Sequential RAS mutations evaluation in cell-free DNA of patients with tissue RAS wild-type metastatic colorectal cancer: the PERSEIDA (Cohort 2) study.

PURPOSE: RAS (KRAS/NRAS) mutational status on a tumor biopsy is mandatory to guide the best treatment in metastatic colorectal cancer (mCRC). Determining the RAS mutational status by tumor-tissue biopsy is essential in guiding the optimal treatment decision for mCRC. RAS mutations are negative predictive factors for the use of EGFR monoclonal antibodies. Cell-free DNA (cfDNA) analysis enables minimally invasive monitoring of tumor evolution. METHODS/PATIENTS: PERSEIDA was an observational, prospective study assessing cfDNA RAS, BRAF and EGFR mutations (using Idylla™) in first-line mCRC, RAS wild-type (baseline tumor-tissue biopsy) patients (cohort 2). Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. RESULTS: 117 patients were included (103 received panitumumab + chemotherapy as first-line treatment). At baseline, 7 (6.8%) patients had RAS mutations, 4 (3.9%) BRAF mutations and no EGFR mutations were detected (cfDNA, panitumumab + chemotherapy subpopulation [panitumumab + Ch]). The baseline RAS mutational status concordance between tissue and liquid biopsies was 94.0% (93.2%, panitumumab + Ch). At 20 weeks, only one patient in the study (included in the panitumumab + Ch) had an emerging cfDNA RAS mutation. No emerging BRAF or EGFR mutations were reported. At disease progression, 6 patients had emergent mutations not present at baseline (RAS conversion rate: 13.3% [6/45]; 15.0% [6/40], panitumumab + Ch). CONCLUSIONS: The concordance rate between liquid and solid biopsies at baseline was very high, as previously reported, while our results suggest a considerable emergence of RAS mutations during disease progression. Thus, the dynamics of the genomic landscape in ctDNA may provide relevant information for the management of mCRC patients.

Pharmacokinetics of Trastuzumab After Subcutaneous and Intravenous Administration in Obese Patients.

Background: Subcutaneous trastuzumab (T-SC) administration does not allow the historical target concentration of 20 µg/mL for efficacy to be reached, from the start of treatment in patients with a body mass index (BMI) >30 kg/m2. Objectives: To analyze the influence of the strategy of dosification (fixed vs adjusted patient's body weight dose) on the initial minimum plasma concentration (Cmin) of trastuzumab in obese patients. Methods: This was an observational, prospective study, which included patients with HER2-positive nonmetastatic breast cancer treated with trastuzumab. The determination of the Cmin of trastuzumab was performed on day +21 of the first cycle using the ELISA technique. Patients were stratified according to the strategy of dosification and BMI. Results: A total of 50 patients were included; 16 patients received the drug intravenously and 34 in a fixed dosage subcutaneous (T-SC) regimen. The proportion of patients who achieved an adequate plasma concentration since the beginning of treatment was significantly higher when the drug was administered intravenously (93.8% vs 67.6%, P = 0.042). These differences are especially greater in T-SC patients with BMI >30 kg/m2, with only 20% of patients exceeding the pharmacokinetic target. Conclusion and Relevance: Our study suggests that trastuzumab SC fixed dose of 600 mg is not equivalent to IV administration, especially in obese patients. An adequate trastuzumab exposure in this population needs patient weight-adjusted IV dosage in the first administration. The clinical relevance of these findings remains to be elucidated, and further research, including larger controlled trials, is warranted.

Efecto de los polimorfismos en UGT, SLCO, ABCB y ABCC en la toxicidad del tratamiento con irinotecán / Effect of UGT, SLCO, ABCB and ABCC polymorphisms on irinotecan toxicity

Antecedentes y objetivos: Evaluar la relación entre la presencia de polimorfismos en los genes implicados en la farmacodinamia del irinotecán (UGT1A, SLCO1B1, ABCB1 y ABCC2) y la seguridad asociada al mismo en el tratamiento del cáncer colorrectal metastásico (CCRm). Pacientes y métodos: Estudio prospectivo observacional y unicéntrico de 30 meses de duración, en el que se incluyeron los pacientes diagnosticados de CCRm tratados con el esquema FOLFIRI. La toxicidad fue evaluada en cada ciclo de tratamiento según la Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. La obtención del ADN genómico se realizó mediante una muestra de sangre periférica a partir de un método de extracción basado en lisis alcalina. La caracterización genética se realizó empleando la plataforma LigthCycler®480 y sondas fluorescentes HybProbe® específicas de alelo. Los polimorfismos analizados fueron: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) y ABCB1 (rs1045642). Resultados: Fueron incluidos 34 pacientes (el 73,5% eran hombres, con una edad media de 59,9 años [27-81]). Los polimorfismos: rs8175347, rs17868323, rs3832043, rs11692021 y rs7577677 se relacionaron con una mayor incidencia de efectos adversos. Por otro lado, se observó que aquellos pacientes wild-type, en la serie de genes de la familia UGT analizada, presentan unas menores tasas de toxicidad asociada al tratamiento con irinotecán que aquellos que poseen alguno de los polimorfismos analizados (p=0,010). Conclusiones: Estos resultados sugieren que la presencia de determinados polimorfismos en la familia de genes UGT1A se encuentra relacionada con el desarrollo de toxicidad en el tratamiento con irinotecán en dosis para el esquema FOLFIRI

