Clinical management of molecular alterations identified by high throughput sequencing in patients with advanced solid tumors in treatment failure: Real-world data from a French hospital

BackgroundIn the context of personalized medicine, screening patients to identify targetable molecular alterations is essential for therapeutic decisions such as inclusion in clinical trials, early access to therapies, or compassionate treatment. The objective of this study was to determine the real-world impact of routine incorporation of FoundationOne analysis in cancers with a poor prognosis and limited treatment options, or in those progressing after at least one course of standard therapy.MethodsA FoundationOneCDx panel for solid tumor or liquid biopsy samples was offered to 204 eligible patients.ResultsSamples from 150 patients were processed for genomic testing, with a data acquisition success rate of 93%. The analysis identified 2419 gene alterations, with a median of 11 alterations per tumor (range, 0–86). The most common or likely pathogenic variants were on TP53, TERT, PI3KCA, CDKN2A/B, KRAS, CCDN1, FGF19, FGF3, and SMAD4. The median tumor mutation burden was three mutations/Mb (range, 0–117) in 143 patients with available data. Of 150 patients with known or likely pathogenic actionable alterations, 13 (8.6%) received matched targeted therapy. Sixty-nine patients underwent Molecular Tumor Board, which resulted in recommendations in 60 cases. Treatment with genotype-directed therapy had no impact on overall survival (13 months vs. 14 months; p = 0.95; hazard ratio = 1.04 (95% confidence interval, 0.48–2.26)].ConclusionsThis study highlights that an organized center with a Multidisciplinary Molecular Tumor Board and an NGS screening system can obtain satisfactory results comparable with those of large centers for including patients in clinical trials

Implication of two biomarkers NTRK2 and CHI3L1 in the new histo-molecular classification of gliomas

Les gliomes, tumeurs cérébrales primaires du système nerveux central, sont souvent de pronostic défavorable, d'autant plus que l'absence de critères indiscutables pour les identifier rend leur diagnostic et leur prise en charge particulièrement difficiles. L’analyse conjointe, d’une cohorte française de 64 patients porteurs de gliomes et d’une cohorte internationale de 671 patients issus du TCGA, a permis de mettre en évidence deux groupes pronostiques constitués par un panel d’expression différentielle de 26 gènes (p = 0,007). Cette stratification en deux groupes pronostiques a été confirmée quels que soient le grade et le groupe moléculaire de la tumeur (p < 0,0001). Nous avons établi une nouvelle stratégie diagnostique à partir de la classification moléculaire des gliomes en intégrant deux biomarqueurs pronostiques CHI3L1 et NTRK2. L’analyse multivariée confirme que ces biomarqueurs sont indépendants du statut IDH et du grade tumoral. Si nous avons mis en évidence par l’analyse protéique de CHI3L1 une concordance avec les transcrits, les résultats divergent pour TrkB. Ainsi, une expression élevée de TrkB et son corécepteur p75NTR serait liée à l’agressivité tumorale indépendamment du statut IDH. Enfin, TrkB et p75NTR sont présents aussi bien dans les exosomes issus du plasma de témoins sains et de patients atteints de gliomes mais leur expression augmente en fonction de l’agressivité de la tumeurGliomas, primary brain tumours of the central nervous system, are often of poor prognosis.The absence of clear criteria to identify them makes their diagnosis and management particularly difficult. The combined analysis of a cohort of 64 glioma patients and an international cohort of 671 patients from the TCGA revealed two prognostic groups of a differential expression panel of 26 genes (p = 0.007). This stratification into two prognostic groups was confirmed independently of the grade and molecular group of the tumor (p <0.0001). We have established a new diagnostic strategy based on the molecular classification of gliomas by integrating two prognostic biomarkers CHI3L1 and NTRK2. Multivariate analysis confirms that these biomarkers are independent of IDH status and tumor grade.While we have demonstrated by the protein analysis of CHI3L1 concordance with the transcripts, the results are different for TrkB. Therefore, a high expression of TrkB and its p75NTR co-receptor would be associated with tumor aggressiveness regardless of IDH status. Lastly, TrkB and p75NTR are present in exosomes from plasma of healthy controls and glioma patients, but their expression increases with the aggressiveness of tumor

Implication des biomarqueurs NTRK2 et CHI3L1 dans la nouvelle classification histo-moléculaire des gliomes

