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

[EN] 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 PlansCONACYT Paraguay, Grant/Award Number: PINV-156/2015; INSTITUTO CARLOS III, Grant/Award Number: 17/00026 and CD15/00153; FONDOS FEDER; BankiaFleitas-Kanonnikoff, T.; Martinez-Ciarpaglini, C.; Ayala, J.; Gauna, C.; Denis, R.; Yoffe, I.; Sforza, S.... (2019). Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy. Wiley Interdisciplinary Reviews. Computational Molecular Science (Online). 8(6):3120-3130. https://doi.org/10.1002/cam4.2191S3120313086Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394-424. doi:10.3322/caac.21492Bray, F., & Piñeros, M. (2016). Cancer patterns, trends and projections in Latin America and the Caribbean: a global context. Salud Pública de México, 58(2), 104-117. doi:10.21149/spm.v58i2.7779Bohorquez, M., Sahasrabudhe, R., Criollo, A., Sanabria-Salas, M. C., Vélez, A., Castro, J. M., … Carvajal-Carmona, L. G. (2016). Clinical manifestations of colorectal cancer patients from a large multicenter study in Colombia. Medicine, 95(40), e4883. doi:10.1097/md.0000000000004883Sartore-Bianchi, A., Trusolino, L., Martino, C., Bencardino, K., Lonardi, S., Bergamo, F., … Siena, S. (2016). Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. The Lancet Oncology, 17(6), 738-746. doi:10.1016/s1470-2045(16)00150-9Martinez-Ciarpaglini, C., Oltra, S., Roselló, S., Roda, D., Mongort, C., Carrasco, F., … Cervantes, A. (2018). Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression. Modern Pathology, 32(2), 306-313. doi:10.1038/s41379-018-0124-5Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., … Schultz, N. (2013). Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal. Science Signaling, 6(269), pl1-pl1. doi:10.1126/scisignal.2004088Chakravarty, D., Gao, J., Phillips, S., Kundra, R., Zhang, H., Wang, J., … Schultz, N. (2017). OncoKB: A Precision Oncology Knowledge Base. JCO Precision Oncology, (1), 1-16. doi:10.1200/po.17.00011Arnold, M., Sierra, M. S., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2016). Global patterns and trends in colorectal cancer incidence and mortality. Gut, 66(4), 683-691. doi:10.1136/gutjnl-2015-310912Ohhara, Y., Fukuda, N., Takeuchi, S., Honma, R., Shimizu, Y., Kinoshita, I., & Dosaka-Akita, H. (2016). Role of targeted therapy in metastatic colorectal cancer. World Journal of Gastrointestinal Oncology, 8(9), 642. doi:10.4251/wjgo.v8.i9.64

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

ACCESO A LA INNOVACION: El cambio de paradigma en el manejo del paciente Oncológico.

Presentación realizada en el marco del “Proyecto multicéntrico de formación multidisciplinar en cáncer y aplicación de la Historia Clínica Electrónica (HCE) con el fin de integrar los datos clínico-moleculares y orientar la estrategia terapéutica”.CONACYT - Consejo Nacional de Ciencias y TecnologíaPROCIENCI

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

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