The recent approval of trastuzumab deruxtecan for human epidermal growth factor receptor 2 (HER2)–low and HER2-ultralow breast cancer mandates an adequate assessment of these categories. Methods: Seven breast pathologists from the Breast Pathology Study Group of the Korean Society of Pathologists held an on-site expert consensus meeting. Fifteen sets of virtual whole slide images (WSI) of hematoxylin and eosin stain and HER2 immunohistochemistry were provided. The pathologists were given 60 minutes to submit their diagnosis of HER2 expression into null, ultralow, 1+, 2+, or 3+. Afterwards, in-depth discussion and consensus diagnoses were made by real-time visualization of the WSI. Results: After the consensus meeting, unanimous 100% agreements were seen only in five (33.3%) of the examined cases, which consisted of three 1+ cases and two 2+ cases. Two cases (13.3%) had mild disagreement, with only one pathologist’s disagreement. Of note, eight cases (53.3%) showed significant disagreement, defined by more than two pathologists’ disagreement. All HER2-null cases were reclassified as ultralow after consensus review, suggesting potential widespread underclassification of ultralow cases in clinical practice. Conclusions: Experts had significant discrepancies in interpreting HER2-low/ultralow status. It is important to assess if the distinction between HER2-low and ultralow is strictly required and if HER2-null breast cancer exists in reality.

Purpose: Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in various malignancies, including breast and gastric cancers, and is associated with poor prognosis. Although HER2-targeted therapies, such as trastuzumab, improve outcomes in HER2-positive tumors, resistance often develops, and HER2-low tumors remain largely untargeted. Trastuzumab deruxtecan (T-DXd; DS-8201a) is a HER2-targeted antibody-drug conjugate with potent activity in HER2-positive and HER2-low tumors. This study evaluates its antitumor mechanisms and efficacy in HER2-positive, HER2-low, and homologous recombination deficiency (HRD)–associated models. Materials and Methods: Effects of T-DXd were assessed in cancer cell lines with diverse HER2 expression and HRD status. In vivo efficacy was evaluated using a xenograft model derived from HER2-low SNU-601 gastric cancer cells. Results: T-DXd reduced HER2 phosphorylation and downstream signaling (AKT, ERK) in HER2-positive cells. It induced DNA damage accumulation, as evidenced by increased γH2AX and p-Chk1 expression, and triggered apoptosis through cleaved poly(ADP-ribose) polymerase and caspase-3 activation, confirmed by annexin V staining. Similar effects were observed in HER2-low cells, with greater sensitivity in HRD cells. In xenografts, T-DXd reduced tumor volume by up to 80% at 4 mg/kg and 10 mg/kg. Histological analyses showed decreased Ki-67 and increased apoptosis. Furthermore, T-DXd induced G2/M cell cycle arrest and nuclear anaplasia, suggesting disruption of chromosomal stability as a potential antitumor mechanism. No significant toxicity, including body weight loss, was observed. Conclusion These findings highlight T-DXd’s effectiveness in HER2-low and HRD tumors, supporting its broader clinical application, including strategies targeting DNA damage repair pathways.

Human epidermal growth factor receptor 2 (HER2) has evolved from a poor prognostic factor to one of the most impactful predictive biomarkers in oncology. The introduction of trastuzumab established HER2 as a binary determinant of therapy, with HER2 immunohistochemistry (IHC) becoming the treatment-guiding diagnostic assay. However, the emergence of antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan, has challenged this paradigm by demonstrating activity in tumors with low and even ultralow HER2 expression. This review outlines the evolution of HER2 testing, from its historical discovery and early assay variability to the ADC era, where categories such as HER2-low and HER2-ultralow have emerged. We highlight key challenges: poor reproducibility at the lower end of IHC scoring, instability of HER2 status across timepoints and between primary and metastatic tumors, and no consistent biological distinction between low, ultralow, and null. Efforts to improve reliability—including structured training, high-sensitivity assays, RNA-based methods, and artificial intelligence-assisted pathology—are summarized. Finally, we reconsider the therapeutic implications of ADCs, with the question of whether the benefit parallels HER2 expression or extends into HER2-null disease. HER2 exemplifies how biomarker interpretation evolves with drug development. As new ADCs target additional antigens, pathologists must balance trial-driven categories with biologic reproducibility to ensure diagnostics remain aligned with therapeutic advances.

