Les prairies, par leur diversité, représentent un nouveau levier pour une gestion intégrée de la santé animale. Certaines espèces prairiales contiennent des métabolites secondaires ayant des propriétés antioxydantes ou encore antiparasitaires. Néanmoins, nous ne savons pas comment les éleveurs s’approprient ce levier dont les connaissances sont en cours de construction. Pour comprendre cela, nous avons étudié comment les éleveurs parlent du service santé associé à la diversité prairiale et comment ils le conçoivent. Trente entretiens semi-directifs ont été conduits auprès d’éleveurs faisant, a priori, un lien entre diversité prairiale et santé animale. Une analyse lexicale a été faite pour identifier ce que le lien entre diversité prairiale et santé animale évoque aux éleveurs. Une analyse thématique a ensuite été réalisée afin de qualifier la place que les éleveurs y accordent dans la gestion du système d’élevage. Les résultats montrent que malgré un échantillonnage ciblé, ce sujet prend encore peu de place dans le discours. Quatre thèmes ont été identifiés pour décrire ce lien : i) les propriétés santé des prairies, ii) la perception de l’effet santé par l’éleveur, iii) l’automédication des animaux et iv) l’importance de la diversité prairiale pour les animaux. Enfin, nous avons distingué 4 profils d’éleveurs selon un gradient d’importance du lien fait : les « pseudo-spécialistes », les « expérimentateurs », les « opportunistes » et les « indifférents ».

High-grade epithelial ovarian cancer (HGOC) harboring a BRCA mutation (BRCAm) are the proof of concept for a homologous recombination deficient tumor. As a result of this defect in a crucial DNA repair pathway, most BRCAm OC are sensitive to first-line platinum-based chemotherapy. However, a small subset of patients (pts) with BRCAm OC demonstrate primary chemo-resistance. We aimed to describe the prevalence, clinico-pathological characteristics, and disease evolution of pts with primary resistant/refractory BRCAm OC (PROC). We conducted a retrospective observational cohort study based on OC data from the Epidemiological Strategy and Medical Economics (ESME) platform which centralizes real-life data of pts aged ≥ 18 years treated for OC in France between 2011 and 2022. PROC was defined as pts who received non-platinum chemotherapy in second-line for progression. Out of the 13,032 pts included in the ESME database, 1505 pts with BRCAm HGOC were identified. The prevalence of PROC among pts with BRCAm OC was 3.3% (43/1302). When comparing BRCAm PROC and BRCAm platinum sensitive OC (PSOC) pts, there were no significant differences in age at diagnosis (p=0.1798), but there was a trend in distribution of BRCA1(77 vs 66%) vs BRCA2 (21 vs 34%) mutations (p=0.0687). BRCAm PROC was more frequently associated with non-serous histology (29% vs 16%, p=0.042), with higher FIGO stage at diagnosis (85% vs 41% stage IV, p=0.0003), and non-operable disease at diagnosis (77% vs 55%, p= 0.004). Pts with BRCAm PROC had higher ca125 values at diagnosis and at last platinum than PSOC patients (mean 3364 vs 2090, p=0.04, and 562 vs 51U/mL, p<0.0001, respectively). Median PFS and OS were 10.2 [7.6-11.7] and 29.2 months [19.0-43.2] respectively in BRCAm PROC pts, and 34.0 [31.9-36.8] and 95.1 months [88.0-104.9] in PSOC pts. PROC is rare among pts with BRCAm OC but their prognosis is catastrophic. BRCAm PROC pts were more likely to have non-serous histology and exhibited more advanced disease at diagnosis than PSOC pts. We did not identify any other predominant features distinguishing PROC pts. These results suggest the importance of early cancer screening in BRCAm pts.

