Summary Individuals with a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) may experience severe life-threatening toxicity when treated with 5-fluorouracil (5-FU). As routine measurement of enzyme activity is not practical in many clinical centres, we have investigated the use of DNA mutation analysis to identify cancer patients with low enzyme levels. We have identified two new mutations at codons 534 and 543 in the DPD cDNA of a patient with low enzyme activity and screened the DNA from 75 colorectal cancer patients for these mutations and the previously reported splice site mutation (Vreken et al, 1996;Wei et al, 1996). In all cases, DPD enzyme activity was also measured. The splice site mutation was detected in a patient (1 out of 72) with low enzyme activity whereas mutations at codons 534 (2 out of 75) and 543 (11 out of 23) were not associated with low enzyme activity. These studies highlight the need to combine DPD genotype and phenotype analysis to identify mutations that result in reduced enzyme activity.Keywords: dihydropyrimidine dehydrogenase; 5-fluorouracil; polymorphism; colorectal cancer 5-Fluorouracil (5-FU) is widely used in the treatment of advanced solid tumours, including colorectal, breast and head/neck tumours. 5-FU is also frequently used in adjuvant chemotherapy for colorectal and breast cancers, in which its mild toxicity profile of mucositis and diarrhoea is well tolerated by patients who are at risk for tumour recurrence but have no current evidence of disease. 5-FU is a pyrimidine analogue and greater than 80% of a dose is degraded in a three-step pathway, initially catalysed by the enzyme dihydropyrimidine dehydrogenase (DPD; E.C. 1.3.1.2., Heggie et al, 1987). Deficiency in DPD enzyme activity is associated with a considerable delay in clearance of 5-FU from the plasma (Diasio et al, 1988;Fleming et al, 1992), leading to severe, life-threatening diarrhoea, neutropenia and in some cases neurotoxicity, incurring prolonged hospitalization . High concentrations of plasma and urine 5-FU, uracil and thymine may be detected along with low mononuclear cell DPD activity in these patients. The toxicity is thought to result from higher levels of 5-FU entering the anabolic pathway, resulting in an increased production of cytotoxic nucleotides. Although thymidine rescue has been attempted in one case (Takimoto et al, 1996), the majority of cases have been managed with supportive care after the cessation of 5-FU-based therapy. DPD activity is found in most human tissues, with the highest levels in the liver and lymphocytes. Population studies of peripheral blood mononuclear cell (PBMNC) DPD have shown that enzyme activity is variable with a seven-to 10-fold range observed (Lu et al, 1993;Etienne et al, 1994;McMurrough and McLeod, 1996). These studies suggest that although total deficiency is rare in adults, as many as 3% of the population may have low enzyme levels and thus be at One mutation in the DPYD gene has been reported to date in patients exhibiting severe toxicity after 5...

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Introduction: TACT2, a multicentre randomized phase III trial in patients with node +ve or high risk node -ve invasive EBC with E-CMF as control (Poole NEJM 2006), tests two hypotheses in a 2×2 factorial design: A) accelerated epirubicin (aE) improves outcomes compared to standard epirubicin (E) (CALGB9741 Citron JCO 2003); and B) capecitabine (X) gives similar efficacy but preferential side-effect profile to CMF. Here we focus on the impact of accelerating epirubicin treatment on patient outcome. Tolerability and toxicity of this regimen have already been presented (Cameron 2010, SABCS); 33/4391 pts did not start chemotherapy. 4261 (97%) completed the initial 4 cycles (E 2143 (96%), aE 2118 (98%)) with RDI >85% for E 2061 (93%) and aE 1985 (91%). Serious CTCAE toxicity was less common with aE compared with E, however patients report poorer global QL, fatigue & role function which does not appear to be explained by impact on daily activities due to individual side-effects. Patients & Methods: Between December 2005 and December 2008, 4391 patients (4371 women, 20 men) were randomized to receive either E (100mg/m2 × 4) q3wk or aE (100mg/m2 × 4 plus pegfilgrastim, 6mg d2) q2wk followed by classical CMF q4wk × 4 or X (2500mg/m2/day × 14) q3wk × 4. Other adjuvant treatment was delivered according to local practice (HER2+ve – sequential trastuzumab for 1 year from June 2006; ER/PgR+ve - endocrine therapy for 5 years). Tumor blocks were collected prospectively to enable central biomarker testing. Median age of patients was 52 years (IQR 46–59). 53% patients had node +ve disease; 59% had tumors >2cm; 57% were grade 3. According to local assessment, of 4366 patients where both ER and HER2 status were known, 60% had ER+ve/HER2-ve tumors, 19% HER2+ve, 21% ER-ve/HER2-ve. Primary endpoint was time to recurrence (TTR), defined as time to loco-regional or distant relapse, or breast cancer-death. Secondary endpoints included disease-free survival (DFS), overall survival (OS), tolerability of regimens and quality of life. TACT2 has over 90% power to detect a clinically meaningful 4% difference in TTR between standard and accelerated epirubicin schedules (from 80% to 84% at 5 years). Survival estimates will be compared using stratified log-rank tests and Cox regression. Results: At 1st June 2012, median follow up was 49 months (interquartile range: 46–60) with 553 TTR events reported. The Independent Data Monitoring Committee consider these data sufficiently mature for presentation of analyses relating to the accelerated epirubicin hypothesis. A further data snapshot, after query resolution, for the main analysis will be taken in Q3 2012. Data to be presented, by treatment group, include TTR, DFS, OS, late toxicity and pre-planned subgroup analyses according to ER, PgR and HER2 status and Ki67 levels. Discussion: TACT2 will provide a definitive analysis to confirm or refute benefits previously reported for accelerating anthracycline chemotherapy in early breast cancer including, via pre-planned subgroup analyses, exploration of the potential benefits in phenotypic subtypes. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-3.

A total of 218 postmenopausal patients were entered in a prospective randomized trial comparing aminoglutethimide (AG) and high-dose medroxyprogesterone acetate (MPA) as second-line hormonal therapy for advanced breast carcinoma. All responses were assessed by the criteria of the International Union Against Cancer. The response rates were 27% (29 of 106 patients) for AG and 31% (35 of 112) for MPA, but if stabilization of previously progressive disease is included, then the overall response rates were 51% (54 of 106) and 54% (61 of 112) for patients receiving AG or MPA, respectively. There was no difference in response to the two drugs at any site of disease, and the durations of response and survival were identical for the two drugs. The time to response was significantly shorter for patients treated with MPA (median, 8.7 wk) than for those treated with AG (median, 15.3 wk) (chi 2 = 9.96, 1 df, P = .0016). The percentage of patients experiencing toxic effects was equivalent in both arms, although the patterns and time courses of these effects were different.

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