Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02047474.

Prevention and Reversion of Pancreatic Tumorigenesis through a Differentiation-Based Mechanism.

Activating mutations in Kras are nearly ubiquitous in human pancreatic cancer and initiate precancerous pancreatic intraepithelial neoplasia (PanINs) when induced in mouse acinar cells. PanINs normally take months to form but are accelerated by deletion of acinar cell differentiation factors such as Ptf1a, suggesting that loss of cell identity is rate limiting for pancreatic tumor initiation. Using a genetic mouse model that allows for independent control of oncogenic Kras and Ptf1a expression, we demonstrate that sustained Ptf1a is sufficient to prevent Kras-driven tumorigenesis, even in the presence of tumor-promoting inflammation. Furthermore, reintroducing Ptf1a into established PanINs reverts them to quiescent acinar cells in vivo. Similarly, Ptf1a re-expression in human pancreatic cancer cells inhibits their growth and colony-forming ability. Our results suggest that reactivation of an endogenous differentiation program can prevent and reverse oncogene-driven transformation in cells harboring tumor-driving mutations, introducing a potential paradigm for solid tumor prevention and treatment.

Metastatic neoplasms to the pancreas diagnosed by fine-needle aspiration/biopsy cytology: A 15-year retrospective analysis.

BACKGROUND: Metastatic tumors to the pancreas are rarely encountered and diagnostically challenging. We aspired to determine the incidence and origin of all metastases to the pancreas at our institution, and to examine their clinicopathologic and cytomorphologic features. We also sought to ascertain the effect of endoscopic ultrasound (EUS) guidance implementation. METHODS: A search of our database was undertaken to review all pancreatic FNA and/or CNB examined from January 2000 through December 2014. RESULTS: During our 15-year study, 636 patients underwent pancreatic FNA/CNB, including 252 (40%) computerized tomography (CT) and 384 (60%) EUS-guided biopsies. Malignancy was diagnosed in 221 (35%). Only 16 had metastases to the pancreas, comprising 2.5% of pancreatic biopsies and 7.2% of malignancies. Three (18.8%) presented with their first manifestation of cancer. EUS guidance was utilized in 50%, with rapid on-site evaluation (ROSE) employed in 14 (88%). The most common primary site was lung (6,38%), followed by 3 (19%) each of renal and gastrointestinal malignancies. The remaining included malignant melanoma, Merkel and gallbladder small cell carcinomas, and olfactory neuroblastoma. CONCLUSION: Cytologic diagnosis of metastasis to the pancreas is rare in our institution, comprising only 2.5% and 7.2% of total and malignant pancreatic FNA/CNB, respectively. FNA/CNB with ROSE proved to be an effective diagnostic modality, thereby obviating the need for more invasive procedures in the setting of pancreatic metastases. EUS-FNA was equally effective as CT-guided biopsies in achieving specimen adequacy and definitive diagnoses. We also present the first known case of a metastatic olfactory neuroblastoma to the pancreas diagnosed by imprint cytology.