Publications by authors named "Tania Fleitas-Kanonnikoff"

6 Publications

  • Page 1 of 1

Neoadjuvant treatment for locally advanced unresectable and borderline resectable pancreatic cancer: oncological outcomes at a single academic centre.

ESMO Open 2020 11;5(6):e000929

CIBERONC, Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain; Department of Medical Oncology, University of Valencia, Valencia, Spain. Electronic address:

Introduction: Pancreatic cancer (PC), even in the absence of metastatic disease, has a dismal prognosis. One-third of them are borderline resectable (BRPC) or locally advanced unresectable PC (LAUPC) at diagnosis. There are limited prospective data supporting the best approach on these tumours. Neoadjuvant chemotherapy (ChT) is being increasingly used in this setting.

Methods: This is a retrospective series of consecutive patients staged as BRPC or LAUPC after discussion in the multidisciplinary board (MDB) at an academic centre. All received neoadjuvant ChT, followed by chemoradiation (ChRT) in some cases, and those achieving enough downstaging had a curative-intent surgery. Descriptive data about patient's characteristics, neoadjuvant treatments, toxicities, curative resections, postoperative complications, pathology reports and adjuvant treatment were collected. Overall survival (OS) and progression-free survival was calculated with Kaplan-Meier method and log-rank test.

Results: Between August 2011 and July 2019, 49 patients fulfilled the inclusion criteria, and all of them received neoadjuvant ChT. Fluorouracil+folinic acid, irinotecan and oxaliplatin was the most frequently used scheme (77%). The most prevalent grade 3 or 4 toxicities were neutropenia (26.5%), neurotoxicity (12.2%), diarrhoea (8.2%) and nausea (8.2%). 18 patients (36.7%) received ChRT thereafter. In total, 22 patients (44,9%) became potentially resectable and 19 of them had an R0 or R1 pancreatic resection. One was found to be unresectable at surgery and two refused surgery. A vascular resection was required in 7 (35%). No postoperative deaths were observed. Postoperative ChT was given to 12 (66.7%) of resected patients. Median OS of the whole cohort was 24,9 months (95% CI 14.1 to 35.7), with 30.6 months for resected and 13.1 months for non-resected patients, respectively (p<0.001).

Conclusion: A neoadjuvant approach in BRPC and LAUPC was well tolerated and allowed a curative resection in 38.8% of them with a potential improvement on OS.
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http://dx.doi.org/10.1136/esmoopen-2020-000929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684818PMC
November 2020

A phase Ib/II study of HER3-targeting lumretuzumab in combination with carboplatin and paclitaxel as first-line treatment in patients with advanced or metastatic squamous non-small cell lung cancer.

ESMO Open 2019 22;4(4):e000532. Epub 2019 Jul 22.

Department of Medical Oncology, Institute of Health Research INCLIVA, University of Valencia, Valencia and CIBERONC, Institute of Health Carlos III, Madrid, Spain.

Purpose: This study investigated the safety and clinical activity of lumretuzumab, a humanised antihuman epidermal growth factor receptor 3 (HER3) monoclonal antibody, in combination with carboplatin and paclitaxel in first-line treatment of patients with squamous non-small cell lung cancer (sqNSCLC). HER3 ligand heregulin and HER3 protein expression were evaluated as potential biomarkers of clinical activity.

Patients And Methods: This open-label, phase Ib/II study enrolled patients receiving lumretuzumab at 800 mg (flat) in combination with carboplatin (area under the curve (AUC) 6 mg/mL×min) and paclitaxel (200 mg/m) administered intravenously on a every 3-week schedule. Adverse event (AE) rates and tumour responses were determined. Heregulin messenger RNA (mRNA) and HER3 protein expression were investigated in archival tumour biopsies.

Results: Altogether, 12 patients received lumretuzumab in combination with carboplatin and paclitaxel. The most frequent AEs were gastrointestinal, haematological and nervous system toxicities, which were generally mild and manageable. Partial responses were observed in 3 of 12 patients lasting 81, 177 and 207 days. All responses were achieved in tumours expressing higher heregulin mRNA levels.

