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Aims: The exposure‐response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time‐dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure‐response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Methods: Bevacizumab pharmacokinetics was described using target‐mediated drug disposition modelling. Relationships between target kinetics, progression‐free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic‐driven and response‐driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Results: Estimated target‐mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4 nM), steady‐state dissociation constant (KSS = 10 nM) and antibody‐target complexes elimination constant (kint = 0.52 day−1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. Conclusion: This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in‐depth description of this relationship. [ABSTRACT FROM AUTHOR]

Mismatch repair‐deficient (dMMR) and/or microsatellite instability‐high (MSI) colorectal cancers (CRC) represent about 5% of metastatic CRC (mCRC). Prognosis and chemosensitivity of dMMR/MSI mCRC remain unclear. This multicenter study included consecutive patients with dMMR/MSI mCRC from 2007 to 2017. The primary endpoint was the progression‐free survival (PFS) in a population receiving first‐line chemotherapy. Associations between chemotherapy regimen and survival were evaluated using a Cox regression model and inverse of probability of treatment weighting (IPTW) methodology in order to limit potential biases. Overall, 342 patients with dMMR/MSI mCRC were included. Median PFS and overall survival (OS) on first‐line chemotherapy were 6.0 and 26.3 months, respectively. For second‐line chemotherapy, median PFS and OS were 4.4 and 21.6 months. Longer PFS (8.1 vs. 5.4 months, p = 0.0405) and OS (35.1 vs. 24.4 months, p = 0.0747) were observed for irinotecan‐based chemotherapy compared to oxaliplatin‐based chemotherapy. The association was no longer statistically significant using IPTW methodology. In multivariable analysis, anti‐VEGF as compared to anti‐EGFR was associated with a trend to longer OS (HR = 1.78, 95% CI 1.00–3.19, p = 0.0518), whatever the backbone chemotherapy used. Our study shows that dMMR/MSI mCRC patients experienced short PFS with first‐line chemotherapy with or without targeted therapy. OS was not different according to the chemotherapy regimen used, but a trend to better OS was observed with anti‐VEGF. Our study provides some historical results concerning chemotherapy in dMMR/MSI mCRC in light of the recent nonrandomized trials with immune checkpoint inhibitors. What's new? Some reports suggest short overall survival (OS) and chemoresistance of mismatch repair‐deficient and/or microsatellite instability‐high metastatic colorectal cancers (dMMR/MSI mCRC). In a large multicenter series of dMMR/MSI mCRC we observed a relatively long OS but short progression‐free survival. Irinotecan‐based chemotherapy was not associated with better OS than oxaliplatin‐based chemotherapy but anti‐VEGF, as compared to anti‐EGFR, was associated with a trend to longer OS. These results could help clinicians to choose treatment in patients with dMMR/MSI mCRC. [ABSTRACT FROM AUTHOR]

Résumé: Les micro-ARN (miR) sont de petits ARN simple brin. Leur rôle est de réguler la traduction d'ARN messager cible. Ils impactent ainsi le fonctionnement global de notre organisme. Leur dérégulation est impliquée dans un grand nombre de mécanismes pathologiques, notamment dans l'initiation et la progression tumorales colorectales. Il est possible de détecter les fluctuations d'expression des miR dans les tissus digestifs, le sang et les selles. Certains miR ont été identifiés comme des potentiels biomarqueurs diagnostiques et pronostiques du cancer colorectal (CCR). Leurs dérégulations participent également aux mécanismes de résistance à certains médicaments anti-tumoraux. La mesure du niveau d'expression de miR est une piste pour la recherche de biomarqueurs prédictifs de l'efficacité des traitements couramment prescrits dans le CCR. Ils sont également des cibles thérapeutiques potentielles car l'induction pharmacologique de la sur- ou sous-expression de certains miR pourrait être utilisée afin de modifier les caractéristiques des tumeurs et servir de base pour de nouvelles thérapies en oncologie. Les miR représentent des éléments-clés du développement du CCR avec des perspectives d'applications prometteuses et innovantes en pratique clinique. MicroRNAs (miR) are small single-stranded RNAs. Their role is to post-transcriptionally regulate the expression of target mRNA. They influence the homeostasis of our organism. Dysregulated expression of many miR is involved in pathogenic mechanisms, particularly colorectal cancer (CRC) initiation and development. MiR levels of expression are detected in blood, stool and digestive tissue. Therefore, certain miR can be used as diagnostic and prognostic biomarkers in CRC. Also, some dysregulated miR contribute to drug resistance. Measuring levels of expression of those miR can be used to categorize patients according to their risk of drug-resistance in order to improve their survival. Lastly, artificially modifying miR regulation can be adopted to treat CRC. MiR are key factors in CRC development and their bedside usage is promising and innovative. [ABSTRACT FROM AUTHOR]

