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Purpose: Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype., Experimental Design: We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences. Classical and basal subtypes were identified using purity independent subtyping algorithm on RNA sequencing, and two cohorts were analyzed: (i) the biomarker cohort included patients with complete molecular profiling data (n = 7,250) and (ii) the outcome cohort included patients with metastatic disease with available survival outcomes (n = 5,335). A total of 3,842 patients were shared between the two cohorts. Kaplan-Meier curves and Cox proportional hazards regression were used to assess patient survival., Results: In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC) and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy sites. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial-mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcome cohort, the SB subtype was associated with shorter overall survival time, regardless of whether they received FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line chemotherapy. The mutant KRAS allele type was prognostic of outcomes; however, this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors., Conclusions: The SB subtype is a strong independent predictor of worse outcomes, regardless of the up-front chemotherapy regimen used. Clinical trials should further investigate pancreatic cancer transcriptional subtypes as a prognostic and predictive biomarker., (©2024 American Association for Cancer Research.)

Background: The role of neoadjuvant stereotactic body radiation therapy (SBRT) in the treatment of pancreatic adenocarcinoma (PDAC) is controversial and the optimal target volumes and dose-fractionation are unclear. The aim of this study is to report on treatment outcomes and patterns of failure of patients with borderline resectable (BL) or locally advanced (LA) pancreatic cancer following preoperative chemotherapy and SBRT., Methods: We conducted a single-institution, retrospective study of patients with BL or LA PDAC. Patients received neoadjuvant chemotherapy and SBRT was prescribed to 30 Gy over 5 fractions to the pancreas planning tumor volume (PTV). A subset of patients received a simultaneous integrated boost to the high risk vascular PTV and/or elective nodal irradiation (ENI). Following neoadjuvant chemoradiation, all patients underwent subsequent resection. Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMPFS), and locoregional control (LRC) estimates were obtained using Kaplan-Meier analysis., Results: Twenty-two patients with BL (18) or LA (4) PDAC were treated with neoadjuvant chemotherapy and SBRT followed by resection from 2011-2022. Following neoadjuvant treatment, 5 patients (23%) achieved a pathologic complete response (pCR) and 16 patients (73%) had R0 resection. At 24 months, there were no isolated locoregional recurrences (LRRs), 9 isolated distant recurrences (DRs), and 5 combined LRRs and DRs. Two LRRs were in-field, 2 LRRs were marginal, and 1 LRR was both in-field and marginal. 2-year median LRC, LRRFS, DMPFS, PFS, and OS were 77.3%, 45.5%, 31.8%, 31.8%, and 59.1%, respectively. For BL and LA cancers, 2-year LRC, DMPFS, and OS were 83% vs. 75%, (p = 0.423), 39% vs. 0% (p = 0.006), and 61% vs. 50% (p = 0.202), respectively. ENI was associated with improved LRC (p = 0.032) and LRRFS (p = 0.033). Borderline resectability (p = 0.018) and lower tumor grade (p = 0.027) were associated with improved DMPFS., Conclusions: Following preoperative chemotherapy and SBRT, locoregional failure outside of the target volume occurred in 3 of 5 recurrences; ENI was associated with improved LRC and LRRFS. Further studies are necessary to define the optimal techniques for preoperative radiation therapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Despite improvement in systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) frequently experience local recurrence. We sought to determine the safety of hypofractionated proton beam radiation therapy (PBT) during adjuvant chemotherapy., Methods and Materials: Nine patients were enrolled in a single-institution phase 1 trial (NCT03885284) between 2019 and 2022. Patients had PDAC of the pancreatic head and underwent R0 or R1 resection and adjuvant modified FOLFIRINOX (mFFX) chemotherapy. The primary endpoint was to determine the dosing schedule of adjuvant PBT (5 Gy × 5 fractions) using limited treatment volumes given between cycles 6 and 7 of mFFX. Patients received PBT on days 15 to 19 in a 28-day cycle before starting cycle 7 (dose level 1, DL1) or on days 8 to 12 in a 21-day cycle before starting cycle 7 (DL2)., Results: The median patient age was 66 years (range, 52-78), and the follow-up time from mFFX initiation was 12.5 months (range, 6.2-37.4 months). No patients received preoperative therapy. Four had R1 resections and 5 had node-positive disease. Three patients were enrolled on DL1 and 6 patients on DL2. One dose-limiting toxicity (DLT) occurred at DL2 (prolonged grade 3 neutropenia resulting in discontinuation of mFFX after cycle 7). No other DLTs were observed. Four patients completed 12 cycles of mFFX (range, 7-12; median, 11). No patients have had local recurrence. Five of 9 patients had recurrence: 3 in the liver, 1 in the peritoneum, and 1 in the bone. Six patients are still alive, 4 of whom are recurrence-free. The median time to recurrence was 12 months (95% CI, 4 to not reached [NR]), and median overall survival was NR (95% CI, 6 to NR; 2-year survival rate, 57%)., Conclusions: PBT integrated within adjuvant mFFX was well tolerated, and no local recurrence was observed. These findings warrant further exploration in a phase 2 trial., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease, with surgery being the only possible cure. However, despite surgery, the majority of patients experience recurrence. Recent evidence suggests that perioperative KRAS-mutated circulating tumor DNA (ctDNA) may have prognostic value. Therefore, we conducted a systematic review and meta-analysis to explore the prognostic significance of preoperative and postoperative KRAS-mutated ctDNA testing in resected PDAC., Methods: We searched PubMed/MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases for studies that reported the effect of preoperative and postoperative KRAS-mutated ctDNA on overall survival (OS) and/or relapse-free survival (RFS) in resected PDAC. We used a random-effects model to determine the pooled OS and RFS hazard ratios (HR) and their corresponding 95 % confidence intervals (CI)., Results: We identified 15 studies (868 patients) eligible for analysis. In the preoperative setting, positive ctDNA correlated with worse RFS in 8 studies (HR, 2.067; 95 % CI, 1.346-3.174, P < 0.001) and worse OS in 10 studies (HR, 2.170; 95 % CI, 1.451-3.245, P < 0.001) compared to negative ctDNA. In the postoperative setting, positive ctDNA correlated with worse RFS across 9 studies (HR, 3.32; 95 % CI, 2.19-5.03, P < 0.001) and worse OS in 6 studies (HR, 6.62; 95 % CI, 2.18-20.16, P < 0.001) compared to negative ctDNA., Conclusion: Our meta-analysis supports the utility of preoperative and postoperative KRAS-mutated ctDNA testing as a prognostic marker for resected PDAC. Further controlled studies are warranted to confirm these results and to investigate the potential therapeutic implications of positive KRAS-mutated ctDNA., Competing Interests: Declaration of competing interest Ali Alqahtani: No conflicts of interest. Abdulrahman Alloghbi: No conflicts of interest. Chao Yin: No conflicts of interest. Reetu Mukherji: No conflicts of interest. Benjamin A. Weinberg: Daiichi Sankyo, AstraZeneca, Taiho, Sirtex, Natera., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments., Experimental Design: Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination., Results: Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden-high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin., Conclusions: KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner., (©2022 American Association for Cancer Research.)

