Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands.

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.

DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update.

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care.

CYP2D6 Metabolism in Frail Elderly Compared to Non-Frail Elderly: A Pilot Feasibility Study.

BACKGROUND: Frailty is a clinical phenotype that is associated with adverse health outcomes. Since frail patients may be more prone for adverse drug events and about 15-20 % of commonly prescribed drugs are metabolized by CYP2D6, we hypothesized that CYP2D6 metabolism is decreased in frail patients compared with healthy subjects. METHODS: The (13)C-dextromethorphan breath test (DM-BT) was used to determine CYP2D6 phenotype using (13)C-dextromethorphan ((13)C-DM) as a probe. Eleven frail and 22 non-frail (according to the Fried criteria) subjects aged 70-85 years were phenotyped for CYP2D6. RESULTS: Despite inequalities in CYP2D6 genotype between frail and non-frail subjects, the CYP2D6 gene activity score was equally distributed between the two groups (1.33 ± 0.50 vs. 1.28 ± 0.752). In male patients, no difference in total and free serum testosterone levels was observed between frail and non-frail men. Serum dehydroepiandrostenedione sulfate (DHEAS) levels were lower in frail subjects (1.56 µmol/L) compared with non-frail subjects (2.36 µmol/L), but the difference was not significant (p = 0.15). Body mass index was significantly correlated to CYP2D6 phenotype, whereas frailty score and individual parameters of frailty, Karnofsky score, and activities of daily living score were not significantly correlated to CYP2D6 phenotype. Although there was no difference in CYP2D6 phenotype observed between frail mean ± standard deviation (mean ± SD) area under the curve for delta over baseline values (0-2 h) (AUCDOB2h) 319 ± 169 ‰ min] and non-frail subjects (mean ± SD AUCDOB2h 298 ± 159 ‰ min), the present sample size is considered too small to draw any firm conclusions regarding a potential phenoconversion of CYP2D6 in frail elderly as compared with healthy subjects. CONCLUSION: Frail and non-frail subjects did not differ in CYP2D6 phenotype, taking into account that the precalculated sample size was not achieved. Further studies with more patients are needed in order to adequately understand a possible correlation.

CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects.

Breast cancer patients with absent or reduced CYP2D6 activity and consequently low endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual's endoxifen level at baseline relative to the average endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.

Further characterization of a ¹³C-dextromethorphan breath test for CYP2D6 phenotyping in breast cancer patients on tamoxifen therapy.

In a previous study, we found that the CYP2D6 phenotype determined by (13)C-dextromethorphan breath test (DM-BT) might be used to predict tamoxifen treatment outcome in breast cancer patients in the adjuvant setting. However, large variation in the delta-over-baseline (DOB) values was observed in the extensive metabolizer predicted phenotype group based on single point measures. In the present work we aimed to analyze the variability of phenotype results and determine reproducibility to further characterize the clinical utility of DM-BT by introducing multiple breath sampling instead of single breath sampling and by administration of a fixed dose of (13)C-DM.

The use of the 13C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels.

PURPOSE: Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in endoxifen levels is only partly explained by CYP2D6 genotype, we explored the use of the (13)C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen. METHODS: In 65 patients with early breast cancer using tamoxifen, CYP2D6 phenotype was assessed by DM-BT. CYP2D6 genotype using Amplichip and serum steady-state levels of endoxifen were determined. Genotype was translated into the gene activity score and into ultrarapid, extensive, heterozygous extensive, intermediate or poor metabolizer CYP2D6 predicted phenotype. RESULTS: CYP2D6 phenotype determined by the DM-BT explained variation in serum steady-state endoxifen levels for 47.5% (R(2) = 0.475, p < 0.001). Positive and negative predictive values for a recently suggested threshold serum level of endoxifen (5.97 ng/mL) for breast cancer recurrence rate were 100 and 90%, respectively, for both CYP2D6 phenotype by DM-BT (delta-over-baseline at t = 50 min (DOB(50)) values of 0.7-0.9) and genotype (CYP2D6 gene activity score of 1.0). CONCLUSION: DM-BT might be, along with CYP2D6 genotyping, of value in selection of individualized endocrine therapy in patients with early breast cancer, especially when concomitant use of CYP2D6 inhibiting medication alters the phenotype.

The tolerability and efficacy of low-dose simvastatin in statin-intolerant patients.

BACKGROUND/AIM: Statin intolerance is increasingly recognized as a therapy limiting factor in the primary and secondary prevention of cardiovascular disease. Since vulnerability to dose related adverse events differ between subjects treated with statins we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients. METHOD: A single center open label prospective observational study was performed assessing tolerability and efficacy of low-dose simvastatin treatment in 35 statin-intolerant patients. Statin intolerance was defined as not being able to tolerate a registered dose statin due to myalgia-myopathy, myositis, or elevation of serum liver enzyme levels. These statin-intolerant patients were treated with simvastatin with an initial dose of 2.5mg every other day. The dose was titrated upwards if possible. Tolerability was defined as remaining on treatment. Efficacy was defined as change of LDL-cholesterol compared to baseline. RESULTS: The reached simvastatin dose ranged from 0.825 to 8.75mg/day with a mean dose of 4mg/day. Fifty-seven percent of the patients tolerated low-dose therapy and remained on treatment. Of these patients, 30% noted recurrent myalgia. Low-dose simvastatin significantly decreased mean(SD) LDL-cholesterol levels with 25.9(12.1)% (p<0.001). Eleven percent of the patients reached LDL-cholesterol target levels (<2.6mmol/l) in an intention to treat analysis and in 20% of patients that tolerated low-dose simvastatin. CONCLUSION: Low-dose simvastatin therapy is tolerated in a considerable proportion of statin-intolerant patients with significant lipid lowering efficacy. Low-dose statin therapy can be considered in multidrug regimens in statin-intolerant patients.

Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis.

3-phosphoglycerate dehydrogenase (PHGDH) deficiency is a disorder of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures. To investigate the molecular basis for this disorder, the PHGDH mRNA sequence was characterized, and six patients from four families were analyzed for sequence variations. Five patients from three different families were homozygous for a single nucleotide substitution predicted to change valine at position 490 to methionine. The sixth patient was homozygous for a valine to methionine substitution at position 425; both mutations are located in the carboxyterminal part of PHGDH. In vitro expression of these mutant proteins resulted in significant reduction of PHGDH enzyme activities. RNA-blot analysis indicated abundant expression of PHGDH in adult and fetal brain tissue. Taken together with the severe neurological impairment in our patients, the data presented in this paper suggest an important role for PHGDH activity and L-serine biosynthesis in the metabolism, development, and function of the central nervous system.