Résumé: Le risque de neutropénie sévère chimio-induite varie selon le schéma de chimiothérapie prescrit et des facteurs clinico-biologiques. Par exemple, dans la prise en charge du cancer colorectal traité par chimiothérapie, les risques de neutropénie sévère de grade 3/4 (< 1 000 polynucléaires neutrophiles/mm3) et fébrile varient respectivement de 2 à 50 % et moins de 1 à 10 % en fonction du schéma prescrit. Pour la majorité des schémas de chimiothérapie prescrits en cancérologie digestive, la prévention et la gestion de cette toxicité hématologique reposent surtout sur le recours à des reports de cures généralement associés à des diminutions de doses de chimiothérapies au détriment de la dose-intensité des schémas prescrits. Pour les schémas associés à des risques plus élevés de neutropénie sévère tels que les schémas DCF, VP16-sel de platine et FOLFIRINOX, la prescription de G-CSF en prophylaxie primaire ou secondaire est à discuter voire à recommander systématiquement. La recherche d'un déficit en DPD avant la prescription de 5-FU contribue à prévenir le risque de toxicité sévère hématologique lié au 5-FU. La gestion du risque de neutropénie imputable à la prescription d'une chimiothérapie nécessite une bonne connaissance des profils de tolérance des chimiothérapies prescrites et des facteurs de risque liés au patient. The risk of severe chemotherapy-induced neutropenia varies according to the chemotherapy regimen and clinico-biological factors. For instance, concerning the chemotherapy-based treatment of colorectal cancer, the risks of severe neutropenia that is grade 3 to 4 (<1.000 neutrophils/mm3) and febrile neutropenia range from 2% to 50 % and <1% to 10 %, respectively. For the majority of chemotherapy regimens prescribed in gastrointestinal oncology, the prevention and management of severe chemotherapy-induced neutropenia is mainly based on delaying cycles generally associated with decreasing drug dosage to the detriment of the regimen's intensity-dose ratio. For regimens associated with a higher risk of severe neutropenia such as DCF, VP16-platinum and FOLFIRINOX regimens, the prescription of G-CSF in primary or secondary prophylaxis should be discussed or recommended systematically. The search for a DPD deficiency before the prescription of 5-FU helps to prevent the risk of severe haematological toxicity related to 5-FU. The management of the risk of neutropenia attributable to the prescription of chemotherapy requires a good knowledge of the tolerance profiles of the prescribed chemotherapies and risk factors related to the patient. [ABSTRACT FROM AUTHOR]

Background and Aims: Bevacizumab-based chemotherapy is a recommended first-line treatment for metastatic colorectal cancer (mCRC). Robust biomarkers with clinical practice applicability have not been identified for patients with this treatment. We aimed to evaluate the prognostic yield of serum mid-infrared spectroscopy (MIRS) on patients receiving first-line bevacizumab-based chemotherapy for mCRC., Methods: We conducted an ancillary analysis from a multicentre prospective study (NCT00489697). All baseline serums were screened by attenuated total reflection method. Principal component analysis and unsupervised k-mean partitioning methods were performed blinded to all patients' data. Endpoints were progression-free survival (PFS) and overall survival (OS)., Results: From the 108 included patients, MIRS discriminated two prognostic groups. First group patients had significantly lower body mass index (p = 0.026) and albumin levels (p < 0.001), and higher levels of angiogenic markers, lactate dehydrogenase and carcinoembryonic antigen (p < 0.001). In univariate analysis, their OS and PFS were shorter with respective medians: 17.6 vs 27.9 months (p = 0.02) and 8.7 vs 11.3 months (p = 0.03). In multivariate analysis, PFS was significantly shorter (HR = 1.74, p = 0.025) with a similar trend for OS (HR = 1.69, p = 0.061)., Conclusion: By metabolomic fingerprinting, MIRS proves to be a promising prognostic tool for patients receiving first-line bevacizumab-based chemotherapy for mCRC., Competing Interests: Declaration of competing interest Authors have declared no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence their work regarding this study., (Copyright © 2024. Published by Elsevier Ltd.)