RESUMEN
PURPOSE: Pancreatic adenocarcinoma is an aggressive disease with poor clinical outcomes. Primary pancreatic tumors originating from the head of the pancreas (H) have different prognostic implications than tumors arising from the body and tail (BT). This is thought to be largely due to anatomic differences, as molecular underpinnings of survival have not been fully explored. We hypothesized that differences in the primary site of H and BT tumors might account for differential molecular outcomes and response to chemotherapy. METHODS: Retrospective data from a single high-volume academic center were analyzed for hypothesis generation. A large-scale, real-world retrospective cohort of 2015 patients with next-generation sequencing (NGS) results were analyzed from a Real-World Evidence database. Progression-free survival (PFS) was evaluated from the initiation of first line of therapy for advanced disease until discontinuation because of progression. HR and P values were computed via Cox regression between first-line FOLFIRINOX and gemcitabine/nanoparticle albumin-bound (gem/nab) paclitaxel. Differences in frequencies of genomic alterations between H and BT were analyzed by Fisher's exact test. RESULTS: Genomic alterations in the DNA damage response (DDR) pathway (such as BRCA1, BRCA2, and PALB2) were enriched (unadjusted P value = .00244) in BT tumors (21.7% of 618) relative to H tumors (15.6% of 942) where BRCA2 was a top contributor within this pathway. Median PFS in BT tumors on first-line FOLFIRINOX was longer than first line gem/nab-paclitaxel (P = .006393); this difference was not identified in H tumors (P = .5546). CONCLUSION: DDR pathway alterations including BRCA1/BRCA2/PALB2 are known predictors of increased benefit from platinum-based chemotherapy. NGS testing for germline and somatic mutations remains important in pancreatic ductal adenocarcinoma, especially in BT tumors where DDR pathway alterations may be more common than in H tumors.
Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Desoxicitidina/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Platino (Metal)/uso terapéutico , Gemcitabina , Reparación del ADNRESUMEN
Epithelial growth, branching, and canalization are important morphogenetic events of the rodent ventral prostate (VP) that take place during the first postnatal week. In this study, we evaluated the effect of knocking out MMP-2 (MMP-2(-/-)), by examining developmental and structural aspects of the VP in MMP-2(-/-) mice. Neonate (day 6) MMP-2(-/-) mice showed fewer epithelial tips, a lower epithelial cell proliferation rate, and also reticulin fiber accumulation. The VP of adult MMP-2(-/-) mice showed lower relative weight, smaller epithelial and smooth-muscle cell volume, and a larger amount of thicker reticulin fibers. No differences in cell proliferation or apoptotic index were noted between adult MMP-2(-/-) and wild-type mice. MMP-9 was found in the adult MMP-2(-/-), but not in the wild-type. In conclusion, MMP-2 function is essential for the epithelial morphogenesis of the mouse VP, and expression of MMP-9 is not sufficient for acquisition of the normal adult histology.