Pancreatic cancer is a devastating illness, and surgical resection offers the only chance of a cure for patients with the disease. Relatively few patients have resectable disease at diagnosis, however, and the cancer frequently recurs even after complete surgical resection. This review discusses clinical trials in which adjuvant therapy with chemotherapy or chemoradiation has prolonged survival in patients following surgery. It also highlights new data from the ESPAC-4 and JASPAC 01 studies that may change the current treatment paradigm for adjuvant therapy. The ESPAC-4 results support the use of adjuvant gemcitabine plus capecitabine in preference to the previous standard of gemcitabine alone, demonstrating that in this instance, more may be better. Finally, the review discusses ongoing trials and new approaches that aim to improve outcomes further for patients with resectable pancreatic cancer.

Pancreatic cancer is one of the most lethal solid tumors. The prognosis of metastatic pancreatic adenocarcinoma remains dismal, with a median survival of less than 1 year, due in large part to the fact that pancreatic adenocarcinoma is notoriously refractory to chemotherapy. However, there recently have been significant improvements in outcomes for patients with pancreatic adenocarcinoma: ongoing trials have shown promise, and these may lead to still further progress. Here we review the current treatment paradigms for metastatic disease, focusing on ways to ameliorate symptoms and lengthen survival. We then summarize recent advances in our understanding of the molecular and cellular aspects of pancreatic cancer. Finally, we outline new approaches currently under development for the treatment of metastatic disease, arising from our improved understanding of the genetic and nongenetic alterations within pancreatic cancer cells-and of interactions between cancer cells, the tumor microenvironment, and the immune system.

