Background and study aims:Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a nonsurgical treatment option for managing pancreatic lesions. We sought to evaluate the safety and efficacy of EUS-RFA for large (≥4 cm) branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs). Patients and methods:Patients with a definitive diagnosis of BD-IPMN who declined or were unfit for surgery underwent EUS-RFA in a single-arm prospective trial. Ablation was performed using a 19G EUS-RFA needle. RFA applications were delivered up to a maximum threshold of 45 seconds or 400 ohms impedance. Safety was assessed using AGREE guidelines. Potential for efficacy was assessed using cyst volume and cyst fluid KRAS GNAS mutations using next-generation sequencing (NGS). Adverse events (AEs) were analyzed per RFA session, while response was analyzed per BD-IPMN. Results:Thirty BD-IPMNs (mean diameter 4.6 ± 1.7 cm; 80% multilocular) in 25 participants (mean age 74.1 ± 8.3 years) underwent 41 EUS-RFA sessions. AEs occurred in 12.2% of procedures (5/41), the majority being AGREE Grade 3A (9.8%, 4/41). During a mean follow-up of 18 ± 5 months, 22 of 28 BD-IPMNs (78.6%) achieved ≥ 50% reduction in cyst volume, and 11 (39.3%) demonstrated complete (≥90%) response. Among 26 BD-IPMNs that revealed KRAS GNAS mutations, follow-up NGS was performed in 17, with 88.2% showing loss of detectable mutations. Conclusions:EUS-RFA in large, predominantly multilocular BD-IPMNs shows promising volumetric efficacy. Safety may be improved through refined energy delivery and technical advances. Molecular response remains exploratory and requires further validation. Long-term studies assessing progression-free outcomes are needed to define its role as an organ-preserving therapeutic option.

BACKGROUND:Molecular subtyping of pancreatic ductal adenocarcinoma (PDAC) may inform prognosis and treatment selection, and its clinical application remains under investigation. Although PurIST is a validated transcriptomic classifier, immunohistochemical (IHC) markers such as GATA6 and CK5 have been proposed as practical surrogates. We evaluated whether GATA6 and CK5 IHC could substitute for transcriptomic PDAC subtyping. METHODS:RNA-seq and GATA6/CK5 IHC were performed on 130 matched tumor samples. Most patients received neoadjuvant therapy. PurIST subtype assignment served as the reference. Concordance was assessed using Cohen's kappa and overall survival using log-rank tests. RESULTS:PurIST classified 8 tumors (6%) as basal-like. GATA6 alone showed poor concordance with PurIST (kappa=0.18, 95% CI -0.06 to 0.42) and was not prognostic of survival (P=0.98). CK5 showed better concordance (kappa=0.39, 95% CI 0.07 to 0.70) but was not significantly prognostic (P=0.084). Combined GATA6/CK5 improved concordance modestly (kappa=0.54, 95% CI 0.18 to 0.90) and stratified OS in the survival cohort (P=0.041), but generated categories that did not align cleanly with established subtypes. GATA6 IHC correlated weakly with RNA-seq expression (rho=0.178, P=0.0429). DISCUSSION:In predominantly post-neoadjuvant PDAC specimens, GATA6 and CK5 capture aspects of subtype biology but are not reliable substitutes for transcriptomic classification.

PURPOSE:This guideline provides evidence-based recommendations on the use of radiation therapy (RT) for the treatment of pancreatic cancer in a variety of clinical settings including patients with resectable, borderline resectable, locally advanced, metastatic, and symptomatic disease. METHODS:The American Society for Radiation Oncology convened a multidisciplinary task force to address 4 key questions: (1) indications for and timing of RT for patients with nonmetastatic pancreatic cancer; (2) appropriate RT dose-fractionation regimens and target volumes for nonmetastatic disease; (3) preferred RT planning and delivery techniques for nonmetastatic disease; and (4) indications for RT in the locally recurrent, metastatic, reirradiation, and palliative settings. Recommendations are based on a systematic literature review and were created using a predefined consensus-based methodology with a system for grading evidence quality and recommendation strength. RESULTS:Multidisciplinary evaluation and decision-making are recommended for all patients. For patients with nonmetastatic pancreatic cancer, RT is conditionally recommended in the preoperative and postoperative settings for resectable disease. RT is recommended preoperatively for borderline resectable disease and definitively in the locally advanced setting. For preoperative RT, conventional fractionation or moderate hypofractionation is recommended. For postoperative RT, conventional fractionation is recommended. In the definitive setting, conventional fractionation is appropriate although emerging evidence supports dose escalation using either stereotactic body radiation therapy or moderate hypofractionation. Adaptive RT is recommended for dose-escalated stereotactic body radiation therapy. Elective coverage of at-risk anatomic regions is recommended for preoperative, postoperative, and definitive RT. In the locally recurrent setting, RT is recommended for patients without prior RT and conditionally recommended for those who have previously received RT. Palliative RT is recommended for patients with bleeding, pain, and obstruction. For patients with oligometastatic and oligoprogressive pancreatic cancer, RT is conditionally recommended to metastatic lesions and the primary tumor if not previously treated with definitive local therapy. Target volumes, simulation and planning techniques, and treatment recommendations are provided. CONCLUSIONS:These evidence-based recommendations provide guidance on the optimal use of RT for pancreatic cancer. Ongoing and future studies should further refine RT indications, sequencing with other therapies, and impact on patient outcomes.

