Abstract
5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in solid tumors, including colon, gastric and breast cancers. The pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency leading to severe toxicity after administration of 5-flourouracil (5-FU) and capecitabine has been well-recognized. However, the data about the association of the target enzyme, thymidylate synthase (TYMS) with the toxicity of these agents is limited. A 50-year-old Caucasian woman with T2N2M0 Stage IIIB squamous cell rectal cancer after local surgical excision initiated 5-FU therapy with mitomycin-C and radiation therapy in the adjuvant setting. Following the first treatment with 5-FU, she developed grade III mucositis and grade IV neutropenia which delayed her second dose of therapy. Following her second dose of 5-FU, she again developed grade III mucositis, grade II diarrhea, pancytopenia, fever, and rectal bleeding requiring hospitalization. She was treated with blood and platelet transfusion, pegfilgrastim, IV antibiotics, and supportive therapy. Due to her severe clinical toxicity following chemotherapy involving 5-FU, we tested her for both DPD deficiency andTYMS polymorphisms. The patient was found to be homozygous for the TYMS polymorphism 5’TSER genotype 2R/2R*f, which has been associated with increased 5-FU drug sensitivity and susceptibility to 5-FU toxicity. Our case report further underlines the fact that TYMS polymorphism not only predicts response to 5-FU by relating to intratumoral-TYMS mRNA expression but also the toxicity in these patients receiving fluoropyrimidines. In brief, TYMS genotype variations present a dilemma in 5-FU-driven cancer therapy- overexpression leads to decreased drug sensitivity and poor prognosis, while underexpression leads to the manifestation of toxic drug effects that may halt therapy altogether. Future prospective translational studies in a larger population are warranted to validate its role as a predictive and prognostic factor.
Highlights
5-Fluorouracil (5-FU) is an irreversible inhibitor of the enzyme thymidylate synthase (TYMS) and is the most frequently used drug in chemotherapy in a variety of gastrointestinal cancers [1]
We report a patient with TYMS 2R/2R (2 tandem repeats), homozygous polymorphic alleles receiving combination 5-FU and mitomycin-C (MMC) and radiation therapy (XRT) for Stage II rectal cancer who developed 5-FU associated toxicity and required hospitalization for severe neutropenia, thrombocytopenia, mucositis, and severe diarrhea
This elevated risk of toxicity is due to a lower level of enzyme in normal tissue cells which means that 5-FU cytotoxic characteristics more harm benign cells, but 5-FU more effectively acts as an antimetabolite in tumor cells due to lower levels of intratumoral TYMS mRNA
Summary
5-Fluorouracil (5-FU) is an irreversible inhibitor of the enzyme thymidylate synthase (TYMS) and is the most frequently used drug in chemotherapy in a variety of gastrointestinal cancers [1]. We report a patient with TYMS 2R/2R (2 tandem repeats), homozygous polymorphic alleles receiving combination 5-FU and mitomycin-C (MMC) and radiation therapy (XRT) for Stage II rectal cancer who developed 5-FU associated toxicity and required hospitalization for severe neutropenia, thrombocytopenia, mucositis, and severe diarrhea. Following a reaction from the initial platelet transfusion involving hives and periorbital edema, she was successfully transfused one unit of packed red blood cells and two units of platelets with a pre-infusion protocol Her neutropenia resolved on Day four of hospitalization with ANC of 2.6 k/uL and she remained afebrile until her discharge on Day five from admission. The 5-Fluorouracil Toxicity and Chemotherapeutic Response Panel (Quest Diagnostics/Nichols Institute – Chantilly, VA), indicated two mutations (2R) of a 28 base-pair tandem repeat in the 5’ promoter enhancer region (5’-TSER) on both alleles (2R/2R) of the thymidylate synthase (TYMS) gene. The commonly found DPYD gene mutations (1679 T>G, 1905+1 G>A, 2846 A>T) were not detected either
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