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Apellaniz-Ruiz M.,Spanish National Cancer Research Center | Lee M.-Y.,Karolinska Institutet | Sanchez-Barroso L.,Spanish National Cancer Research Center | Gutierrez-Gutierrez G.,Hospital Universitario Infanta Sofia | And 16 more authors.
Clinical Cancer Research

Purpose: Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a wholeexome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy. Experimental Design: Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes. Results: WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4∗20 allele) and a novel missense variant (CYP3A4∗25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4∗20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4∗8 and the novel CYP3A4∗27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2- And 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P 1/4 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7- And 3-fold higher risk for loss-of-function and missense variants, respectively, P 1/4 5.9 10-5). Conclusion: This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization. © 2014 American Association for Cancer Research. Source

Seiwert T.Y.,University of Chicago | Fayette J.,University of Lyon | Cupissol D.,Institute Du Cancer Of Montpellier Val Daurelle | del Campo J.M.,Hospital Universitario Vall dHebron | And 7 more authors.
Annals of Oncology

Background: Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy. Patients and methods: An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1: 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m2/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR). Results: A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab. Conclusion: Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Rodriguez-Pascual J.,Centro Integral Oncologico Clara Campal CIOCC | Sha P.,Johns Hopkins University | Garcia-Garcia E.,Centro Integral Oncologico Clara Campal CIOCC | Rajeshkumar N.V.,Johns Hopkins University | And 7 more authors.
Investigational New Drugs

Summary: A high throughput screening for anticancer activity of FDA approved drugs identified mycophenolic acid (MPA), an inhibitor of inositol monophosphate dehydrogenase (IMPDH) as an active agent with an antiangiogenesis mode of action. Exposure of pancreatic cancer cell lines to MPA resulted in growth inhibition and reduced the expression of VEGF that was reversed by supplementing the media with guanosine supporting and IMPDH-dependant mechanism. In preclinical in vivo study, MPA showed a moderate inhibition of tumor growth in a panel of 6 human derived pancreatic cancer xenografts but reduced the expression of VEGF. To investigate the effects of MPA in human pancreatic cancer, a total of 12 patients with resectable pancreatic cancer (PDA) received increasing doses of mycophenolate mofetil (MMF) in cohorts of 6 patients each from 5-15 days prior to surgical resection. Treatment was well tolerated with one episode of grade 1 muscle pain, one episode of grade 2 lymphopenia (2 gr/day dose) and one episode of grade 2 elevantion in LFT (all in the 2 gr./day dose). Patients recovered from surgery uneventfully with no increased post-operative complications. Assessment of CD31, VEGF, and TUNEL in resected specimens compared to a non treated control of 6 patients showed no significant variations in any of the study endpoints. In conclusion, this study shows the feasibility of translating a preclinical observation to the clinical setting and to explore a drug mechanism of action in patients. MPA, however, did not show any hints of antiangiogenesis of anticancer clinical activity questioning if this agent should be further developed in PDA. © 2012 Springer Science+Business Media, LLC. Source

Duran I.,Centro Integral Oncologico Clara Campal CIOCC | Duran I.,Hospital Universitario Virgen Del Rocio | Garzon C.,Instituto Catalan Oncologia ICO IDIBELL | Sanchez A.,Hospital Universitario Puerta Of Hierro | And 7 more authors.
Clinical and Translational Oncology

Purpose: To estimate the cost per skeletal-related event (SRE) in patients with bone metastases secondary to solid tumours in the Spanish healthcare setting. Methods: Patients diagnosed with bone metastases secondary to breast, prostate or lung cancer were included in this multicentre, observational study. SREs are defined as pathologic fracture (vertebral and non-vertebral fracture), radiation to bone, spinal cord compression or surgery to bone. Health resource utilisation associated with these events (inpatient stays, outpatient, emergency room and home health visits, nursing home stays and procedures) were collected retrospectively for all SREs that occurred in the 97 days prior to enrolment and prospectively during follow-up. Unit costs were obtained from the 2010 eSalud healthcare costs database. Results: A total of 93 Spanish patients with solid tumours were included (31 had breast cancer, 21 prostate cancer and 41 lung cancer), contributing a total of 143 SREs to this cost analysis. Inpatient stays (between 9.0 and 29.9 days of mean length of stay per inpatient stay by SRE type) and outpatient visits (between 1.7 and 6.4 mean visits per SRE type) were the most frequently reported types of health resources utilised. The mean cost per SRE was between €2,377.79 (radiation to bone) and €7,902.62 (spinal cord compression). Conclusion: SREs are associated with a significant consumption of healthcare resources that generate a substantial economic burden for the Spanish healthcare system. © 2013 The Author(s). Source

Sanmamed M.F.,University of Navarra | Rodriguez I.,University of Navarra | Schalper K.A.,Yale University | Onate C.,University of Navarra | And 14 more authors.
Cancer Research

A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cellsurface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4+ T cell-mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patientderived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFNγ and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations. © 2015 American Association for Cancer Research. Source

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