Abstract Background: In metastatic cancer, Circulating Tumor cells (CTCs) are established prognostic indictors of patients (pts) less likely to respond to new lines of systemic therapy, with poor clinical outcomes, such as shorter progression free survival (PFS) and overall survival (OS). However, CTCs are typically found in specific malignancies (breast, prostate & colon), often in <20% of pts with metastatic disease, and pts without CTCs may also rapidly progress. Recently, an inflammatory pro-tumorigenic macrophage emanating from tumor stroma (i.e. Cancer associated macrophage-like cell [CAML]) was found in >90% of metastatic cancer pts, and whose phagocytic engorgement appears to correlate with poor outcomes, independent of CTCs. As CTCs and CAMLs are isolated in conjunction from a single blood sample, and both are prognostic for outcomes, we evaluated their utilization prior to induction of new systemic therapy in 6 types of metastatic cancer to model pt risk stratification based on 2 year outcomes. Methods: A prospective 2 year blind multi-institutional study was undertaken to model CTCs and CAMLs in prognosticating outcomes prior to induction of a new line of systemic therapy (n=233) in metastatic: Breast (n=60), Prostate (n=40), Pancreas (n=25), Colon (n=28), Renal Cell Carcinoma (RCC) (n=39), and Lung (n=40). Blood was filtered by CellSieveTM filters with subtypes of CTCs & hyper-enlarged CAMLs (≥100µm) enumerated. A machine learning algorithm was trained on this initial data set to develop predictive models which could stratify pt populations by risk for likelihood of PFS & OS over 2 years, including known clinical variables. Results: CTCs were absent in 80% (n=185/233) of pts, and their absence was prognostic for better PFS (HR=1.6, p=0.046), but not OS (HR=1.3, p=0.2045). In parallel, enlarged CAMLs (≥100µm) were found in 28% (n=51/185) of pts without CTCs, and were also prognostic for worse PFS (HR=2.0, p=0.0082) and OS (HR=1.9, p=0.0412). Specifically, CTCs were found in 55% (n=33) breast, 20% (n=8) prostate, 12% (n=3) pancreas, 11% (n=3) colon, 0% (n=0) RCC, and 0% (n=0) lung pts. Enlarged CAMLs were found in 45% (n=27) breast, 20% (n=8) prostate, 44% (n=11) pancreas, 44% (n=17) colon, 18% (n=7) RCC and 20% (n=8) lung pts. Overall, models indicated that ≥1 CTC (n=47) had mPFS=3.9 & mOS=14.9, while pts with 0 CTCs and ≥100µm CAMLs (n=51) had a mPFS=6.9 & mOS=13.8, and pts with 0 CTCs and <100µm CAMLs (n=134) had a mPFS=10.7 & mOS>24 months. Conclusions: These initial models confirm that both CTCs and enlarged CAMLs are prognostic indicators of worse PFS & OS. The simultaneous quantification both CTCs and CAMLs allows for more accurate pan-cancer risk stratification in an array of cancer pt populations. Additional clinical variables incorporated into the models may allow better risk subtyping and possibly forecast optimal treatment regimens. Citation Format: Daniel L. Adams, Steven H. Lin, Massimo Cristofanilli, Carolina Reduzzi, Saranya Chumsri, Martin J. Edelman, Susan Tsai, Raymond C. Bergan, Mohammed Aldakkak, Thai H. Ho, Cha-Mei Tang. Combining circulating tumor cells and cancer associated macrophage-like cells enhances risk stratification models in pan-cancer metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1068.