First-line (1L) anti-HER2 therapy has dramatically improved survival for patients (pts) with HER2+ metastatic breast cancer (MBC). We investigated clinicopathologic predictors of never progressive disease (PD) in the multicenter, real-world ESME-MBC cohort (NCT03275311). We selected women with HER2+ MBC diagnosed between 2008 and 2021 and treated with 1L anti-HER2-based therapy who had not experienced PD within 36 months (mo) of MBC diagnosis and with ≥60 mo of follow-up (fu). We used a multivariable logistic regression model with backward selection and bootstrap cross-validation to identify clinicopathologic characteristics of pts who never had PD at the last fu (still in 1L). Among 4, 697 pts with HER2+ MBC, 1, 083 had not experienced progression at 36 mo, of whom 318 were excluded due to fu <60mo, yielding a final study population of 765 pts. Of them, 523 (68.3%) never developed PD during fu (median fu of 97.9 mo (95%CI 94.8-101.9). Median progression-free survival (PFS) was 106.4mo (95%CI 92.8-130.8), and 60mo PFS was 68.4% (IC95% 65.1-71.7). Hormone receptor negative (HR-) status, use of 1L chemotherapy (CT) + dual HER2 inhibition, and absence of visceral metastases at diagnosis were independently associated with never PD at last fu (Odds Ratio (OR) 1.74 (1.23 – 2.48), 1.51 (1.07 – 2.14), 0.51 (0.24 – 1.12), respectively Table). The model's predictive performance had an AUC of 0.64.Table: 204PMultivariable predictors of never PDNOR [95%CI]PTumor gradeI/II39310.004III2811.48 [1.05 ; 2.09]Undeterminate482.90 [1.37 ; 6.91]Age at MBC<55 yrs36310.022≥55 yrs3590.68 [0.49 ; 0.95]First-line regimenCT + H28510.045CT+HP3681.51 [1.07 ; 2.14]Other690.98 [0.56 ; 1.73]HRHR+45310.002HR-2691.74 [1.23 ; 2.48]Metastases site at diagnosisNon-visceral33110.037Visceral non CNS3580.68 [0.48 ; 0.95]CNS330.51 [0.24 ; 1.12]H: Trastuzumab, P: Pertuzumab Open table in a new tab H: Trastuzumab, P: Pertuzumab In this large cohort, pts who had at least 3 years of disease control under 1L anti-HER2 therapy had 68.4% odds of remaining progression-free 2 years later. Negative hormone receptor status was the main driver of this long-term control. This may support de-escalation strategies in HER2+ patients with long-standing response to therapy. However, effective biomarkers to predict never PD beyond clinicopathologic features are warranted.

The HER2-targeted antibody-drug conjugate (ADC) T-DXd demonstrated efficacy in heavily pretreated HER2-over- and -low expressing ABC. We aimed to assess the activity of T-DXd in HER2-over/low expressing or IHC-0 ABC, to describe the drug mechanisms of action and to identify biomarkers associated to drug response or resistance. DAISY is an open-label phase II trial to assess the efficacy of T-DXd in ABC with extensive biomarkers analysis (1) in 3 cohorts: Cohort 1 (HER2 over-expressing: 3+ on IHC or ISH+), Cohort 2 (HER2 low-expressing: 1+ or 2+/ISH-) and cohort 3 (HER2-IHC 0). The primary endpoint was the confirmed objective response rate (ORR). Secondary endpoints were clinical benefit rate, duration of response (DOR), progression-free (PFS), overall survival (OS) and safety. Here we report clinical activity and safety with a longer follow-up of 38.4 months [95%CI: 35.3-40.9]. 185 women and 1 man were enrolled between 2019 and 2021. Among the safety population (179 pts), median [range] age was 55 [24-82] years, median number of previous metastatic line was 5 [0-17] and 12 pts harbored triple-negative ABC. Median number of cycles was 10 [1-63]. In December 2023, 6 pts were still on-treatment. The table shows T-Dxd activity in the full analysis set population (177 pts). Important to note, PFS rate at 24 months was 31% [95%CI: 20-43] in cohort 1. A total of 173 pts (96.6%) had at least one treatment-related adverse event (TRAE). Eight pts (4.5%) had drug related ILD or pneumonitis (grade (G) 1 in 6 pts, G2 and G5 in 1 pt each), 18 pts discontinued treatment due to TRAEs.Table: 7PTotalCohort 1Cohort 2Cohort 3BOR confirmed n/N [95%CI]86/177 (48.6%) [41.0; 56.2]48/68 (70.6%) [58.3; 81.0]27/72 (37.5%) [26.4; 49.7]11/37 (29.7%) [15.9; 47.0]Median DOR (months) [95%CI]8.5 [6.8; 9.7]9.7 [7.2; 17.9]7.6 [4.4; 9.4]6.8 [2.8; 17.5]Median PFS (months) [95%CI]7.1 [6.6; 8.7]11.1 [8.5; 14.4]6.8 [4.6; 8.5]4.2 [2.0; 5.7]Median OS (months) [95%CI]19.6 [16.1; 22.3]31.2 [22.4; Not Reached]19.3 [11.5; 22.1]12.1 [8.3; 15.0] Open table in a new tab Consistent with previously reported data, T-DXd showed clinically meaningful activity in pts with HER2-overexpressing ABC and antitumour activity in those with HER2-low and non-expressing ABC during extended follow-up. Safety profile was consistent with previous reports. (1) Mosele F and alNat Med 2023

