53 research outputs found
BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer
Inhibidor de BRAF; Binimetinib; CĂĄncer de colonBRAF inhibitor; Binimetinib; Colon cancerInhibidor de BRAF; Binimetinib; CĂ ncer de cĂČlonIntroduction:
BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates.
Areas covered:
This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented.
Expert opinion:
Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Instituto de Salud Carlos III (ISCIII) FIS/FEDER (PI17/00947, PI20/00968) and from the European Unionâs Horizon 2020 research and innovation programme under grant agreement No 635342
Current professional standing of young medical oncologists in Spain : a nationwide survey by the Spanish Society of Medical Oncology + MIR section
There is a lack of knowledge about the career paths and employment situation of young medical oncologists. The aim of our study was to evaluate the current professional standing of these professionals in Spain. The Spanish Society of Medical Oncology + MIR section conducted a national online survey in May 2021 of young medical oncology consultants (< 6 years of expertise) and final year medical oncology residents. A total of 162 responses were eligible for analysis and included participants from 16 autonomous communities; 64% were women, 80% were consultants, and 20% were residents. More than half of the participants performed routine healthcare activity and only 7% research activity. Almost three quarters (73%) were subspecialized in a main area of interest and almost half of these chose this area because it was the only option available after residency. Half of the respondents (51%) considered working abroad and 81% believed the professional standing in Spain was worse than in other countries. After finishing their residency, only 22 were offered a job at their training hospital. Just 16% of participants had a permanent employment contract and 87% were concerned (score of â„ 5 on a scale of 1-10) about their job stability. In addition, one quarter of the participants in our study showed an interest in increasing their research activity. The choice of subspecialty in medical oncology may depend on job opportunities after residency rather than personal interest. The abundance of temporary contracts may have influenced the job stability concerns observed. Future mentoring strategies should engage in building a long-term career path for young medical oncologists. The online version contains supplementary material available at 10.1007/s12094-022-02989-3
Impact of circulating tumor DNA mutant allele fraction on prognosis in RASâmutant metastatic colorectal cancer
Metastatic colorectal cancer; RAS analysis; Prognostic biomarkerCĂĄncer colorrectal en metĂĄstasis; AnĂĄlisis RAS; Biomarcador como pronĂłsticoCĂ ncer colorectal en metĂ stasi; AnĂ lisi RAS; Biomarcador com a pronĂČsticDespite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RASâmutant allele fraction (MAF) in plasma in mCRC. Fortyâseven plasma samples from 37 RASâmutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before firstâ and/or secondâline treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19â9 levels, primary site location, and treatment line) and clinical outcome [progressionâfree survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRIâGOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and firstâline PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease (P = 0.007). Patients with low MAFs at baseline in the CAPRIâGOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5â9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07â5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice.This work was supported partially by the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad) and `Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa' grants [FIS PI12-01589 to RS] and RETICC Cancer
Handbook for Moving towards Multiprofessional Work
This handbook was supposed to be a choral artwork and the result is a very choral
and artistic patchwork.
In the process of building up the project âMOMU â Moving towards
Multiprofessional Workâ, we sewed, we combined patterns to define new ones. We
knew our shapes were different as were our fabrics but we learned to measure and
cut in order to create a larger design. The results of this is what you can see in this
handbook. We hope youâll agree that the whole is greater than the sum of the parts.
It has not been easy to piece this together. These types of processes bring with
them discussions, arguments, discoveries, hopes, despair and bureaucratic
requirements; all inevitable parts of such a complex process. However, it is
honest to say that the process has been exciting and paves the way for future and
productive collaborations.
Along the way some of the participants left us: Carola Boehm and Esther Mercado;
some others joined us: Pedro de la Paz. Some changes took place in our universities,
new roles were assumed. This is also part of the richness of the tapestry. We are
very thankful to all of them for their contribution.
We thank the European Union for funding this project. For all of us it was the first
time we had developed an Erasmus+ KA2 project and we had to apply the âlearning
by doing formulaâ, but we managed.
We are very thankful to teachers who volunteered to participate in the training
sessions, to practitioners who gave us important input and feedback and showed us
how to improve and make our teaching more practical. Thanks also to our national
steering groups for their clarity and recommendations. Importantly, our gratitude
extends to our students: social work and art students, who were open to new
perspectives and ways of exploring their place in the world and the job market.
Youth unemployment in Europe continues to be an issue, but projects like MOMU
aim to address this challenge in creative ways. However, we are at the very starting
point and further steps are needed to make the new competence framework we
have created a reality.
This handbook intends to suggest and inspire instead of guiding the reader. It
offers training packages to be adapted depending on contexts, whilst highlighting
our successes and failures. We suggest it is read, considered and adapted. In other
words, each person willing to put it into practice will have to assume that they will
have to make their own patchwork
Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer
Colorectal cancer; Personalized medicine; ResistanceCĂĄncer colorrectal; Medicina personalizada; ResistenciaCĂ ncer colorectal; Medicina personalitzada; ResistĂšnciaBackground
Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics.
