Chang Gon Kim

Clinical and Molecular Hepatology

Background: Central nervous system (CNS) involvement remains a major cause of mortality in patients with epidermal growth factor receptor (EGFR)‐mutated nonsmall cell lung cancer (NSCLC), particularly, after progression on EGFR tyrosine kinase inhibitors (TKIs). This pooled analysis evaluated the efficacy of lazertinib in patients with EGFR ‐mutated NSCLC and CNS involvement, using data from two Phase II trials. Patients and Methods: Patients with EGFR ‐mutated NSCLC and CNS involvement following prior EGFR TKI therapy enrolled in the KCSG‐LU20‐15 and KCSG‐LU21‐01 were included. Overall and intracranial objective response rate (ORR), disease control rate (DCR), and progression‐free survival (PFS) were assessed. Results: Seventy‐two patients were included. The median age was 63 years and 45 patients (62.5%) had leptomeningeal metastases (LM). T790M status was positive in 7 patients, negative in 44, and unknown in 21. Intracranial tumor responses were evaluable in 46 patients; the intracranial ORR was 50.0%, and the intracranial DCR was 97.8%. The median intracranial PFS was 15.2 months. Among 66 patients evaluable for systemic response, the overall ORR and DCR were 22.7% and 97.0%, respectively. The median PFS and overall survival were 10.6 and 17.8 months, respectively. Patients with LM experienced inferior OS and intracranial PFS compared with those without LM. No significant differences in clinical outcomes were observed according to T790M status. Conclusion: Lazertinib demonstrated meaningful CNS activity in patients with EGFR ‐mutated NSCLC and CNS involvement after prior EGFR TKI exposure, including those with LM. Notably, this activity was observed in a cohort with a low prevalence of confirmed T790M positivity.

Purpose: This study aimed to evaluate the prognostic significance of GATA6 alterations in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel after androgen receptor pathway inhibitor (ARPI) failure.Materials and Methods: In this retrospective exploratory cohort study, patients with mCRPC who received docetaxel after prior ARPI therapy were included. Clinical and genomic data were reviewed, and Cox proportional hazards models were used to evaluate the prognostic impact of genomic alterations present in ≥5% of the cohort.Results: A total of 90 patients were analyzed (median age, 70.5 years; median follow-up, 17.7 months). GATA6 alteration was identified in 5 patients (5.6% of the cohort). In the gene-only analysis, GATA6 alteration was associated with shorter radiographic progression-free survival (rPFS) in both univariate (hazard ratio [HR], 7.44; 95% confidence interval [CI], 2.72–20.33; p<0.001) and multivariate models (HR, 5.15; 95% CI, 1.70–15.62; p=0.004). After adjustment for relevant clinical variables, GATA6 alteration remained significantly associated with shorter rPFS (HR, 7.38; 95% CI, 2.61–20.91; p<0.001). Kaplan-Meier analysis also showed shorter rPFS in patients with GATA6 alterations (log-rank p=0.005). GATA6 alteration was also associated with shorter prostate-specific antigen progression-free survival (PSA-PFS) in Cox analysis (HR, 7.37; p<0.001), and Kaplan- Meier analysis showed shorter PSA-PFS (log-rank p=0.037). For overall survival, GATA6 alteration showed a nonsignificant trend (HR, 2.15; p=0.106).Conclusion: GATA6 alteration was associated with shorter rPFS and PSA-PFS in this cohort and may be aprognostic biomarker of poor outcomes in patients receiving docetaxel after ARPI therapy. Further studiesare needed to validate these findings.

Programmed death‐ligand 1 (PD‐L1) blockade improves outcomes in patients with various malignancies; however, biomarkers for monitoring treatment responses are lacking. This study presents a surface‐enhanced Raman scattering (SERS)‐based platform for the ultrasensitive detection of PD‐L1 on circulating epithelial cell adhesion molecule‐positive (EpCAM ⁺ ) extracellular vesicles (EVs). The platform is validated using interferon‐gamma‐treated epithelial tumor cell line‐derived EVs. The platform is further applied to paired pre‐ and post‐treatment plasma samples from patients with non‐small‐cell lung cancer ( n = 140) and head and neck squamous cell carcinoma ( n = 73) receiving anti‐PD‐(L)1 immunotherapy. Dynamic changes in PD‐L1 expression on EV are shown to correlate with clinical outcomes. A post‐treatment decrease in PD‐L1 expression on EpCAM ⁺ EVs (EpCAM ⁺ EV PD‐L1) is associated with improved 5‐year progression‐free and overall survival. These results establish EpCAM ⁺ EV PD‐L1 as a dynamic, non‐invasive biomarker for monitoring immunotherapy responses and demonstrate the utility of SERS‐based profiling in predicting long‐term responses to immune checkpoint blockade.