Purpose: Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world. Materials and Methods: We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform—FiRST Cancer Panel (FCP)—over 7 years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis. Results: NGS tests were conducted on 548 samples from 522 patients with BC. Ninety-seven point six percentage of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53 (56.2%), PIK3CA (31.2%), GATA3 (13.8%), BRCA2 (10.2%), and amplifications of CCND1 (10.8%), FGF19 (10.0%), and ERBB2 (9.5%). NGS analysis of ERBB2 amplification correlated well with human epidermal growth factor receptor 2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. Ten point three percent of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs. Conclusion Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.

Purpose: It is well known that the majority of the extranodal marginal zone lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas) are associated with microbiota, e.g., gastric MALT lymphoma with Helicobacter pylori. In general, they are very sensitive to low-dose radiotherapy and chemotherapeutic agents. The microbiota profile is not clearly elucidated in bronchus-associated lymphoid tissue (BALT) lymphoma, a rare type of MALT lymphoma in the lung. Thus, this study aimed to clarify the intratumor microbiome in BALT lymphoma using the third-generation next-generation sequencing (NGS) method. Materials and Methods: DNAs were extracted from 12 formalin-fixed paraffin-embedded (FFPE) tumor tissues obtained from BALT lymphoma patients diagnosed between 1990 and 2016. 16S rRNA gene was amplified by polymerase chain reaction. Amplicons were sequenced using a Nanopore platform. Next-generation sequencing analysis was performed to assess microbial profiles. For comparison, FFPE specimens from nine non-cancerous lung tissues were also analyzed. Results: Specific bacterial families including Burkholderiaceae, Bacillaceae, and Microbacteriaceae were associated with BALT lymphoma by a linear discriminant analysis effect size approach. Although the number of specimens was limited, BALT lymphomas exhibited significantly higher microbial abundance and diversity with distinct microbial composition patterns and correlation networks than non-cancerous lung tissues. Conclusion This study provides the first insight into intratumor microbiome in BALT lymphoma using the third-generation NGS method. A distinct microbial composition suggests the presence of a unique tumor microenvironment of BALT lymphoma.

Purpose: Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world. Materials and Methods: We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform—FiRST Cancer Panel (FCP)—over 7 years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis. Results: NGS tests were conducted on 548 samples from 522 patients with BC. Ninety-seven point six percentage of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53 (56.2%), PIK3CA (31.2%), GATA3 (13.8%), BRCA2 (10.2%), and amplifications of CCND1 (10.8%), FGF19 (10.0%), and ERBB2 (9.5%). NGS analysis of ERBB2 amplification correlated well with human epidermal growth factor receptor 2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. Ten point three percent of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs. Conclusion Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.

Purpose: It is well known that the majority of the extranodal marginal zone lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas) are associated with microbiota, e.g., gastric MALT lymphoma with Helicobacter pylori. In general, they are very sensitive to low-dose radiotherapy and chemotherapeutic agents. The microbiota profile is not clearly elucidated in bronchus-associated lymphoid tissue (BALT) lymphoma, a rare type of MALT lymphoma in the lung. Thus, this study aimed to clarify the intratumor microbiome in BALT lymphoma using the third-generation next-generation sequencing (NGS) method. Materials and Methods: DNAs were extracted from 12 formalin-fixed paraffin-embedded (FFPE) tumor tissues obtained from BALT lymphoma patients diagnosed between 1990 and 2016. 16S rRNA gene was amplified by polymerase chain reaction. Amplicons were sequenced using a Nanopore platform. Next-generation sequencing analysis was performed to assess microbial profiles. For comparison, FFPE specimens from nine non-cancerous lung tissues were also analyzed. Results: Specific bacterial families including Burkholderiaceae, Bacillaceae, and Microbacteriaceae were associated with BALT lymphoma by a linear discriminant analysis effect size approach. Although the number of specimens was limited, BALT lymphomas exhibited significantly higher microbial abundance and diversity with distinct microbial composition patterns and correlation networks than non-cancerous lung tissues. Conclusion This study provides the first insight into intratumor microbiome in BALT lymphoma using the third-generation NGS method. A distinct microbial composition suggests the presence of a unique tumor microenvironment of BALT lymphoma.

