Faculty Bibliography

INTRODUCTION/BACKGROUND:Current guidelines for treatment for locally advanced pancreatic cancer recommend chemotherapy ± radiation, or radiation alone when multimodal therapy is contraindicated. In a subset of patients, guideline-recommended treatment (GRT) achieves sufficient response to qualify for potentially curative resection. This study evaluated trends in treatment utilization and aimed to identify barriers to GRT. METHODS:Patients with clinical T4M0 disease in the National Cancer Database from 2010 to 2017 were included. Potential predictors were assessed by relative risk regression with Poisson distribution and compared by log-link function. RESULTS:In total, 28 056 patients met the criteria. Among 17 059 (67.67%) patients treated primarily with chemotherapy, 41.19% also had radiation and 8.89% went onto resection. Many received no cancer-directed treatment or failed to receive GRT. Another 710 patients had radiation (±surgery) without chemotherapy despite few contraindications to chemotherapy. Over time, patients were more likely to undergo resection after chemotherapy (aRR = 1.58; p < 0.0001) and less likely to have chemoradiation (aRR = 0.78; p < 0.0001) or go untreated (aRR = 0.90; p < 0.0001). Socioeconomic factors (race, education, income, and insurance status) affected the likelihood of receiving chemotherapy and surgery. Median overall survival (OS) was significantly improved for patients treated with chemotherapy and particularly in those patients who went on to receive RT or undergo surgical resection. OS was also longer for patients treated at high-volume academic centers. Patients insured by Medicaid, Medicare, or those without insurance had worse OS. CONCLUSIONS:Despite improvement over time, many patients go untreated. Clinical factors were influential, but the impact of vulnerable social standing suggests persistent inequity in access to care.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations^1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants³. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS⁴. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

BACKGROUND/OBJECTIVES/OBJECTIVE:Overall survival for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remains limited, with a median survival of 12 to 15 months. Irreversible electroporation (IRE) is a local tumor ablation method that induces cancerous cell death by disrupting cell membrane homeostasis. The DIRECT Registry study was designed to assess the effectiveness and safety of IRE when combined with standard of care (SOC) treatment for Stage 3 PDAC versus SOC alone in a real-world setting after at least 3 months of induction chemotherapy; Methods: Patients with Stage 3 PDAC treated with IRE plus SOC or SOC alone were prospectively enrolled in a multicenter registry study. Enrollment required 3 months of active multi-agent chemotherapy with no progression before enrollment. Endpoints were 30- and 90-day mortality and adverse events (AEs). RESULTS:= 0.0066). All IRE procedures were performed using an open approach. The 90-day all-cause mortality was 5/83 (6.0%) and 2/27 (7.4%) for the IRE and SOC groups, respectively. Two subjects in the IRE group died from treatment-related complications, and one patient in the SOC group died due to chemotherapy-related complications. CONCLUSIONS:Initial results from the DIRECT registry study indicate the use of IRE for curative intent tumor ablation in combination with induction chemotherapy has equivalent morbidity and mortality rates when compared to standard-of-care chemotherapy alone.

PURPOSE:The Enhanced Recovery After Surgery (ERAS) protocol is a multimodal perioperative care bundle aimed to improve pancreatic surgery outcomes. This work evaluates whether a Whipple ERAS protocol can be safely implemented at a quaternary care center. We also aimed to assess if race and socioeconomic factors are associated with disparities in outcomes in patients undergoing a Whipple ERAS protocol. METHODS:A retrospective review identified demographic and clinical data for 458 patients undergoing pancreaticoduodenectomies (PDs) at a single institution from October 2017 to May 2022. Patients were split into two cohorts: pre-ERAS (treated before implementation) and ERAS (treated after). Outcomes included length of stay (LOS), 30-day readmission and mortality rates, and major complications. RESULTS:There were 213 pre-ERAS PD patients, and 245 were managed with an ERAS protocol. More ERAS patients had a BMI > 30 (15.5% vs. 8.0%; p = 0.01) and received neoadjuvant chemotherapy (15.5% vs. 4.2%; p < 0.001). ERAS patients had a higher rate of major complications (57.6% vs. 37.6%; p < 0.001). Medicaid patients did not have more complications or longer LOS compared to non-Medicaid patients. On univariate analysis, race/ethnicity or gender was not significantly associated with a higher rate of major complications or prolonged LOS. CONCLUSION:A Whipple ERAS protocol did not significantly change LOS, readmissions, or 30-day mortality. Rate of overall complications did not significantly change after implementation, but rate of major complications increased. These outcomes were not significantly impacted by race/ethnicity, gender, tumor staging, or insurance status.