Gliomas, primary brain tumours of the central nervous system, are often of poor prognosis.The absence of clear criteria to identify them makes their diagnosis and management particularly difficult. The combined analysis of a cohort of 64 glioma patients and an international cohort of 671 patients from the TCGA revealed two prognostic groups of a differential expression panel of 26 genes (p = 0.007). This stratification into two prognostic groups was confirmed independently of the grade and molecular group of the tumor (p <0.0001). We have established a new diagnostic strategy based on the molecular classification of gliomas by integrating two prognostic biomarkers CHI3L1 and NTRK2. Multivariate analysis confirms that these biomarkers are independent of IDH status and tumor grade.While we have demonstrated by the protein analysis of CHI3L1 concordance with the transcripts, the results are different for TrkB. Therefore, a high expression of TrkB and its p75NTR co-receptor would be associated with tumor aggressiveness regardless of IDH status. Lastly, TrkB and p75NTR are present in exosomes from plasma of healthy controls and glioma patients, but their expression increases with the aggressiveness of tumor.Les gliomes, tumeurs cérébrales primaires du système nerveux central, sont souvent de pronostic défavorable, d'autant plus que l'absence de critères indiscutables pour les identifier rend leur diagnostic et leur prise en charge particulièrement difficiles. L’analyse conjointe, d’une cohorte française de 64 patients porteurs de gliomes et d’une cohorte internationale de 671 patients issus du TCGA, a permis de mettre en évidence deux groupes pronostiques constitués par un panel d’expression différentielle de 26 gènes (p = 0,007). Cette stratification en deux groupes pronostiques a été confirmée quels que soient le grade et le groupe moléculaire de la tumeur (p < 0,0001). Nous avons établi une nouvelle stratégie diagnostique à partir de la classification moléculaire des gliomes en intégrant deux biomarqueurs pronostiques CHI3L1 et NTRK2. L’analyse multivariée confirme que ces biomarqueurs sont indépendants du statut IDH et du grade tumoral. Si nous avons mis en évidence par l’analyse protéique de CHI3L1 une concordance avec les transcrits, les résultats divergent pour TrkB. Ainsi, une expression élevée de TrkB et son corécepteur p75NTR serait liée à l’agressivité tumorale indépendamment du statut IDH. Enfin, TrkB et p75NTR sont présents aussi bien dans les exosomes issus du plasma de témoins sains et de patients atteints de gliomes mais leur expression augmente en fonction de l’agressivité de la tumeu

Implication des biomarqueurs NTRK2 et CHI3L1 dans la nouvelle classification histo-moléculaire des gliomes

Gliomas, primary brain tumours of the central nervous system, are often of poor prognosis.The absence of clear criteria to identify them makes their diagnosis and management particularly difficult. The combined analysis of a cohort of 64 glioma patients and an international cohort of 671 patients from the TCGA revealed two prognostic groups of a differential expression panel of 26 genes (p = 0.007). This stratification into two prognostic groups was confirmed independently of the grade and molecular group of the tumor (p <0.0001). We have established a new diagnostic strategy based on the molecular classification of gliomas by integrating two prognostic biomarkers CHI3L1 and NTRK2. Multivariate analysis confirms that these biomarkers are independent of IDH status and tumor grade.While we have demonstrated by the protein analysis of CHI3L1 concordance with the transcripts, the results are different for TrkB. Therefore, a high expression of TrkB and its p75NTR co-receptor would be associated with tumor aggressiveness regardless of IDH status. Lastly, TrkB and p75NTR are present in exosomes from plasma of healthy controls and glioma patients, but their expression increases with the aggressiveness of tumor.Les gliomes, tumeurs cérébrales primaires du système nerveux central, sont souvent de pronostic défavorable, d'autant plus que l'absence de critères indiscutables pour les identifier rend leur diagnostic et leur prise en charge particulièrement difficiles. L’analyse conjointe, d’une cohorte française de 64 patients porteurs de gliomes et d’une cohorte internationale de 671 patients issus du TCGA, a permis de mettre en évidence deux groupes pronostiques constitués par un panel d’expression différentielle de 26 gènes (p = 0,007). Cette stratification en deux groupes pronostiques a été confirmée quels que soient le grade et le groupe moléculaire de la tumeur (p < 0,0001). Nous avons établi une nouvelle stratégie diagnostique à partir de la classification moléculaire des gliomes en intégrant deux biomarqueurs pronostiques CHI3L1 et NTRK2. L’analyse multivariée confirme que ces biomarqueurs sont indépendants du statut IDH et du grade tumoral. Si nous avons mis en évidence par l’analyse protéique de CHI3L1 une concordance avec les transcrits, les résultats divergent pour TrkB. Ainsi, une expression élevée de TrkB et son corécepteur p75NTR serait liée à l’agressivité tumorale indépendamment du statut IDH. Enfin, TrkB et p75NTR sont présents aussi bien dans les exosomes issus du plasma de témoins sains et de patients atteints de gliomes mais leur expression augmente en fonction de l’agressivité de la tumeu