Background: Liver transplantation (LT) is the standard treatment for end-stage liver disease; however, it can lead to biliary strictures in 25%–30% of cases. We aimed to develop a biodegradable stent loaded with paclitaxel that could be inserted during surgery without requiring removal. We evaluated the safety and efficacy of this stent using a porcine model. Methods: Fourteen pigs underwent simulated ischemic injury during LT, and a biodegradable paclitaxel-eluting stent was inserted after duct-to-duct anastomosis.Pigs were divided into four groups: no stent (n=3), bare stent (n=3), 300 µg paclitaxel stent (n=4), and 900 µg paclitaxel stent (n=4). After 3 months of follow-up, autopsies were conducted to obtain common bile duct tissue samples, and inflammation and fibrosis thicknesses were assessed under a microscope. Results: Most tissues had resolved the inflammatory reactions by the 3-month mark. The thinnest fibrosis thickness was observed in the 900 µg group (359.08±167.23 µm); however, no statistical significance was observed. Conclusion This study demonstrated the safety of paclitaxel-eluting biodegradable biliary stents and their positive effects on fibrosis in an ischemic bile duct porcine model. This biodegradable stent represents a potential approach for overcoming the complications associated with biliary strictures after LT.

Purpose: Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world. Materials and Methods: We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform—FiRST Cancer Panel (FCP)—over 7 years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis. Results: NGS tests were conducted on 548 samples from 522 patients with BC. Ninety-seven point six percentage of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53 (56.2%), PIK3CA (31.2%), GATA3 (13.8%), BRCA2 (10.2%), and amplifications of CCND1 (10.8%), FGF19 (10.0%), and ERBB2 (9.5%). NGS analysis of ERBB2 amplification correlated well with human epidermal growth factor receptor 2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. Ten point three percent of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs. Conclusion Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.

Purpose: It is well known that the majority of the extranodal marginal zone lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas) are associated with microbiota, e.g., gastric MALT lymphoma with Helicobacter pylori. In general, they are very sensitive to low-dose radiotherapy and chemotherapeutic agents. The microbiota profile is not clearly elucidated in bronchus-associated lymphoid tissue (BALT) lymphoma, a rare type of MALT lymphoma in the lung. Thus, this study aimed to clarify the intratumor microbiome in BALT lymphoma using the third-generation next-generation sequencing (NGS) method. Materials and Methods: DNAs were extracted from 12 formalin-fixed paraffin-embedded (FFPE) tumor tissues obtained from BALT lymphoma patients diagnosed between 1990 and 2016. 16S rRNA gene was amplified by polymerase chain reaction. Amplicons were sequenced using a Nanopore platform. Next-generation sequencing analysis was performed to assess microbial profiles. For comparison, FFPE specimens from nine non-cancerous lung tissues were also analyzed. Results: Specific bacterial families including Burkholderiaceae, Bacillaceae, and Microbacteriaceae were associated with BALT lymphoma by a linear discriminant analysis effect size approach. Although the number of specimens was limited, BALT lymphomas exhibited significantly higher microbial abundance and diversity with distinct microbial composition patterns and correlation networks than non-cancerous lung tissues. Conclusion This study provides the first insight into intratumor microbiome in BALT lymphoma using the third-generation NGS method. A distinct microbial composition suggests the presence of a unique tumor microenvironment of BALT lymphoma.