11058 Background: DPD deficiency is an inherited syndrome resulting from loss-of-function mutations within the DPYD gene. The IVS14+1G>A variant is associated with DPD deficiency as a result of a 165-bp deletion in the DPD mRNA. A rare mutation, 2846A>T, is characterized by a change of the acidic aspartic acid to the aliphatic valine with potential impairment of enzyme activity (Amstutz et al., 2011). In this study, we describe the spectrum of toxicities of 5-FU and capecitabine in patients carrying the IVS14+1G>A and 2846A>T variants. Methods: Data were collected from 450 patients with gastrointestinal, breast and pancreas cancers. They were evaluated for DPD genotype upon development of grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) secondary to standard fluoropyrimidine-containing regimens in combination with other cytotoxic agents and/or EGFR and VEGF antibodies. DNA was extracted from blood and IVS14+1G>A and 2846T>C DPD variants were screened on a Real-Time Life Sciences 7900 HT platform. The study was approved by the local Ethics Committee. Results: A total of 23 IVS14+1GA, four 2846AT, one IVS14+1AA and one 2846TT subjects were identified. Toxicities in all subjects were G3/4 diarrhea (100%), G3/4 mucositis (48%), febrile neutropenia (45%), G3/4 thrombocytopenia (38%), G3/4 anemia (24%), G2/3 hand-foot syndrome (14%), G3 dermatitis (7%) and G2/4 alopecia (7%). The homozygous IVS14+1AA patient survived because she was given a reduced 5-FU 250 mg/sqm test dose without folates, while the 2846TT patient deceased after the first cycle of FOLFOX4 treatment. Conclusions: Patients carrying the deleterious IVS14+1G>A and 2846T>C variant alleles display severe toxicities which is fatal in homozygous variant subjects. This finding suggests the usefulness of pre-treatment screening of DPD in patients candidates to fluoropyrimidine treatment. Acknowledgmnents. This study was supported by the Italian Association for Cancer Research (AIRC, Milano) and the Istituto Toscano Tumori (ITT, Firenze, Italy). Reference. Amstutz U, Froehlich TK, Largiadèr CR. Pharmacogenomics 2011;12:1321-36.