BACKGROUND:Minimally-invasive approaches to pancreatic surgery are increasingly utilized. We aimed to evaluate the implementation of robotic pancreatoduodenectomy (RPD) across the United States. METHODS:The National Cancer Database was queried for all patients undergoing pancreatoduodenectomy (PD) for pancreatic cancer in the United States between 2010 and 2020. The primary outcome was utlization of robotic PD. Secondary outcomes included perioperative outcomes following PD. RESULTS:There were 48,781 patients who underwent PD with 78.0 % and 5.2 % performed by an open and robotic approach, respectively. Utilization of RPD increased from 1.1 % to 10.3 % between 2010 and 2020 (p < 0.001). Robotic converted to open PD decreased from 22.2 % to 11.1 % over the study period (p = 0.006). Patients undergoing open or RPD had similar R0 resection, 30-day unplanned readmission, and 90-day mortality. The 10 highest volume centers for RPD performed 41.8 % of all RPD and had lower rates of conversion to open, post-operative length of stay, and a higher number of lymph nodes examined compared with other centers performing RPD (all p < 0.001). CONCLUSION:Robotic PD is increasingly utilized in the United States but still represents a small fraction of patients undergoing PD. Given improved outcomes observed in high-volume centers, deliberate initiatives to expand RPD programs while ensuring continued centralization are important.

Therapies targeting the RAF-MEK-ERK pathway are generally considered to have limited efficacy in KRAS-mutant cancers. However, specific KRAS mutants exhibit distinct behaviors. Notably, KRASG12R pancreatic ductal adenocarcinoma (PDAC) tumors have shown sensitivity to MEK inhibitors (MEKi) in combination with autophagy inhibitors, but a better understanding of the underlying mechanisms is needed to optimize this treatment strategy. Using a systems-level approach, we uncovered a mechanistic explanation for this phenomenon. Due to distinct biophysical properties, KRASG12R had an impaired ability to activate wild-type HRAS and NRAS (WT-RAS) compared with other KRAS mutants, such as KRASG12D. This reduced activation stemmed from the weaker interaction between KRASG12R and guanine exchange factors (SOS), as well as the tumor suppressor neurofibromin (NF1), crucial in regulating WT-RAS activity. The impaired ability to activate WT-RAS led to weaker holistic MAPK signaling in KRASG12R-driven tumors, which conferred increased sensitivity to MEKi. To substantiate the preclinical findings, the utility of MEKi in combination with the autophagy inhibitor hydroxychloroquine was analyzed in patients with KRASG12R-mutated metastatic PDAC. Five of the eight (62.5%) patients treated in first- or second-line settings had a progression-free survival exceeding 6 months. Three patients had impressive disease control: two had stable disease of 11 and 22.7 months, and one achieved a partial response with an 83% decrease in tumor size that lasted for 8.9 months. Overall, this work highlights how systems-based approaches in precision medicine can uncover mechanistic insights to guide the identification of patients with PDAC most likely to benefit from tailored therapeutic strategies. SIGNIFICANCE:The unique sensitivity of KRASG12R-mutant cancers to MEK inhibitors offers a critical advancement in understanding MAPK signaling and paving the way for precision-targeted therapies in previously untreatable contexts. See related commentary by Tiriac and Engle, p. 1817 See related article by Burge et al., p. 1854 See related article by Burge et al., p. 1868.

Advances in technology have allowed for the characterization of tumors at the genomic, transcriptomic, and proteomic levels. There are well-established targets for biliary tract cancers, with exciting new targets emerging in pancreatic ductal adenocarcinoma and potential targets in hepatocellular carcinoma. Taken together, these data suggest an important role for molecular profiling for personalizing cancer therapy in advanced disease and need for design of novel neoadjuvant studies to leverage these novel therapeutics perioperatively in the surgical patient.

Clinicogenomic characteristics and treatment lines of 8 patients with metastatic PDAC and KRAS G12R alteration treated with MEK inhibitor + hydroxychloroquine

Multidisciplinary tumor board (TB) meetings are used to generate consensus recommendations for the diagnosis and management of patients with cancer, yet no documentation standards exist. Since lack of documentation could contribute to patient outcomes, we aimed to characterize TB documentation practices at a single institution. A retrospective audit of patients discussed at six TBs at a National Cancer Institute (NCI)-designated comprehensive cancer center from January 2024 to June 2024 was conducted. The presence and quality of TB documentation in the medical records were recorded. Associations with clinicodemographic variables and patient outcomes were assessed. Among 991 patients (307 liver, 235 breast, 166 colorectal, 153 pancreas, 110 cutaneous, 20 gastroesophageal), the median age was 63 years, 84.5