Supplementary Figures and Tables

Purpose:This study aimed to evaluate the prognostic relevance of HER2 positivity and the clinical impact of anti-HER2 therapy in the management of advanced biliary tract cancers using integrated multi-institutional data.Experimental Design:This retrospective analysis included 388 patients with advanced biliary tract cancers and known HER2 status from Yonsei Cancer Center and MD Anderson Cancer Center between 2009 and 2023. HER2 positivity was defined as HER2 IHC 3+, IHC 2+ with in situ hybridization positivity, or ERBB2 amplification by next-generation sequencing. Clinical outcomes, including survival, and genomic profiling with curated oncogenic pathway enrichment were analyzed.Results:HER2 positivity was observed in 25.2% of the epidemiology analysis cohort (n = 309). In the survival analysis (n = 310), HER2-positive biliary tract cancers were associated with shorter overall survival [(OS); 13.7 vs. 17.1 months; HR, 1.25; 95% confidence interval (CI), 0.97–1.60] and significantly shorter first-line progression-free survival (5.1 vs. 7.4 months; HR, 1.91; 95% CI, 1.46–2.48) than HER2-negative biliary tract cancers. Anti-HER2 therapy significantly improved OS among HER2-positive patients (18.2 vs. 8.1 months; HR, 0.39; 95% CI, 0.21–0.62). Genomic analysis showed the strongest enrichment of angiogenesis pathway alterations in HER2-positive patients, whereas KRAS mutations were predominant in HER2-negative biliary tract cancers.Conclusions:HER2 is a clinically meaningful biomarker with prognostic and predictive relevance in advanced biliary tract cancers. Anti-HER2 therapy significantly improves survival in HER2-positive patients. These findings support routine HER2 testing, standardization of HER2 diagnostic criteria, and further prospective evaluation of HER2-targeted strategies for biliary tract cancers.See related commentary by Fitzpatrick and Harding, p. 1603

PurposeLimited treatment options exist for patients with metastatic castration-resistant prostate cancer (mCRPC) after the failure of taxane-based chemotherapy and novel hormonal therapy. Here, we report the safety and efficacy of ifosfamide and mesna in patients with mCRPC after the failure of taxane-based chemotherapy and novel hormonal therapy (NCT06236789).Materials and MethodsPatients with histologically confirmed prostate cancer who had failed taxane-based chemotherapy and novel hormonal therapy received ifosfamide 2,500 mg/m2 and mesna 1,500 mg/m2 on days 1–3, repeated every 21 days. Safety, objective response rate, disease control rate, reduction in serum prostate-specific antigen (PSA) concentration by >50% (PSA50) or >90% (PSA90), radiographic progression-free survival (rPFS), and overall survival (OS) were analyzed.ResultsA total of 47 patients with mCRPC were included in the study. The median number of lines of treatment was 5 (range, 3 to 7). All patients were previously administered docetaxel and novel hormonal therapies including abiraterone (51.1%) and/or enzalutamide (61.7%). Thirty-eight patients (80.9%) were administered cabazitaxel. The objective response and disease control rates were 21.3% and 80.9%, respectively. PSA50 and PSA90 were achieved in 31.9% and 10.6%, respectively. During a median follow-up duration of 54.3 months, rPFS and OS were 5.0 and 9.0 months, respectively. All the patients experienced treatment-related adverse events of any grades; however, no new safety signs were detected. Genomic biomarker analysis revealed that alterations in the TP53 pathway were associated with inferior rPFS and OS.ConclusionIfosfamide and mesna showed appreciable efficacy and manageable safety profiles in heavily treated patients with mCRPC.