Background: Breast cancer (BC) is the second most common cancer that metastasizes to the brain. Particularly up to half of patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (mBC) may develop brain metastases over the course of the disease. Nevertheless, little is known about the prevalence and the outcome of brain and leptomeningeal metastases (BLMM) in HER2-low BC. We compared the cumulative incidence of BLMM and associated outcomes among patients with HER2-low, HER2-negative (HER2-) and HER2+ mBC. Patients and methods: This cohort study was conducted from the Epidemiological Strategy and Medical Economics (ESME) mBC database and included patients treated for mBC between 2012 and 2020 across 18 French comprehensive cancer centers and with known HER2 and hormone receptor (HR) status. The cumulative incidence of BLMM after metastatic diagnosis was estimated using a competing risk methodology with death defined as a competing event. Results: 19 585 patients were included with 6118 (31.2%), 9943 (50.8%) and 3524 (18.0%) being HER2-low, HER2- and HER2+ mBC, respectively. After a median follow-up of 48.6 months [95% confidence interval (CI) 47.7-49.3 months], BLMM were reported in 4727 patients: 1192 (25.2%) were diagnosed with BLMM at first metastatic diagnosis and 3535 (74.8%) after metastatic diagnosis. Multivariable analysis adjusted for age, histological grade, metastases-free interval and HR status showed that the risk of BLMM at metastatic diagnosis was similar in patients with HER2compared to HER2-low mBC [odds ratio (OR) (95% CI) 1.00 (0.86-1.17)] and higher in those with HER2+ compared to HER2-low [OR (95% CI) 2.23 (1.87-2.66)]. Similar results were found after metastatic diagnosis; the risk of BLMM was similar in HER2- compared to HER2-low [subdistribution hazard ratio (sHR) (95% CI) 1.07 (0.98-1.16)] and Conclusions: The prevalence and evolution of BLMM in HER2-low mBC are similar to those in patients with HER2tumors. In contrast to patients with HER2+ mBC, the prognosis of BLMM remains dismal in this population.

Grasslands cover a substantial share of land area in the world and in Europe, where they are used to feed herbivores and provide a range of ecosystem services. Grasslands also help in animal health maintenance by hosting a diversity of plant species with antioxidant components. This animal health benefit has been under-researched. The aim of this study is to capture how farmers perceive links between grassland diversity and animal health, and to examine whether their perceptions are related to their farm and its structure. For that purpose, we conducted 103 surveys in three regions of France to collect farmers’ perceptions regarding animal health, grassland diversity, and the link between the two. We then used factorial analysis of mixed data to study the relationship between the farmers’ perceived links between grassland and animal health and their type of farm structure and management. For 61 farmers, there was a strong link between grassland diversity and animal health. However, we found no statistical relationship between the type of farm and the type of farmer-perceived link between grassland diversity and animal health, and the farmers who perceived a strong link employed a wide range of feeding systems. Further research is needed to deeply analyze farmers’ practices and perceptions of grassland–health links.

