrence following curative-intent hepatectomy for colorectal liver metastases (CRLMs) remains a significant clinical challenge. This study investigates risk factors for recurrence within 6 and 12 months and evaluates the impact of salvage surgery on long-term survival. Methods: We conducted a retrospective cohort study of 109 patients who underwent liver resection for CRLMs between 2013 and 2024. The primary outcome was the identification of predictors for early recurrence using Cox proportional-hazards models. The secondary outcomes focused on overall survival (OS) stratified by the timing of recurrence and subsequent treatment. Results: High tumor burden (>4 metastases) was an independent predictor of recurrence at both 6 months (HR 3.526; p = 0.008) and 12 months (HR 3.115; p = 0.004). Intraoperative blood loss >1000 mL was significantly associated with 6-month recurrence (HR 3.356; p = 0.004) and 12-month recurrence (HR 2.171; p = 0.041). For the 12-month window, independent predictors included AJCC T3/T4 stage (HR 6.513; p = 0.011) and RAS mutation (HR 2.740; p = 0.006). Notably, patients with early recurrence who underwent salvage re-hepatectomy achieved 5-year OS rates that did not statistically differ from those without recurrence (p = 0.907 for <6 months; p = 0.433 for <12 months); however, these subgroup analyses are highly underpowered. Conclusions: High tumor burden (>4 metastases), RAS mutations, significant blood loss (>1000 mL), and primary tumor T3/T4 identify patients at high risk for early recurrence. While aggressive salvage re-hepatectomy is associated with prolonged survival in select patients, the non-significant p-values in our small salvage cohorts cannot be interpreted as evidence of survival equivalence. The observed survival benefits in the salvage cohort are heavily confounded by inherent selection biases, and therefore, the true extent of this ‘rescue’ effect must be interpreted with extreme caution and validated in larger, adequately powered multicenter studies. Full article

Circulating tumor DNA (ctDNA) was initially conceived as a minimally invasive surrogate for interrogating cancer biology; however, three decades of evidence have demonstrated that plasma is not a passive reservoir of tumor-derived material, but rather a dynamic and biologically heterogeneous milieu in which multiple competing genomic signals coexist. This review explores the level of interpretive rigor required to translate ctDNA detection into clinically actionable precision oncology. Clonal hematopoiesis of indeterminate potential (CHIP) is discussed not as an occasional confounder, but as an intrinsic source of biological background noise, underscoring the critical importance of matched leukocyte sequencing to discriminate tumor-derived alterations from hematopoietic variants, particularly in older individuals and in patients previously exposed to cytotoxic therapies. The widespread assumption that variant allele frequency (VAF) directly reflects tumor burden is critically re-evaluated through the mathematical relationships linking VAF to tumor fraction, local copy-number architecture, and mutation multiplicity. Within this framework, estimation of cancer cell fraction (CCF) and probabilistic discrimination between clonal and subclonal events are examined, including the emergence of reversion mutations as molecular evidence of therapy-driven evolutionary adaptation. The review also addresses the central paradox of ultra-sensitive sequencing technologies: although unique molecular identifiers and duplex sequencing can extend analytical sensitivity below 0.01% VAF, sensitivity in the absence of contextual specificity risks conflating technical artifacts and biologically insignificant alterations with clinically meaningful disease. Equal emphasis is placed on pre-analytical variables, highlighting how sample collection, stabilization, and processing protocols define the upper limit of downstream analytical reliability. Beyond single-nucleotide variants, fragmentomic and methylation-based approaches are presented as complementary orthogonal dimensions capable of revealing tumor-associated signals even when mutational evidence is limited or absent. Longitudinal ctDNA assessment is argued to provide substantially greater biological and clinical insight than isolated static measurements, while robust clinical reporting is shown to depend on transparent disclosure of assay limitations, residual uncertainty related to CHIP, and structured bidirectional communication between molecular laboratories and treating clinicians. Ultimately, the transition from a biomarker-centered model toward an integrated systems-based framework, combining genomics, epigenomics, fragmentomics, and evolutionary modeling, emerges as the defining challenge for the next generation of liquid biopsy in precision oncology. Full article

Squamous cell lung cancer (SqCLC) accounts for 20–30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10–15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1–3% and HER2 amplifications observed roughly in 2–4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC. Full article