Kaplan-Meier estimates of progression-free survival

Supporting Data for Isogenic cells

TPS797 Background: Resectable pancreatic ductal adenocarcinoma (R-PDA) continues to be associated with high recurrence and poor long-term outcomes. While neoadjuvant chemotherapy is increasingly utilized, its superiority over upfront resection with adjuvant therapy remains uncertain. Tumor treating fields (TTFields) exert anti-mitotic effects by disrupting microtubule assembly and impairing cytokinesis through alternating electric fields. Preclinical models and clinical data suggest additive activity with chemotherapy. In the phase II PANOVA trial (n=40) in advanced PDA, TTFields combined with gemcitabine-based therapy demonstrated promising activity with acceptable safety, the main device-related adverse event being grade 3 dermatitis. Methods: This multicenter, single-arm phase II trial will assess perioperative TTFields in combination with gemcitabine plus nab-paclitaxel (GNP) in patients with R-PDA. Key eligibility criteria include: visible pancreatic mass, measurable disease, ≤180° venous involvement without arterial encasement, patent portal–splenic confluence, and no distant metastasis or extra-regional lymphadenopathy. Patients will initiate treatment with TTFields (compliance goal >80%) and three cycles of GNP, followed by restaging. Those proceeding to resection will receive an additional three cycles of adjuvant GNP with TTFields. The Bayesian Optimal Phase II (BOP2) design specifies dual primary endpoints: 2-year overall survival (OS) and resection rate. The null hypotheses are OS of 40% (vs. 60% target) and resection rate of 60% (vs. 75% target). A total of 30 evaluable patients are required, with an interim analysis after 15 patients; early termination occurs if ≤8 resections are achieved at that point (power 83%, type I error 10%). Secondary objectives include safety/tolerability, overall response rate, TTFields compliance, relative dose intensity, and long-term survival outcomes. The study opened to accrual with a planned enrollment of 38 patients. At the time of submission, two patients had been enrolled, and one patient had resection (ClinicalTrials.gov identifier: NCT05624918). Clinical trial information: NCT05624918 .

Importance:Cancer antigen 19-9 (CA19-9) is used to assess treatment response among patients with pancreatic ductal adenocarcinoma (PDAC); however, nearly 30% of patients with PDAC do not produce elevated CA19-9. Objective:To develop, validate, and apply an electronic tumor marker (e19-9) derived from routine laboratory data available in the electronic health record to assess treatment response and predict outcomes among patients with PDAC who do not produce CA19-9. Design, Setting, and Participants:In this cohort study, an artificial intelligence (AI) model was trained using routinely collected serum laboratory data from patients with PDAC and elevated CA19-9. The model was externally validated and then applied to a separate cohort of CA19-9 nonproducers. Model development and internal testing were conducted at a single institution using patient data from 2010 to 2022. External validation used a deidentified patient network across 58 health care organizations over the same period. The training cohort included 3239 patients with pancreatic cancer and elevated CA19-9. The external validation cohort included 4384 similar patients. The model was applied to 121 patients with resectable or borderline resectable PDAC who did not produce elevated CA19-9 and received neoadjuvant therapy with curative intent. These data were analyzed from November 2021 through March 2025. Main outcomes and measures:Model performance was assessed using root mean square error and R2. Clinical outcomes included completion of all neoadjuvant treatment and surgery, metastatic progression, and overall survival (OS). Results:The final fitted model demonstrated stable performance across both internal and external validation cohorts. Among 121 patients (59 female and 62 male) with localized PDAC who did not produce elevated CA19-9, a 50% or more decline in e19-9 (area under the curve [AUC], 0.79) and e19-9 level of less than 100 (AUC, 0.84) were objectively determined cut points associated with prognosis. A total of 93 patients (77%) completed all planned neoadjuvant therapy and surgery. A 50% or more decline in e19-9 levels and an e19-9 level less than 100 was associated with completion of all intended therapy (odds ratio [OR], 5.00; 95% CI, 1.60-15.66; P = .006 and OR, 19.31; 95% CI, 5.80-64.26; P < .001). An e19-9 level less than 100 was independently associated with OS (hazard ratio, 0.49; 95% CI, 0.25-0.97; P = .04). Conclusions and relevance:In this study, e19-9 was a noninvasive AI-derived marker that may provide accurate and relevant information to assess treatment response for the approximately 30% of patients with PDAC who do not produce CA19-9 at elevated levels. The development and validation of scalable, noninvasive screening methods using machine-learning algorithms may pave the way for early detection, prognostication, and treatment of cancers.

Clinical-grade RAS inhibitors raise an unresolved question as to whether KRAS alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, mutants with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRASMUT primarily through steric occlusion of effector binding, while engaging RASWT only modestly (~20%). KRASG12R was marked by its inability to transactivate RASWT, and daraxonrasib resistant KRASG12R PDAC cells utilized EGFR/RASWT-GTP signaling as the dominant adaptive route. In contrast, KRASG12D resistance arose through retained KRASG12D-GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRASG12R dependence to EGFR/RASWT dependence conferred sensitivity to trametinib. As clinical confirmation, a KRASG12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RASWT activation, and rapid 3D-bioprinted patient-derived tumoroid modeling predicted sensitivity to trametinib-based combination therapy. Despite the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control, and this patient ultimately achieved 40 months of overall survival, far exceeding the 8-12 month median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC.