Biomedical subjects

Olca Basturk

Publications and source records attributed to Olca Basturk.

3 recordsLinked to original sources

PubMed2026

Molecular and Clinical Determinants of Targeted Therapy Treatment in Biliary Tract Cancer.

PURPOSE: Actionable genomic alterations occur in all anatomic subsets of biliary tract cancer; however, targeted therapies have not shown a survival advantage over cytotoxics, and resistance mechanisms require further characterization. EXPERIMENTAL DESIGN: We analyzed a prospectively maintained cohort of 1,254 patients with histologically confirmed biliary tract cancer who underwent molecular profiling using an FDA-authorized targeted next-generation sequencing (NGS) assay. We defined actionable alterations across anatomic subsets, compared outcomes with targeted therapy versus cytotoxics, and evaluated genomic correlates of resistance using longitudinal samples. RESULTS: Overall, 59% of patients harbored at least one OncoKB alteration, and 32.2% (intrahepatic 40%, extrahepatic 15%, and gallbladder 22%) had a level 1/2 alteration. Emerging targets included KRAS alterations (17%), MTAP deletions (12.8%), MDM2 amplification (6.5%), and MET amplification (1.5%). Targeted therapy was associated with improved progression-free survival but not overall survival. Co-occurring TP53/RAS pathway and SMAD4 alterations were associated with inferior outcomes in IDH1/FGFR2-and ERBB2-driven tumors, respectively. Longitudinal profiling demonstrated ERBB2 loss in ERBB2-driven tumors, whereas IDH-, FGFR-, BRAF-, and NTRK-driven tumors retained the primary oncogenic driver. Acquired resistance was associated with alterations in RAS, MEK, MET, MYC, and CDKN2A. CONCLUSIONS: This comprehensive molecular profiling study illustrates the real-world utility and limitations of targeted NGS of biliary tract cancer and affirms the use of precision medicine in patients with these diseases. Genomic heterogeneity and therapeutic resistance observed in this study has the potential to inform ongoing drug development efforts for biliary tract cancer.

Humans↗

PubMed2026

Target Antigen Identification for Antibody Drug Conjugate Therapy in Biliary Tract Cancer.

BACKGROUND: Data on antibody-drug conjugates (ADCs) target expression prevalence, intertumoral heterogeneity, genomic concordance, and its effect on clinical outcomes is limited in biliary tract cancers (BTC). METHODS: Resected primary BTC specimens, and when available, matched metastatic samples were assembled into tissue microarrays and tested for CLDN18.2, c-MET, Nectin-4, TROP2, and HER2 expression by immunohistochemistry (IHC). A subset underwent targeted next-generation sequencing using MSK-IMPACT (NCT01775072). Exploratory associations of target expression with clinicopathologic parameters, genomic alterations, recurrence-free (RFS), and overall (OS) survival were evaluated. RESULTS: 65 patients with resected BTC and 18 paired metastatic sites were identified-43% extrahepatic cholangiocarcinoma, 40% intrahepatic cholangiocarcinoma, and 17% gallbladder cancer. All evaluated target antigens were expressed; percent positivity and H-score ≥200 were: TROP2 (83%, 26%), c-MET (75%, 26%), Nectin-4 (66%, 35%), and CLDN18.2 (46%, 7.7%). HER2 overexpression occurred in 3.1% of tumors. Overall agreement among paired primary and metastatic samples on calling either positive or negative ranged from 43% to 75% with the highest observed for HER2 [75%; κ=0.29 (95%CI: -0.32 to 0.91)] and TROP2 (71%; κ not available) and lowest for c-MET, CLDN18.2, and Nectin-4. Frequently altered genes included TP53 (36%), SMAD4 (27%), ELF3 (21%). We observed no significant association between target antigen expression with genomics, RFS, or OS. CONCLUSIONS: BTC displays frequent but heterogeneous expression of multiple ADC targets. These hypothesis generating findings suggest inherent complexity of target protein quantification, target threshold determination, and target sampling discordance. Future studies will be required to refine our understanding the utlitiy of ADCs in BTC.

Journal Article↗

PubMed2026

Intraductal Papillary Squamous Neoplasm (IPSN) of the Pancreas: Histological and Molecular Characterization of a Novel and Distinct Intraductal Cancer Precursor.

We report 6 intraductal papillary squamous neoplasms (IPSNs) of the pancreas, a rare but distinctive tumor whose biological features remain largely unknown. Five cases were investigated using an integrated approach combining histomorphological evaluation, immunohistochemistry, and multiregional molecular profiling through whole-exome DNA sequencing and whole-transcriptome RNA sequencing. Only targeted DNA sequencing was available on a sixth recently diagnosed case. Histologically, the intraductal lesions were characterized by large, confluent papillae with fibrovascular cores lined by multilayered epithelial cells with diffuse squamous differentiation. All cases harbored a concomitant invasive carcinoma. The associated invasive carcinomas consistently included a pancreatic tubular/ductal adenocarcinoma; in 5 cases, a poorly differentiated squamous cell carcinoma was also present, the proportion/features of which met the diagnostic criteria of adenosquamous carcinoma in 2 of them. Genomic analyses revealed that IPSNs and their matched invasive carcinomas shared the majority of somatic alterations, supporting a shared clonal origin for the 2 components. Activating KRAS mutations and biallelic inactivation of CDKN2A were detected in all cases. Recurrent mutations involved members of the SWI/SNF chromatin-remodeling complex and KMT2D. Additionally, FGFR1 and MYC amplifications were identified in 2 distinct cases (1 case each). Molecular alterations restricted to the invasive component involved mediators of the transforming growth factor-β signaling pathway. Transcriptomic profiling demonstrated a basal-like expression pattern in all IPSNs and squamous cell carcinomas, although in 2 cases, the matched pancreatic tubular/ductal adenocarcinoma shifted toward a classical transcriptomic subtype. In conclusion, through integrated histological assessment and multiregional molecular sequencing, we demonstrate that IPSN represents a bona fide precursor of invasive pancreatic cancer, a new addition to the intraductal neoplasms category. This study challenges the current paradigm that pancreatic squamous epithelium plays no role in the initiation of pancreatic carcinogenesis, providing the first evidence of its involvement in early tumorigenic processes and yielding immediate implications for pancreatic tumor classification and biological understanding.

Humans↗