ABSTRACT
Although sequence-based studies show that basal-like features lead to worse prognosis and chemotherapy-resistance compared to the classical subtype in advanced pancreatic ductal adenocarcinoma (PDAC), a surrogate biomarker distinguishing between these subtypes in routine diagnostic practice remains to be identified. We aimed to evaluate the utility of immunohistochemistry (IHC) expression subtypes generated by unsupervised hierarchical clustering based on staining scores of four markers (CK5/6, p63, GATA6, HNF4a) applied to endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) materials. EUS-FNAB materials taken from 190 treatment-naïve advanced PDAC patients were analyzed, and three IHC patterns were established (Classical, Transitional, and Basal-like pattern). Basal-like pattern (high co-expression of CK5/6 and p63 with low expression of GATA6 and HNF4a) was significantly associated with squamous differentiation histology (p < 0.001) and demonstrated the worst overall survival among our cohort (p = 0.004). IHC expression subtype (Transitional, Basal vs Classical) was an independent poor prognosticator in multivariate analysis [HR 1.58 (95% CI 1.01-2.38), p = 0.047]. Furthermore, CK5/6 expression was an independent poor prognostic factor in histological glandular type PDAC [HR 2.82 (95% CI 1.31-6.08), p = 0.008]. Our results suggest that IHC expression patterns successfully predict molecular features indicative of the Basal-like subgroup in advanced PDAC. These results provide the basis for appropriate stratification for therapeutic selection and prognostic estimation of advanced PDAC in a simplified manner.
Subject(s)
Biomarkers, Tumor , Carcinoma, Pancreatic Ductal , GATA6 Transcription Factor , Hepatocyte Nuclear Factor 4 , Immunohistochemistry , Pancreatic Neoplasms , Humans , GATA6 Transcription Factor/metabolism , GATA6 Transcription Factor/genetics , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Male , Female , Hepatocyte Nuclear Factor 4/metabolism , Hepatocyte Nuclear Factor 4/genetics , Aged , Biomarkers, Tumor/metabolism , Middle Aged , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/genetics , Prognosis , Keratin-5/metabolism , Keratin-6/metabolism , Aged, 80 and over , Adult , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Transcription Factors , Tumor Suppressor ProteinsABSTRACT
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate used for cancer treatment comprising an anti-human epidermal growth factor receptor type 2 (HER2) antibody and the topoisomerase I inhibitor DXd. The present study investigated the intratumor fate of T-DXd. Fluorescence-labeled T-DXd was found to accumulate in tumors of HER2-positive tumor xenograft mice and was observed to be distributed within lysosomes of in vitro tumor cells in accordance with their HER2 expression. DXd was released by cysteine proteases, including cathepsins, in lysosomal fractions in vitro in response to the pH. Tumor slices obtained from HER2-positive tumor xenograft mice treated with T-DXd were examined by semi-quantitative and three-dimensional immunohistochemical assays using phosphor-integrated dots, which visualized DXd-related signals in the nucleus, the site of topoisomerase I inhibition. In addition, based on the data showing the antibody component of T-DXd barely distributed in the nucleus, it was suggested that the DXd-related signals detected in the nucleus were predominantly derived from free DXd. These observations help support the mode of action of T-DXd from the perspective of drug disposition.
Subject(s)
Camptothecin , Immunoconjugates , Trastuzumab , Xenograft Model Antitumor Assays , Trastuzumab/pharmacology , Animals , Humans , Mice , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Camptothecin/metabolism , Immunoconjugates/pharmacology , Female , Mice, Nude , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/metabolism , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Cell Line, Tumor , Mice, Inbred BALB C , Antineoplastic Agents, Immunological/pharmacologySubject(s)
Ovarian Neoplasms , RNA-Binding Protein FUS , Sex Cord-Gonadal Stromal Tumors , Testicular Neoplasms , Female , Humans , Biomarkers, Tumor/genetics , Oncogene Proteins, Fusion/genetics , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , RNA-Binding Protein FUS/genetics , Sex Cord-Gonadal Stromal Tumors/genetics , Sex Cord-Gonadal Stromal Tumors/pathology , Testicular Neoplasms/genetics , Testicular Neoplasms/pathology , AgedABSTRACT
Most of esophageal squamous cell carcinoma (ESCC) develop in smoking males in Japan, but the genomic etiology and immunological characteristics of rare non-smoking female ECSS remain unclear. To elucidate the genomic and immunological features of ESCC in non-smoking females, we analyzed whole-genome or transcriptome sequencing data from 94 ESCCs, including 20 rare non-smoking female cases. In addition, 31,611 immune cells were extracted from four ESCC tissues and subject to single-cell RNA-seq. We compared their immuno-genomic and microbiome profiles between non-smoking female and smoking ESCCs. Non-smoking females showed much better prognosis. Whole-genome sequencing analysis showed no significant differences in driver genes or copy number alterations depending on smoking status. The mutational signatures specifically observed in non-smoking females ESCC could be attributed to aging. Immune profiling from RNA-seq revealed that ESCC in non-smoking females had high tumor microenvironment signatures and a high abundance of eosinophils with a favorable prognosis. Single-cell RNA-sequencing of intratumor immune cells revealed gender differences of eosinophils and their activation in female cases. ESCCs in non-smoking females have age-related mutational signatures and gender-specific tumor immune environment with eosinophils, which is likely to contribute to their favorable prognosis.