Background: To consolidate literature reports of serious late gastrointestinal toxicities after hypofractionated radiation treatment of pancreatic cancer and attempt to derive normal tissue complication probability (NTCP) parameters using the Lyman-Kutcher-Burman model., Methods: Published reports of late grade 3 or greater gastrointestinal toxicity after hypofractionated treatment of pancreatic cancer were reviewed. The biologically equivalent dose in 1.8 Gy fractions was calculated using the EQD model. NTCP parameters were calculated using the LKB model assuming 1-5% of the normal tissue volume was exposed to the prescription dose with α/β ratios of 3 or 4., Results: A total of 16 human studies were examined encompassing a total of 1160 patients. Toxicities consisted of ulcers, hemorrhages, obstructions, strictures, and perforations. Non-hemorrhagic and non-perforated ulcers occurred at a rate of 9.1% and were the most commonly reported toxicity. Derived NTCP parameter ranges were as follows: n = 0.38-0.63, m = 0.48-0.49, and TD50 = 35-95 Gy. Regression analysis showed that among various study characteristics, dose was the only significant predictor of toxicity., Conclusions: Published gastrointestinal toxicity reports after hypofractionated radiotherapy for pancreatic cancer were compiled. Median dose was predictive of late grade ≥ 3 gastrointestinal toxicity. Preliminary NTCP parameters were derived for multiple volume constraints.

Background & Aims: The natural history and management of pancreatic cysts, especially for branch duct intraductal papillary mucinous neoplasms (BD-IPMNs), remain uncertain. We developed evidence-based nomograms to assist with clinical decision making., Methods: We used decision analysis with Markov modeling to compare competing management strategies in a patient with a pancreatic head cyst radiographically suggestive of BD-IPMN, including the following: (1) initial pancreaticoduodenectomy (PD), (2) yearly noninvasive radiographic surveillance, (3) yearly invasive surveillance with endoscopic ultrasound, and (4) "do nothing." We derived probability estimates from a systematic literature review. The primary outcomes were overall and quality-adjusted survival. We depicted the results in a series of nomograms accounting for age, comorbidities, and cyst size., Results: Initial PD was the dominant strategy to maximize overall survival for any cyst greater than 2 cm, regardless of age or comorbidities. In contrast, surveillance was the dominant strategy for any lesion less than 1 cm. However, when measuring quality-adjusted survival, the do-nothing approach maximized quality of life for all cysts less than 3 cm in patients younger than age 75. Once age exceeded 85 years, noninvasive surveillance dominated. Initial PD did not maximize quality of life in any age group or cyst size., Conclusions: Management of pancreatic cysts can be guided using novel Markov-based clinical nomograms, and depends on age, cyst size, comorbidities, and whether patients value overall survival vs quality-adjusted survival. For patients focused on overall survival, regardless of quality of life, surgery is optimal for lesions greater than 2 cm. For patients focused on quality-adjusted survival, a 3-cm threshold is more appropriate for surgery except for the extreme elderly.

Background & Aims: The 2006 Sendai Consensus Guidelines recommend surgical resection for all suspected branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) greater than 3 cm irrespective of symptoms, and those less than 3 cm with worrisome features. We aimed to evaluate the surgical characteristics of these guidelines retrospectively in pathologically confirmed cases of BD-IPMN., Methods: IPMNs resected at our institution (1995-2006) were classified as main-duct predominant or branch-duct (BD) predominant based on preoperative imaging and postoperative histology. Resected BD-IPMNs were classified histologically: low risk (adenoma, borderline) and high risk (carcinoma in situ or invasive cancer). Clinical data (presence of symptoms, mural nodule, dilated pancreatic duct, and cyst size) were correlated with pathology., Results: Between 1995 and 2006, there were 204 patients who underwent surgical resection of pancreatic cysts. Sixty-one patients had IPMN including 31 with BD-IPMN. A total of 74.2% (23 of 31) of BD-IPMNs would have been recommended for surgical resection including 69.2% (18 of 26) of low-risk lesions and 100% (5 of 5) of high-risk lesions. All 8 cases of BD-IPMN that would have been recommended for nonsurgical management were low-risk lesions. The positive predictive value of the guidelines is 21.7% (95% confidence interval, 9.7%-41.9%). The negative predictive value is 100% (95% confidence interval, 67.6%-100.0%). Between 2000 and 2007, 351 patients with likely BD-IPMN were evaluated but not resected., Conclusions: Implementation of the Consensus Guidelines to our single-institution, referral-based, surgical BD-IPMN population would have recommended resection of all histologically high-risk lesions. All lesions recommended for nonsurgical management were histologically low-risk lesions. For presumed BD-IPMNs less than 3 cm, the application of the Consensus Guidelines may reduce the resection rate for low-risk lesions.