Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment.

AIMS: The importance of polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD) for the prediction of severe toxicity in 5-fluorouracil (5-FU)-based chemotherapy is still unclear. This study aims to assess the predictive value of DPYD variation with respect to previously described DPYD variants for 5-FU toxicity. It represents the first analysis of the gene at the haplotype level, also capturing potentially important genetic variation located outside the coding regions of DPYD. MATERIALS & METHODS: The entire coding sequence and exon-flanking intronic regions of DPYD were sequenced in 111 cancer patients receiving fluoropyrimidine-based chemotherapy. DPYD haplotypes were inferred and their associations with severe 5-FU toxicity were assessed. RESULTS: None of the previously described deleterious variants (IVS14+1G>A, c.2846A>T and c.1679T>G) were detected in 24 patients who experienced severe 5-FU toxicity. A potential association was observed between a haplotype containing three novel intronic polymorphisms (IVS5+18G>A, IVS6+139G>A and IVS9-51T>G) and a synonymous mutation (c.1236G>A), which was observed five- out of eight-times in patients with severe adverse effects. CONCLUSION: The association of a haplotype containing no nonsynonymous or splice-site polymorphisms indicates that additional important genetic variation may be located in noncoding gene regions. Furthermore, a comparison with other studies suggests that the relative importance of particular DPYD mutations (IVS14+1G>A and c.2846A>T) for predicting severe 5-FU toxicity differs geographically across Europe.

Hypermethylation of the DPYD promoter region is not a major predictor of severe toxicity in 5-fluorouracil based chemotherapy.

BACKGROUND: The activity of dihydropyrimidine dehydrogenase (DPD), the key enzyme of pyrimidine catabolism, is thought to be an important determinant for the occurrence of severe toxic reactions to 5-fluorouracil (5-FU), which is one of the most commonly prescribed chemotherapeutic agents for the treatment of solid cancers. Genetic variation in the DPD gene (DPYD) has been proposed as a main factor for variation in DPD activity in the population. However, only a small proportion of severe toxicities in 5-FU based chemotherapy can be explained with such rare deleterious DPYD mutations resulting in severe enzyme deficiencies. Recently, hypermethylation of the DPYD promoter region has been proposed as an alternative mechanism for DPD deficiency and thus as a major cause of severe 5-FU toxicity. METHODS: Here, the prognostic significance of this epigenetic marker with respect to severe 5-FU toxicity was assessed in 27 cancer patients receiving 5-FU based chemotherapy, including 17 patients experiencing severe toxic side effects following drug administration, none of which were carriers of a known deleterious DPYD mutation, and ten control patients. The methylation status of the DPYD promoter region in peripheral blood mononuclear cells was evaluated by analysing for each patient between 19 and 30 different clones of a PCR-amplified 209 base pair fragment of the bisulfite-modified DPYD promoter region. The fragments were sequenced to detect bisulfite-induced, methylation-dependent sequence differences. RESULTS: No evidence of DPYD promoter methylation was observed in any of the investigated patient samples, whereas in a control experiment, as little as 10% methylated genomic DNA could be detected. CONCLUSION: Our results indicate that DYPD promoter hypermethylation is not of major importance as a prognostic factor for severe toxicity in 5-FU based chemotherapy.

Infiltrating lobular carcinoma of the breast: systemic treatment.

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer after invasive ductal carcinoma (IDC). It is characterized by unique clinical, biological and molecular properties. ILC is almost always positive for the estrogen receptor and is typically of a lower grade compared with IDC. We have reviewed selected literature on preoperative (neoadjuvant) and adjuvant systemic therapy of breast cancer focusing on the differential therapy of ILC. Despite the importance of this type of breast cancer, information about its specific treatment is sparse, in particular with regard to adjuvant systemic chemotherapy. ILC has significantly lower rates of response to neoadjuvant chemotherapy compared with IDC; however, the low chemosensitivity seems not to result in a survival disadvantage. Adjuvant hormonal therapy studies do not distinguish between ILC and IDC. Thus, recommendations about endocrine therapies are made using the same criteria as for IDC.