Precision medicine for metastatic breast cancer

Genomic studies have shown that large numbers of candidate targets are observed in breast cancer. Nevertheless, only a few of them are validated as relevant targets in clinical studies. Estrogen receptor (ER) and HER2 expressions could be associated with a level I evidence. Beyond ER and HER2, BRCA and PIK3CA mutations (when targeted with alpha-specific PI3K inhibitors) could be considered as promising targets in breast cancer since they have been associated with objective responses in phase I/II trials. In addition to these four molecular alterations, several others have shown promising results in preclinical studies and are being investigated in clinical trials. These genomic alterations include AKT1, ERBB2, and ESR1 mutations. These considerations highlight the lack of evidence for using multiplex technologies to individualize therapy in metastatic breast cancer. Sequencing multiple genes to treat metastatic breast cancer is very promising but should be done in the context of clinical trials, either to enrich phase I/II trials in patients with genomic alterations or to show medical usefulness of new biotechnologies like next-generation sequencing (NGS). Although most current approaches of precision medicine are aiming at targeting drivers, additional applications could be developed in the future. This includes the identification of DNA repair deficiencies, mechanisms of immune suppression, and identification of minority lethal subclones. Finally, one of the very promising applications of genomics for metastatic breast cancer is the identification of pathway activation or defects at the individual level. For example, gene expression and single nucleotide polymorphisms (SNP) signatures are being developed to detect kinase (such as mammalian target of rapamycin [mTOR]/CDK4) activations or DNA repair deficiencies

Can the Six-Minute Walk Test Be Used to Individualize Physical Activity Intensity in Patients with Breast Cancer?

International audienceBackground: Adapted physical activity (APA) aids breast cancer patients. It is necessary to use an adapted target heart rate (HR) when prescribing exercise intensity. Methods: In total, 138 patients previously included in two published randomized clinical trials underwent the CPET and 6MWT before and after adjuvant therapy. Of these patients, 85 had performed APA, and 53 had received only the usual therapy. HRs were recorded during the two tests. Results: Before starting chemotherapy, good agreement (intraclass correlation (ICC) 0.69; confidence interval at 95% IC0.95 (0.591–0.769); p < 0.001) and a moderate correlation were evident between the 6MWT-HR and ventilatory threshold HR of the CPET (r = 0.70; p < 0.001). Good agreement and a high positive correlation were noted only in the group who engaged in APA (ICC 0.77; IC0.95 (0.659–0.848); p < 0.001; r = 0.8; p < 0.01); moderate agreement and a moderate positive correlation were apparent in the control group (ICC 0.57; IC0.95 (0.329–0.74); p < 0.001; r = 0.6; p < 0.01). The correlations were independent of age and body mass index. Conclusions: The 6MWT-HR can be used to prescribe exercise intensity for breast cancer patients both before and after specific treatment with concomitant APA

Indice de masse corporelle et pronostic du cancer du sein : étude de 1638 cancers du sein.

International audienc

Impact of body composition on outcome in patients with early breast cancer

International audiencePURPOSE:We investigated the impact of body composition on outcomes of patients with early breast cancer. Skeletal muscle mass, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and muscle fat infiltration or inter-muscular adipose tissue areas (IMAT), obtained by computed tomography (CT), were assessed.METHODS:A total of 119 female patients who had breast cancer were included in this retrospective study. The total skeletal muscle and fat tissue areas were evaluated in two adjacent axial slices obtained at the third lumbar vertebra by CT used for disease staging. The women were assigned to either a sarcopenia or non-sarcopenia group based on their skeletal muscle index (cut-off 41.0 cm2/m2). They also were classified into high and low VAT/SAT ratio groups and assigned to either the high or low IMAT index group. The association of the body composition parameters and prognosis was statistically analyzed.RESULTS:Among the 119 evaluable patients, 58 were sarcopenic (48.8%), 55 (46.2%) had a high VAT/SAT ratio, and 62 (52.1%) had a high IMAT index. Median follow-up was 52.4 months. Multivariate analysis revealed sarcopenia and IMAT index as independent prognostic factors for disease-free survival (p = 0.02 and p = 0.04, respectively) and overall survival (p = 0.05 and p = 0.02, respectively). BMI was not significantly associated with disease-free survival, but a trend was observed (p = 0.09).CONCLUSIONS:Sarcopenia and IMAT index are independent prognostic factors in early breast cancer; therefore, assessing body composition could be a simple and useful approach to integrate into patient management

Indice de masse corporelle et pronostic du cancer du sein : étude de 1638 cancers du sein.

International audienc