Materials and methods
We used viable tumor tissue from two cohorts of patients with mCRC, naĂŻve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping.
Results
A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOXâbevacizumab and mitomycinâcapecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumabâsecond mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy.
Conclusions
Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.This Translational Research Fellowship Project was supported by the ESMO with the aid of a grant from Amgen, by the Accelerator (ACRCelerator) [grant number A26825] and Ayuda a mĂ©dicos jĂłvenes investigadores from Fundacion CientĂficaâAsociacion Española Contra el Cancer (FC-AECC)/Associazione Italiana per la Ricerca sul Cancro (AIRC)/Cancer Research United Kingdom (CRUK) and by Familia ArmanguĂ©. Any views, opinions, findings, conclusions or recommendations expressed in this material are those solely of the author(s) and do not necessarily reflect those of ESMO or Amgen. We thank Regione Campania (I-Cure Research Project) [grant number: Cup 21C17000030007], ESMO Translational Research Fellowship Program
A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy
Biomarkers; Colorectal cancer; ImmunotherapyBiomarcadors; CĂ ncer colorectal; ImmunoterĂ piaBiomarcadores; CĂĄncer colorrectal; InmunoterapiaThe search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.This research was funded by Merck Research Grants (Call 2018) in the Area of Colorectal Cancer Clinical Investigation
Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.This work has been supported by grants from FundaciĂłn cientĂfica
AECC -Asociación Española contra el Cåncer- (GCAEC20030CERV) to
A.Ce., from Instituto de Salud Carlos III (ISCIII) co-funded by the European
Union (CP16/00151, PI17/00211, PI20/00011; Spanish Ministry of
Economy and Competitiveness) to A.Ca. and PI20/00625 to P.N., from la
Caixa Foundation (LCF/PR/HR19/52160018) and MICINN (PID2020-
119917RB-I00) to E.B., from Spanish Ministerio de Economia y Competitividad
(MINECO) and FEDER funds (PID2019-104948RB-I00) to R.R.G.
This work was supported by Grant PT20/00023, funded by Instituto de
Salud Carlos III (ISCIII) and co-funded by the European Union, and the
Xarxa de Bancs de tumors sponsored by Pla Director dâOncologia de
Catalunya (XBTC). A.Ca. is the recipient of funding from the Instituto de
Salud Carlos III co-funded by the European Union (MS16/00151; CPII21/00012). J.L. is the recipient of a Junior Clinician fellowship from FundaciĂłn
cientĂfica AECC (CLJUN19004LINA)
Modeling and optimization of sensory changes and shelf-life in vacuum-packaged cooked ham treated by E-beam irradiation
[EN] The E-beam irradiation of vacuum-packaged RTE cooked ham was carried out to establish the dose required to achieve the food safety objective (FSO) and to minimize changes in selected sensory attributes. Cooked ham was irradiated with doses ranging 1-4 kGy. After the treatment, the microbial inactivation of Listeria monocytogenes, the shelf-life of the product and some sensory attributes (appearance, odor, and flavor) were determined. The inactivation of L monocytogenes was satisfactorily described by a first-order kinetics equation (R2=0.99). The influence of the irradiation dose on appearance, odor, and flavor was modeled through Gompertz (R2=0.99, for appearance) and Activation/Inactivation (R2=0.99, for odor and flavor) equations. A model was also developed to determine the shelf-life of irradiated cooked ham depending on the irradiation dose (R2 > 0.91). The dose that maximized the scores of the sensory attributes was 0.96 kGy resulting in an acceptable sensory quality for 80 days. It is possible to apply up to 2 kGy to ensure microbial safety, while provoking no significant changes in the above mentioned sensory attributes. (C) 2010 Elsevier Ltd. All rights reserved.The authors acknowledge the financial support from the Project CSD2007-00016 (CONSOLIDER-INGENIO 2010) funded by the Spanish Ministry of Science and Innovation.Benedito Fort, JJ.; Cambero, MI.; Ortuño Cases, C.; Cabeza, MC.; Ordoñez, JA.; De La Hoz, L. (2011). Modeling and optimization of sensory changes and shelf-life in vacuum-packaged cooked ham treated by E-beam irradiation. Radiation Physics and Chemistry. 80(3):505-513. https://doi.org/10.1016/j.radphyschem.2010.11.001S50551380
Impact of high-intensity pulsed electric fields variables on vitamin C, anthocyanins and antioxidant capacity of strawberry juice
Effect of high-voltage pulsed electric field (HPEF) pretreatment on biogas production rates of hybrid Pennisetum by anaerobic fermentation
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