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.

FOLFIRINOX treatment for pancreatic cancer often causes severe neutropenia, leading to dose reductions and potentially fatal outcomes. Despite this, high-level evidence supporting pegylated granulocyte colony-stimulating factor (peg-GCSF) as the primary prophylaxis is lacking. This study aimed to determine whether primary prophylaxis of peg-GCSF can prevent severe neutropenia in patients with pancreatic cancer treated with modified-(m)FOLFIRINOX. This was an investigator-initiated, open-label, multi-institutional, randomized phase 2 trial in patients aged ≥19 years with treatment-naïve locally advanced or metastatic pancreatic cancer. Patients received oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 150 mg/m², and fluorouracil 2400 mg/m² via continuous infusion, every other week. After 1:1 randomization, peg-GCSF (pegteograstim 6 mg, GC Biopharma Corp.) was subcutaneously administered on day 4 for the initial eight cycles for the primary prophylaxis group, whereas no G-CSF was given to the control group. Crossover to administering peg-GCSF was permitted if patients in the control group developed grade 3–4 neutropenia during the initial eight cycles. Co-primary endpoints were grade 3–4 neutropenia or febrile neutropenia within the first eight cycles. Secondary endpoints included survival, relative dose intensity, patient-reported quality of life (QOL), and bone pain. This trial is registered with the CRIS (KCT0006536) and ClinicalTrials.gov (NCT06353581). Seventy-seven patients were enrolled from February 2022 to January 2024, with 38 in the peg-GCSF primary prophylaxis group and 39 in the control group. The primary endpoints were achieved, with significantly lower grade 3–4 neutropenia in the peg-GCSF group (2.6% vs. 38.5%, P = 0.0001) compared to the control group, and febrile neutropenia occurring only in controls (12.8%). With a median follow-up duration of 19.7 months, survival outcomes favored peg-GCSF, although not statistically significant. The adjusted mean change of global health status or QOL scores were significantly higher for the peg-GCSF primary prophylaxis group than for the control group (P = 0.0264), without an increase in reported bone pain. Survival, QOL, and bone pain were secondary endpoints. Peg-GCSF primary prophylaxis significantly reduced grade 3–4 neutropenia and febrile neutropenia in patients with locally advanced or metastatic pancreatic cancer treated with mFOLFIRINOX. Peg-GCSF primary prophylaxis also provided a numerical survival benefit with better patient-reported QOL. This study provides a rationale for peg-GCSF primary prophylaxis in patients with pancreatic cancer treated with mFOLFIRINOX. GC Biopharma Corp.; Severance Hospital Research Fund for Clinical Excellence; 10.13039/501100003725 National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT).

Sang Hun Lee, Do Young Kim, Hyo Jung Kim, Young Mi Seol, Young Jin Choi. Med Biol Sci Eng 2024;7:47-50. https://doi.org/10.30579/mbse.2024.7.1.47

Sang Hun Lee, Young Jin Choi, Young Mi Seol. Med Biol Sci Eng 2025;8:33-9. https://doi.org/10.30579/mbse.2025.8.1.33

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

Acute myeloid leukemia (AML) is a type of hematological malignancy with a poor prognosis caused by diverse genetic mutations. One effective treatment approach is to induce the differentiation of AML cells, which may help curb their unrestrained proliferation. In search of novel differentiation-inducing drug candidates, a phenotypic screen of a chemical library was performed, and Azvudine, a new anti-HIV agent approved by the China FDA in 2021, was identified as the most effective agent. Azvudine efficiently drove differentiation in multiple human AML cell lines, which was strongly associated with G2/M cell cycle arrest and apoptosis in vitro. In vivo analyses using murine xenograft models showed that this drug efficiently stimulated the differentiation of AML cells, diminished the tumor burden and metastasis, and prolonged the survival of mice. Importantly, the anti-leukemic effects of Azvudine were recapitulated in AML patient samples with various mutations, including TP53, a genetic lesion associated with adverse risk. Mechanistic studies showed that the inhibitory activity of Azvudine was directed mainly against telomerase reverse transcriptase (TERT), causing telomerase dysfunction and telomere shortening. This was accompanied by a DNA damage response, culminating in p21 upregulation and subsequent cellular differentiation in AML. In addition, increased ROS levels in the mitochondria by Azvudine modulated the Bcl-2 family proteins and promoted apoptosis, acting as a further anti-AML mechanism. Considering that telomerase-targeted therapies are currently under active clinical investigation, these compelling preclinical data justify the repositioning of Azvudine as an AML differentiation-inducing therapy.