Long term treatment related toxicity is a major issue for breast cancer patients in the adjuvant setting. Predicting toxicities may allow us to adapt the treatment strategy. We assessed whether the metabolomic profile of patients may predict long-term toxicities. High-resolution untargeted metabolomics was performed at baseline for 857 ER-positive, HER2- breast cancer patients from the CANTO prospective cohort. Four metabolomic profiles per patient were produced: (i) shared and annotated metabolites (n=224), (ii) annotated but not always common metabolites (n=456), (iii) annotated but not always shared metabolites (n=766) and (iv) all metabolites (n=1693, FullMet). Samples were split into a discovery and validation set. We benchmarked algorithms adapted for high dimensional analysis (LASSO, Adaptive LASSO, machine learning, and deep learning) in order to select best models for prediction. 30.0% of patients were >65 years old, 24.4% <50 years old, 20.4% had BMI>30, 12.7% had previous history of neurological disorders, 6.1% had diabetes. 69.6% presented with pT1, 25.7% with pT2 and 3.4% with pT3; 11.1% had lymph node involvement. Among all benchmarked, adaptive LASSO was the most interesting statistical method with limited optimism bias. It also allows the selection of a subset of metabolites of particular interest. The addition of rare metabolites as well as non-annotated metabolites significantly increase the predictive power of models. Metabolic toxicity prediction mainly relied on endogenous metabolites while neurological toxicities were partly predicted using exogenous/environmental metabolites. In the validation set, compared to clinical data alone (AUC 0.50-0.54), addition of metabolomics data shows moderate (AUC = 0.55-0.60) but significant (p<0.05 adjusted for multiple comparison) predictive ability for neurological and metabolic toxicities. Breast cancer patient metabolomic profile at baseline improves toxicity prediction after adjuvant chemotherapy, similar to what is reported for genomic fingerprints. Untargeted metabolomics allows the achievement of higher performance by taking into account environmental exposure, metabolites linked to microbiota as well as rare and uncommon metabolites.

Background: The combination of endocrine treatment with cycline-dependent-kinase 4/6 inhibitor is the new standard of treatment in hormone receptor-positive HER2 negative metastatic breast cancer. The optimal subsequent treatment after CDK4/6 inhibitor remain unclear. As recommended by standard guidelines, capecitabine, an oral chemotherapy is a therapeutic option in endocrine resistant metastatic breast cancer. The objective of this study was to evaluate capecitabine efficacy after disease progression under combination of ET and CDK4/6 inhibitor in a hormone receptor positive metastatic breast cancer population. Patients and Methods: Patients progressing under CDK 4/6 inhibitor plus ET and treated with capecitabine, between January 2016 and December 2020, were retrospectively included. Primary endpoint was time to treatment failure (TTF) on capecitabine. Logistic regression were used to identify predictive factors: exclusive bone versus visceral metastases, first-line versus >= 2 lines of combination therapy, aromatase inhibitor (AI) versus fulvestrant. Results: Fifty-six patients with a 62-year median age (IC95% 42-81) were analyzed. The CDK 4/6 inhibitor and ET combination was prescribed in first-line setting in 26 patients (46%). Twenty-five patients (44%) had exclusive bone metastasis. Median TTF was 6.1 months. Six patients discontinued capecitabine due to toxicity. Outcomes were not significantly different regardless of metastases localization, ET, and treatment line of the combination of CDK 4/6 inhibitor and ET. Median PFS was 7.1 months. Median OS was 41.3 months. Conclusion: Compared to other data of capecitabine prescribed in patients with hormonal resistant MBC, this retrospective study suggests that capecitabine remains effective after CDK 4/6 inhibitor plus ET progression, regardless of therapeutic-line setting and metastases localization. Micro Abstract: Cycline dependant kinase 4/6 inhibitor plus endocrine therapy have become the standard of care in metastatic hormone receptor positive (HR+) breast cancer (BC). Few data reported the optimal subsequent therapy after progression under the combination. Capecitabine is a therapeutic option in endocrine resistant HR+/HER2- metastatic breast cancer. Data evaluating efficacy of capecitabine after disease progression on endocrine therapy plus cycline-dependant kinase 4/6 inhibitor are poor. This study showed a 6.1-month median time to treatment failure on capecitabine. Capecitabine remained effective regardless of therapeutic-line setting and metastases localization.

