Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population.

Importance Pancreatic ductal adenocarcinoma (PDAC) is a relatively uncommon cancer, with approximately 60 430 new diagnoses expected in 2021 in the US. The incidence of PDAC is increasing by 0.5% to 1.0% per year, and it is projected to become the second-leading cause of cancer-related mortality by 2030. Observations Effective screening is not available for PDAC, and most patients present with locally advanced (30%-35%) or metastatic (50%-55%) disease at diagnosis. A multidisciplinary management approach is recommended. Localized pancreas cancer includes resectable, borderline resectable (localized and involving major vascular structures), and locally advanced (unresectable) disease based on the degree of arterial and venous involvement by tumor, typically of the superior mesenteric vessels. For patients with resectable disease at presentation (10%-15%), surgery followed by adjuvant chemotherapy with FOLFIRINOX (fluorouracil, irinotecan, leucovorin, oxaliplatin) represents a standard therapeutic approach with an anticipated median overall survival of 54.4 months, compared with 35 months for single-agent gemcitabine (stratified hazard ratio for death, 0.64 [95% CI, 0.48-0.86];P = .003). Neoadjuvant systemic therapy with or without radiation followed by evaluation for surgery is an accepted treatment approach for resectable and borderline resectable disease. For patients with locally advanced and unresectable disease due to extensive vascular involvement, systemic therapy followed by radiation is an option for definitive locoregional disease control. For patients with advanced (locally advanced and metastatic) PDAC, multiagent chemotherapy regimens, including FOLFIRINOX, gemcitabine/nab-paclitaxel, and nanoliposomal irinotecan/fluorouracil, all have a survival benefit of 2 to 6 months compared with a single-agent gemcitabine. For the 5% to 7% of patients with aBRCApathogenic germline variant and metastatic PDAC, olaparib, a poly (adenosine diphosphate [ADB]-ribose) polymerase inhibitor, is a maintenance option that improves progression-free survival following initial platinum-based therapy. Conclusions and Relevance Approximately 60 000 new cases of PDAC are diagnosed per year, and approximately 50% of patients have advanced disease at diagnosis. The incidence of PDAC is increasing. Currently available cytotoxic therapies for advanced disease are modestly effective. For all patients, multidisciplinary management, comprehensive germline testing, and integrated supportive care are recommended.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients¹, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines ^2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8⁺ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

Colorectal cancer is the second leading cause of cancer death in North America. Fluorouracil became the only cytotoxic drug indicated for colorectal cancer in the 1990s¹ when the adoption of continuous infusion of this agent was found to have improved the median overall survival from 12 to 15 months.² Since then, combination therapies of fluorouracil with leucovorin and either irinotecan (FOLFIRI regimen³) or oxaliplatin (mFOLFOX6 regimen⁴) were found to further improve survival and have become the main chemotherapeutic treatment options for colorectal cancer. A randomized crossover trial showed that these combination regimens were not statistically different, with patients receiving these agents in any sequence surviving a median 18 to 20 months.^5,6

Background: Despite data suggesting a rising worldwide incidence, intrahepatic cholangiocarcinoma (IHC) remains an uncommon disease. This study analyzes changes in IHC frequency, demographics, and treatment outcome in a consecutive and single institutional cohort. Methods: Consecutive patients with confirmed IHC seen and treated over a 16-year period were included. The trend in IHC frequency over the study period was compared with that of hilar cholangiocarcinoma patients (HCCA) seen during the same time. Demographics and patient disposition, histopathologic, treatment, recurrence, and survival data were analyzed; changes in these variables over time were assessed. Results: From December 1990 through July 2006, 594 patients were evaluated (IHC = 270, HCCA = 324). Over the study period, the average annual increase in new IHC patients was 14.2% (P < 0.001). Relative to HCCA, the proportional increase in IHC was nearly 3-fold, and new IHC patients have outnumbered those with HCCA by 2:1 over the last 3 years. Conditions associated with IHC were rarely seen, with only 7 patients having a history of sclerosing cholangitis and/or inflammatory bowel disease and none with hepatolithiasis or biliary parasitic disease; however, heavy tobacco use (27%) and diabetes mellitus (16.4%) were particularly prevalent. The majority of patients were not candidates for resection, most commonly because of advanced hepatic disease. After resection (n = 82), median disease-specific survival was 36 months; recurrence was observed in 62.2% of patients at a median follow-up of 26 months, with the liver remnant involved most frequently (62.7%). Multiple hepatic tumors (P < 0.001), regional nodal involvement (P = 0.012), and large tumor size (P = 0.016) independently predicted poor recurrence-free survival. Most patients (n = 115, 73.7%) with unresectable disease were treated with chemotherapy, either systemic alone (n = 75) or combined with regional hepatic arterial floxuridine (FUDR) (n = 28). Compared with the first 10 years of the study (1990–2000), the last 6 years saw an overall improvement in disease-specific survival for all patients (22 vs. 12 months, P = 0.002), which was particularly notable for patients with unresectable disease (15 vs. 6 months, P = 0.003). Conclusions: At Memorial Sloan-Kettering Cancer Center, IHC incidence has increased dramatically in the last 16 years. Resection offers the best opportunity for long-term survival but is possible in the minority, and patients with large, node-positive or multifocal IHC seem to derive little benefit. Establishing and maintaining control of the intrahepatic disease remains the biggest problem for all IHC patients. The recent increase in survival seems largely because of improved nonoperative therapy for unresectable disease.