Background and objectives: Evaluate the relationship between the presence of polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer (mCRC). Patients and methods: Prospective observational, single-centre study of 30 months duration, which included patients diagnosed with mCRC treated with FOLFIRI was carried out. Toxicity was evaluated in each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. Genomic DNA was obtained with a peripheral blood sample from an extraction method based on alkaline lysis. Genetic characterisation was performed using the LigthCycler®480 platform and allele-specific HybProbe® fluorescent probes. Analysed polymorphisms were: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) and ABCB1 (rs1045642). Results: Thirty-four patients were included (73.5% were male, mean age 59.9 years [27-81]) in the study. Polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Furthermore, it was observed that those patients with wild-type in UGT family genes analysed have lower rates of toxicity associated with irinotecan treatment than those with certain mutated allele (P=.010). Conclusions: These results suggest that the presence of certain polymorphisms in the UGT1A family of genes is related to the development of toxicity during treatment with irinotecan

Effect of UGT, SLCO, ABCB and ABCC polymorphisms on irinotecan toxicity. / Efecto de los polimorfismos en UGT, SLCO, ABCB y ABCC en la toxicidad del tratamiento con irinotecán.

BACKGROUND AND OBJECTIVES: Evaluate the relationship between the presence of polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Prospective observational, single-centre study of 30 months duration, which included patients diagnosed with mCRC treated with FOLFIRI was carried out. Toxicity was evaluated in each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. Genomic DNA was obtained with a peripheral blood sample from an extraction method based on alkaline lysis. Genetic characterisation was performed using the LigthCycler®480 platform and allele-specific HybProbe® fluorescent probes. Analysed polymorphisms were: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) and ABCB1 (rs1045642). RESULTS: Thirty-four patients were included (73.5% were male, mean age 59.9 years [27-81]) in the study. Polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Furthermore, it was observed that those patients with wild-type in UGT family genes analysed have lower rates of toxicity associated with irinotecan treatment than those with certain mutated allele (P=.010). CONCLUSIONS: These results suggest that the presence of certain polymorphisms in the UGT1A family of genes is related to the development of toxicity during treatment with irinotecan.

SEOM clinical guidelines for the treatment of follicular non-Hodgkin's lymphoma.

Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin's lymphoma (NHL) in the Western world. FL constitutes the most frequent indolent lymphoma, well characterized by its clinical presentation related to nodal involvement and its morphologic and biologic features. It is often managed as an incurable disease. However, several active therapeutic approaches from the "wait and watch" strategy to the allogeneic transplantation are available for management of patients with FL and clearly have changed the natural history of this disease, achieving a long-term disease-free survival. Therapeutic decision is mostly conditioned by patient's characteristics, stage, histological grade, tumor burden, and risk-predicting factors. This article try to summarizes the diagnosis and treatment of this heterogeneous group of patients.

A phase II trial of gemcitabine and weekly high-dose 5-fluorouracil in a 48-hour continuous-infusion schedule in patients with advanced pancreatic carcinoma. A study of the Spanish Cooperative Group for Gastrointestinal Tumour Therapy (TTD)

Aim. A multi-centred, open-labelled, phase II study containing 46 patients was conducted to evaluate the clinical benefit of gemcitabine (1,400 mg/m2) combined with 5-FU (3 g/m2) in a 48h continuous infusion (CI). Methods. Both drugs were administered on days 1, 8 and 15 of every 4 week cycle in chemotherapy-naïve patients with locally advanced un-resectable metastatic pancreatic carcinoma. The minimum follow-up was 6 months. Results. Clinical benefit response was the primary endpoint and this was achieved by 24.4% of the patients. Quality of life (QoL) improved in 16.6% of patients. Objective response was observed in 7% of the patients. The median progression-free survival (PFS) was 14.4 weeks and the median overall survival (OS) time was 22.7 weeks. One-year survival was 25%. The most frequent grade 3-4 toxicities were neutropenia (45%), mucositis (7.5%) and hyperbilirubinaemia (10.5%). Conclusions. This schedule was not superior in terms of clinical benefit, response rate, PFS and OS than standard gemcitabine treatment