Peter J. Allen

Morbidity after pancreatectomy is commonly due to leakage of exocrine secretions resulting in abscess or pancreatic fistula (PF). Previously, we authored a double-blind randomized controlled trial demonstrating that perioperative pasireotide administration lowers abscess or PF formation by >50%. Accordingly, we adopted pasireotide use as standard practice after pancreatectomy in October 2014 and hypothesized a similar PF/abscess rate reduction would be observed. A prospectively maintained database was queried for all patients who underwent pancreatectomy between October 2014 and July 2017. Pasireotide was administered preoperatively and twice daily for 7 days postoperatively or until discharge. The primary end point was clinically relevant PF/abscess requiring procedural intervention, identical to the earlier trial outcomes. Logistic regression was used to compare outcomes with the placebo arm of the earlier randomized trial and to control known PF risk factors. During the 34-month study period, 652 patients underwent pancreatectomy (211 distal pancreatectomy, 441 pancreaticoduodenectomy). Compared with the historical placebo group (n = 148), the observational group had an increased prevalence of higher American Society of Anesthesiologists scores (69% vs 54%; p < 0.001) and high-risk cases (small duct and soft gland, 47% vs 36%; p = 0.030). The primary end point occurred in 13.3% of patients receiving pasireotide vs 20.9% in the placebo arm of the earlier trial trial (odds ratio 0.58; 95% CI 0.37 to 0.92; p = 0.020). Biliary leakage was lower in those receiving pasireotide (0.6% vs 3.4%; p = 0.014), and other morbidity was unchanged. No subpopulation was identified more likely to benefit from pasireotide. At our center, adoption of pasireotide has allowed us to achieve a clinically significant abscess or pancreatic leak rate of 13.3%, approximating the effect observed in the randomized trial of pasireotide during routine surgical practice.

Background: Efforts to characterize the mutational landscape in pancreatic cancer have revealed almost ubiquitous activating mutation of KRAS, high incidence of inactivation of TP53, SMAD4, CDKN2A and KDM6A but a very low prevalence of currently actionable targets. However, patients with high genomic instability suggesting defective DNA maintenance (up to 20%) show high response rate to platinum agents with or without PARP inhibition. While no more than 5% of patients harbor germline BRCA1/2 inactivation, molecular alterations in other genes related to homologous recombination are also found in these pancreatic tumors. These observations support the concept of BRCAness in pancreatic cancer, where tumors showing traits of defective homologous recombination (HR) even in the absence of BRCA1/2 deficiency are associated with exquisite sensitivity to DNA-damaging agents. This study seeks to identify new molecular determinants of BRCAness in Pancreatic cancer and what assay constitutes the best predicator of a favorable response to therapeutic targeting HR defects. Methods: Given the heterogeneous mechanisms that can drive BRCAness, we have performed a comprehensive analysis of a large repository of pancreatic cancer patient-derived organoids including molecular characterization by next-generation sequencing (exome and transcriptome) allowing quantification of genomic scars and mutational signatures concomitantly to an evaluation of HR proficiency by IRIF assay and drug sensitivity profiling including platinum-based agents and PARPi. Results: Multidimensional characterization of 75 pancreatic cancer led to the identification of 9 tumors (12%) so far that showed clear evidence of BRCAness, featuring high HR deficiency score (elevated amount of genomic scars), sub-micromolar sensitivity to cisplatin and PARPi, low induction of rad51 foci following irradiation and a highly operative BRCA mutational signature. Interestingly, in the absence of alteration in BRCA1 and BRCA2 some of these specimens show enrichment in alterations of HR component genes (RAD51, PALB2) and in RecQ helicase family (BLM, WRM) or ATM. Conclusions: This study identifies evidence of BRCAness in pancreatic cancer tumors without any deficiency in BRCA1 and BRCA2 and therefore broadens the scope of patients who may benefit from platinum and/or PARP therapy.

Although IPMN are thought to represent a whole-gland disease, segmental resection remains the most frequently performed treatment. We sought to determine t

Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community. The first set of challenges involves nominating and verifying biomarkers. Candidate biomarkers need to discriminate disease from benign controls with high sensitivity and specificity for an intended use, which we describe as a two-tiered strategy of identifying and screening high-risk patients. Community-wide efforts to share samples, data, and analysis methods have been beneficial and progress meeting this challenge has been achieved. The second set of challenges is assay optimization and validating biomarkers. After initial candidate validation, assays need to be refined into accurate, cost-effective, highly reproducible, and multiplexed targeted panels and then validated in large cohorts. To move the most promising candidates forward, ideally, biomarker panels, head-to-head comparisons, meta-analysis, and assessment in independent data sets might mitigate risk of failure. Much more investment is needed to overcome these challenges. The third challenge is achieving clinical translation. To moonshot an early detection test to the clinic requires a large clinical trial and organizational, regulatory, and entrepreneurial know-how. Additional factors, such as imaging technologies, will likely need to improve concomitant with molecular biomarker development. The magnitude of the clinical translational challenge is uncertain, but interdisciplinary cooperation within the PDAC community is poised to confront it.