UNLABELLED:Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. SIGNIFICANCE:Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275.

Historically, the management of pancreatic cystic neoplasms (PCN) has been operative. Early intervention for premalignant lesions, including intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN), offers an opportunity to prevent pancreatic cancer-with potential decrement to patients' short-term and long-term health. The operations performed have remained fundamentally the same, with most patients undergoing pancreatoduodenectomy or distal pancreatectomy using oncologic principles. The role of parenchymal-sparing resection and total pancreatectomy remains controversial. We review innovations in the surgical management of PCN, focusing on the evolution of evidence-based guidelines, short-term and long-term outcomes, and individualized risk-benefit assessment.

BACKGROUND:In an era of more effective chemotherapy for pancreatic ductal adenocarcinoma (PDAC), the paradigm of local treatment is changing. However, the efficacy of local treatment in patients with isolated liver metastasis remains unclear. Therefore, we aimed to evaluate the effectiveness of pancreatectomy ± local treatment for metastasis (cytoreductive surgery) in PDAC patients with isolated synchronous liver metastasis. METHODS:In total, 239 patients with isolated liver metastasis were extracted from Seoul National University Hospital (SNUH). For comparison, another 12 637 patients were extracted from the National Cancer Database (NCDB). Propensity score matching was performed to minimize confounding in both cohorts. Survival analyses stratified by the treatment delivered were performed using Kaplan-Meier estimates and log-rank tests. RESULTS:In the SNUH cohort, the median (interquartile range) survival was 20.5 (13.0-42.0) months for patients who underwent cytoreductive surgery plus chemotherapy versus 12.0 (10.0-18.0) months for those who received chemotherapy alone (P < .001). With the NCDB cohort, the median (interquartile range) survival was 15.6 (8.9-31.2) months for patients who underwent cytoreductive surgery plus chemotherapy versus 7.4 (3.4-13.2) months for those who received chemotherapy alone (P < .001). CONCLUSION/CONCLUSIONS:Patients with isolated synchronous liver metastasis should be considered for cytoreductive surgery in addition to effective chemotherapy.

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of >13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

BACKGROUND:This study aimed to assess contemporary knowledge, attitudes and behaviors around transfusion of intraoperative salvaged blood (sRBCt) during hepato-pancreatico-biliary (HPB) operations. Findings are meant to inform the design of future studies that address provider concerns to change behaviors and improve patient outcomes. METHODS:A survey was designed and assessed for relevance, readability and content, and distributed to an international audience of surgeons performing HPB operations. RESULTS:The 237 respondents were predominantly distributed across North America (37.55%), Europe (27.43%) and Asia (19.83%). Roughly one-half (52.74%) of respondents had used sRBCt in HPB surgery before. Transplantation surgeons were more likely than HPB surgeons to have previously used sRBCt [odds ratio = 5.18 (95% CI 1.89-14.20)]. More respondents believed sRBCt was safe for non-cancer versus cancer operations (68.57% vs. 24.17%, p < 0.0001). Less than half (45.71%) of respondents believed that sRBCt was safe in clean-contaminated fields. Most did not utilize preoperative strategies to avoid donor transfusion. CONCLUSION:Practices related to sRBCt in HPB operations vary widely and there is no consensus on its use. Concerns seem primarily related to cancer-specific and infectious outcomes. While further studies are pursued, surgeons may increase their utilization of preoperative strategies to boost hemoglobin levels for at risk patients.