A Prospective Pilot Study Of Pharmacogenetic-Based Dosing Of 5-Fluouracil (5-Fu) And Irinotecan (Iri) In Patients (Pts) With Gastrointestinal (Gi) Malignancies.

e16138 Background: 5-FU and IRI are core components of chemotherapies for GI malignancies. Previous studies have shown that mutations in DPYP and TYMS predispose the pts to 5-FU toxicities. Mutations in UGT1A1 predispose pts to increased IRI toxicities. Retrospective data suggest that these mutations may have implications in selecting dosage and/or schedule of 5-FU and IRI. We present here a prospective study of upfront pharmacogenetic testing with tailored dose of respective drugs in pts with these mutations. Methods: Pts with GI malignancies were tested for DPYD, TYMS and UGT1A1 mutations before initiating 5-FU and/or IRI. Mutation analyses were performed at Quest Diagnostics Nichols Institute. Pts were dosed at 50% if DPYD was abnormal and 25% dose reduction if indicated by TYMS or UGT1A1 * 28 (homozygous) abnormality. Adverse events (AEs) were graded according to CTCAE v.5.0. We compared AEs to our previously collected data in DPYD, TYMS deficient pts who underwent genetic testing due to toxicity to 5-FU. Results: Of 226 pts screened, 5 pts had DPYP mutations with genotypes (3: c.1905+1G/A; 1: c.2846A/T; 1: c.557A/G). TYMS mutations were identified in 24 pts. For 3'-UTR, distributions were: intermediate expression genotype 4: INS/DEL, low expression genotype 5: DEL/DEL. For 5'TSER, distributions were: low expression genotypes (6:2R/2R; 3:2R/3RC; 4: 3RC/3RC) and high expression genotypes (2: 2R/3RG, 2: 3RG/3RC, 1: 3RG/3RG). UGT1A1*28 mutation was identified in 53 pts – 19 homozygous and 34 heterozygous. No grade ≥3 neutropenia was observed with reduced dose of IRI in UGT1A 1 variant pts compared to 33% reported in pts not tested. For TYMS and DPYD variants, no grade ≥3 AEs were seen. Comparison of AEs in pts with post treatment genetic testing is listed in Table. Conclusions: Pharmacogenetic based dosing of 5-FU and IRI led to less frequent, less severe toxicities and no death related to AEs was observed in our pts. This can improve pts’ quality of life and lessen economic burden of managing severe AEs. Currently, there are no formal guidelines regarding testing for DPYD, TYMS and UGT1A1. Although non-randomized, this study advocates for systemic screening of pharmacogenetic testing in pts with GI malignancies. [Table: see text]