Background/Aims: Biliary tract cancer (BTC) is a rare malignancy with poor prognosis. We investigated genomic determinants of clinical benefit from gemcitabine, cisplatin, and nab-paclitaxel (GAP) versus gemcitabine and cisplatin (GC) in advanced BTC.Methods: Clinical and genomic data using TruSight Oncology 500 were analyzed from patients treated with GAP (N=198) or GC (N=89) as first-line therapy.Results: With a median follow-up of 33.0 months, GAP modestly improved progression-free survival (PFS) (hazard ratio [HR] 0.764; 95% confidence interval [CI] 0.591–0.989) without significant overall survival (OS) difference compared to GC. Genomic profiling revealed frequent alterations in TP53 (35.2%), KRAS (16.4%), SMAD4 (10.5%), and TNFRSF14 (10.5%), involving RTK/RAS (44.3%), TP53 (41.8%), and PI3K (20.2%) pathways. Single-gene mutations did not predict treatment benefit. However, pathway-level analysis identified PI3K pathway activation as significantly associated with inferior PFS (HR 2.148; 95% CI 1.478–3.124) and OS (HR 2.096; 95% CI 1.413–3.109) in patients receiving GAP, an effect not observed with GC. Importantly, GAP conferred clinical benefit only in patients without PI3K pathway activation, while no survival advantage was seen in those with such alterations (Pinteraction=0.023 for PFS, Pinteraction=0.003 for OS). Similar results were obtained in the independent validation cohort treated with GAP (N=103) or GC (N=64) for BTC.Conclusions: Genomic profiling using next-generation sequencing identified PI3K pathway activation as key molecular determinant that differentiates patient outcomes between GAP and GC treatments in advanced BTC.

Purpose: This study aimed to evaluate the prognostic relevance of HER2 positivity and the clinical impact of anti-HER2 therapy in the management of advanced biliary tract cancers using integrated multi-institutional data. Experimental Design: This retrospective analysis included 388 patients with advanced biliary tract cancers and known HER2 status from Yonsei Cancer Center and MD Anderson Cancer Center between 2009 and 2023. HER2 positivity was defined as HER2 IHC 3+, IHC 2+ with in situ hybridization positivity, or ERBB2 amplification by next-generation sequencing. Clinical outcomes, including survival, and genomic profiling with curated oncogenic pathway enrichment were analyzed. Results: HER2 positivity was observed in 25.2% of the epidemiology analysis cohort (n = 309). In the survival analysis (n = 310), HER2-positive biliary tract cancers were associated with shorter overall survival [(OS); 13.7 vs. 17.1 months; HR, 1.25; 95% confidence interval (CI), 0.97–1.60] and significantly shorter first-line progression-free survival (5.1 vs. 7.4 months; HR, 1.91; 95% CI, 1.46–2.48) than HER2-negative biliary tract cancers. Anti-HER2 therapy significantly improved OS among HER2-positive patients (18.2 vs. 8.1 months; HR, 0.39; 95% CI, 0.21–0.62). Genomic analysis showed the strongest enrichment of angiogenesis pathway alterations in HER2-positive patients, whereas KRAS mutations were predominant in HER2-negative biliary tract cancers. Conclusions: HER2 is a clinically meaningful biomarker with prognostic and predictive relevance in advanced biliary tract cancers. Anti-HER2 therapy significantly improves survival in HER2-positive patients. These findings support routine HER2 testing, standardization of HER2 diagnostic criteria, and further prospective evaluation of HER2-targeted strategies for biliary tract cancers.

Background: This study aimed to develop and validate a radiologic clustering model using CT imaging features to stratify clear cell renal cell carcinoma (ccRCC) patients by prognosis and identify key imaging predictors of 5-year progression free survival (PFS). Methods: This retrospective study included 164 ccRCC patients with multiphase kidney CT and next-generation sequencing (NGS) between September 2003 and October 2024. Qualitative imaging features were extracted, and unsupervised consensus clustering was performed to classify tumors based on radiologic characteristics. A nomogram-based C1 score was derived from features predictive of the high-risk cluster. Model performance was evaluated using C-index and 5-year area under the receiver operating curve (AUC). Genetic alterations and copy number variations (CNVs) were also analyzed for associations with imaging features and survival. Results: Clustering revealed two distinct radiologic subtypes. Cluster C1 characterized by aggressive behavior such as tumor heterogeneity ( p = 0.011), exophytic growth pattern ( p = 0.002), non-smooth margin ( p = 0.019), and renal sinus extension ( p = 0.016), and was independently associated with poorer 5-year PFS ( p = 0.018). The C1 score demonstrated an AUC of 0.992 for predicting cluster C1 in the test-set. Using a cutoff of 0.75, the model achieved 96.3% sensitivity and 96.4% specificity. For predicting 5-year PFS, the C1 score showed moderate performance (AUC 0.65; C-index 0.65), which improved when combined with nodal/distant metastasis and BAP1 mutation status (AUC 0.71; C-index 0.67). Conclusions: Radiologic clustering using CT features enables non-invasive prognostic stratification of ccRCC. The C1 score derived from this approach may serve as a practical tool to guide surveillance and treatment decisions. Trial registration: Retrospectively registered.