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690 Background: Recent pancreatic cancer surveillance programs of high-risk individuals have reported improved outcomes. This study assessed to what extent outcomes of pancreatic ductal adenocarcinoma (PDAC) in patients with a CDKN2A/p16 pathogenic variant (PV) diagnosed during surveillance are better as compared to PDAC patients diagnosed outside surveillance. Methods: In a propensity score matched cohort using data from the Netherlands Cancer Registry, we compared resectability, stage and survival between patients diagnosed in surveillance with non-surveillance PDAC patients. Survival analysis were repeated after adjustment for lead-time bias. Results: Between January 2000 and December 2020, 43 762 patients with PDAC were identified from the NCR. Thirty-one patients with PDAC in surveillance were matched in a 1:5 ratio with 155 non-surveillance patients based on age at diagnosis, sex, and year of diagnosis. In total, 71% of patients in surveillance, as compared to 16% of non-surveillance patients underwent a surgical resection (OR 14.03; 95% CI, 5.92 – 35.85). In surveillance, 39% of patients was diagnosed with stage I cancer, as compared to 6% of non-surveillance PDAC patients (OR 0.10; 95% CI, 0.04 – 0.21). Patients in surveillance had a better prognosis, reflected by a 3-year survival of 32.4% and a median overall survival (OS) of 26.8 months vs. 1.4% 3-year survival and 5.3 months median OS in non-surveillance patients (HR 0.22; 95% 0.14 – 0.36). After adjustment for lead time, PDAC diagnosis in surveillance remained strongly associated with improved survival. Conclusions: Surveillance for PDAC in carriers of a CDKN2A/p16 PV results in earlier detection, increased resectability and improved survival as compared to non-surveillance PDAC patients.[Table: see text]

3574 Background: Irinotecan is commonly used in the treatment of advanced colorectal and pancreatic cancer. The polymorphisms UGT1A1*28 (7 TA repeats) and UGT1A1*93 (SNP -3156G > A) are significantly associated with increased systemic exposure of irinotecan’s active metabolite SN-38 and subsequently severe irinotecan-associated adverse-events (AEs) including (febrile) neutropenia and diarrhea. Severe AEs may lead to hospitalization, loss of quality of life, treatment delay and/or treatment discontinuation. Nonetheless, prospective genetic screening is not yet routinely performed. The aim of this study was to determine the safety and pharmacokinetics of UGT1A1 genotype-guided dosing of irinotecan in UGT1A1 poor metabolizers (PMs), i.e. UGT1A1 *28/*28 and/or UGT1A1*93/*93 individuals, in order to reduce the incidence of severe irinotecan-associated AEs. Methods: A prospective, multi-center, non-randomized study was conducted in patients intended to be treated with irinotecan at a dose of ≥ 180 mg/m2 or 450-600 mg flat dose. All patients were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1*93. In UGT1A1 PMs, an initial 30% dose reduction in the first cycle was applied followed by further individual dose titration based on neutrophil count and clinical tolerability. The primary endpoint was the incidence of febrile neutropenia in the first 2 cycles of irinotecan treatment. UGT1A1 PMs were compared to 1] historical control patients, i.e. homozygous polymorphic patients treated with full dose therapy identified from systematic literature review and to 2] UGT1A1 non-PMs treated with standard dose therapy. In addition, systemic SN-38 exposure (AUC0-500h) of reduced dosing in the UGT1A1 PM cohort was compared to a standard dosed irinotecan patient cohort [doi: 10.1200/JCO.2000.18.1.195] by an independent T-test. Results: A total of 349 patients were pre-therapeutically genotyped and included for analysis. Thirty-one (8.9%) patients were UGT1A1 PM, in whom an initial median 30% dose reduction was applied. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical controls (n = 50) (p = 0.042) and comparable with the incidence (4.1%; p = 0.632) in UGT1A1 non-PMs treated with full dose therapy. The systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs (n = 17) was comparable to the systemic exposure of the standard dosed irinotecan patient cohort (n = 46) with a relative difference of +24% (p = 0.054) with a geometric mean (CV) of SN-38 AUC0-500h of 391 (43.7%) versus 298 (75.3%) ng*h/mL, respectively. Conclusions: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan. In addition, systemic drug exposure remained adequate, despite the 30% dose reduction. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve the individual patient safety. Clinical trial information: Trial NL6270 (NTR6612).