Conclusion: Lumretuzumab in combination with carboplatin and paclitaxel was well tolerated. Objective responses were enriched in tumours expressing higher heregulin mRNA levels.
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http://dx.doi.org/10.1136/esmoopen-2019-000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678014PMC
July 2019

In the literature: June 2019.

ESMO Open 2019 20;4(3):e000547. Epub 2019 Jun 20.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain.

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http://dx.doi.org/10.1136/esmoopen-2019-000547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590957PMC
June 2019

Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications.

ESMO Open 2019 27;4(3):e000470. Epub 2019 May 27.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain.

Background: The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors.

Material And Methods: We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation.

Results: Forty-five (18%) cases presented MSI and 13 (6%) were positive for EBV. MSI was associated with female sex, older age, distal location and distal non-diffuse type of the modified Lauren classification. EBV expression was most frequent in proximal location and proximal non-diffuse type. The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry for the microsatellite study were 91%, 98%, 91% and 98%, respectively. In the multivariate analysis, MSI was an independent predictor of favourable (MSI: HR: 0.37, 95% CI 0.12 to 0.95, p=0.04).

Conclusions: The MSI status and the EBV expression should be incorporated in routine pathological report for two reasons. First, MSI defines a different pathological entity with a better outcome. Second, MSI and EBV may be useful biomarkers to identify patients who will respond to immune checkpoint blockade inhibitors. For this purpose, immunohistochemical study for MMR proteins and in situ hybridisation study for EBV evaluation are feasible and cost-effective methods.
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http://dx.doi.org/10.1136/esmoopen-2018-000470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555614PMC
May 2019

Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy.

Cancer Med 2019 06 6;8(6):3120-3130. Epub 2019 May 6.

Department of Medical Oncology, CIBERONC, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.

Somatic mutation analysis and evaluation of microsatellite instability (MSI) have become mandatory for selecting personalized therapy strategies for advanced colorectal cancer and are not available as routine methods in Paraguay. The aims of this study were to analyze the molecular profile as well as the microsatellite status in a series of advanced colorectal patients from two public hospitals from Paraguay, to introduce these methodologies in the routine practice to guide the therapeutic decisions. Thirty-six patients diagnosed with advanced colorectal cancer from two referent public hospitals from Paraguay were recruited from May 2017 to February 2018. Sequenom Mass spectrometry, Oncocarta Panel V.1 was applied to analyze the mutational profile from formalin-fixed paraffin-embedded samples. The microsatellite status was tested by immunohistochemistry (IHC). The mean age of the patients was 52 years with a range from 20 to 74 years. Eighty-three percent of the patients included in the study have advanced-stage tumors at the moment of the diagnosis. Sixteen patients (44.4%) were wild-type for all the oncogene regions analyzed with the Oncocarta panel. Thirty-two hot-spot pathogenic variants on seven oncogenes, among 20 patients (55.6%), were identified, including KRAS, NRAS, BRAF, PI3KCA, FGFR, epidermal growth factor receptor, and PDGFRA. Moreover, 14 (38.8%) of these patients presented pathogenic variants in KRAS/NRAS or BRAF genes that have implications in the clinical practice decisions. Five patients (14%) presented MSI. The IHC study for microsatellite status and the molecular profile analysis through Sequenom mass spectrometry are feasible and useful methods, due to identify those patient candidates for targeted therapies and for the budgetary calculations of the National Health Plans.
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http://dx.doi.org/10.1002/cam4.2191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558499PMC
June 2019

First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors.

Clin Cancer Res 2016 Feb 13;22(4):877-85. Epub 2015 Oct 13.

Department of Oncology, Rigshospitalet, Copenhagen, Denmark.

Purpose: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.

Experimental Design: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.

Results: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration-time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥ 400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80-225 days).

Conclusions: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1683DOI Listing
February 2016
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