Efficacy of endocrine therapy in HR+/HER2− metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation. The ESME metastatic breast cancer platform (NCT03275311) is a French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1). A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR [95% CI] 1.26 [1.03–1.55]). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR [95% CI] = 1.54 [1.03–2.32]) and PFS1 (adjusted HR [95% CI] 1.58 [1.17–2.12]) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 [0.88–1.41], p = 0.350; PFS1: 1.09 [0.90–1.31], p = 0.379). In this large cohort of HR+/HER2− MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.

Immune checkpoint inhibitors (ICIs) are one of the major therapeutic advances in cancer treatment. Anti-PD(L)1 ICIs have been shown to improve progression-free survival and OS, in patients with metastatic triple-negative breast cancer (TNBC), and pCR and event-free survival in patients with early TNBC. Nevertheless, some patients treated with anti-PD(L)1 ICIs experience recurrence or do not achieve sustained clinical benefit. Expanding the efficacy and therapeutic target of currently available ICIs is an area of high unmet need. Several targeted agents (e.g. anti-VEGF, PI3KCA or AKT inhibitors) have been shown to impact the tumor-immune microenvironment (TIME) by influencing aspects of the immune response. Preclinical evidence supports the notion that AKT/VEGF inhibition can enhance anti-PDL1/PD1 efficacy through its effect on the TIME. BIS Program is a window of opportunity trial designed to evaluate the biological effects of immunotherapy-based treatment combinations in patients (pts) with stage I-III, untreated, HER2-positive (HER2+)or TNBC that are eligible for upfront surgery or neoadjuvant systemic treatment (NST). The study, which will recruit 210 pts(147 in the TNBC cohort and 63 in the HER2+ cohort), builds on an adaptive, open, prospective randomized model that aims to determine whether short-treatment immunotherapy increases the level of activated GzmB+/CD8+ T cells between baseline and post-treatment samples. In the TNBC Cohort: pts are randomized 1:2:2:2 to observation, Atezolizumab (Atz), Atz + Ipatasertib or Atz + Bevacizumab; in the HER2+ cohort: pts are randomized 1:2 to observation or Atz + Trastuzumab + Pertuzumab. Primary endpoint: Two-fold increase in GzmB+/CD8+ T cell levels from baseline to post-study treatment samples. Secondary objectives: Effect of study treatment on pCR, immune biomarkers, and immune-related gene expression. Two FFPE and one frozen sample are collected at (1) the time of enrollment and (2)following surgical treatment in those who undergo upfront surgery or dedicated biopsy after study treatment in those who undergo NST. Blood samples will be collected at the time of enrollment, before surgery or the start of NST, and at the end of the study visit. NCT05180006. Gustave Roussy, Cancer Campus, Grand Paris. This research collaboration was supported through the imCORE network on behalf of F. Hoffmann-La Roche.

Purpose A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules. Methods Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules. Results Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0 months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2 months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1 months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries. Conclusion PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

By summarizing research projects performed over the past 10 years on grasslands in cattle production, we seek to understand the way of farming with grassland and cattle farmers’ way of thinking about it. Based on the combined perspective of sociologists and animal scientists, the cross-analysis we realized reveals that the local context is the main element necessary to understand grassland management practices on livestock farms. Many groups of drivers influence how farmers develop their perceptions about forage services, think about forage production and practice it (i.e., “forage rationales”): (i) soil and climate conditions, (ii) professional network and (iii) existence of networks bringing together farmers and other stakeholders to discuss grassland issues. From the diversity of production contexts, we reveal different perceptions that livestock farmers have about the services that grasslands provide mainly at farm scale: animal production, economic, agronomic, ecological and environmental. The structuring of these perceptions outlines an array of forage rationales in which grasslands have a relatively central place in cattle production. Finally, we show that the farmer’s rationale can evolve over time due to debates with peers and non-agricultural stakeholders. This leads us to discuss how evolution of livestock farmers’ grassland rationales and practices can be supported, and finally to formulate recommendations for maintaining grasslands.

Older cancer patients are underrepresented in clinical trials. We aimed to evaluate the enrollment of older women aged 70 years old (yo) or over with metastatic breast cancer (MBC) in clinical trials. We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real-life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment in older ones. 5552 women were aged ≥ 70 (median 74yo; IQR 72–77). 14,611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 [95%CI 0.33–0.76] for the 80–85yo class; OR 0.17 [95%CI 0.06–0.39] for the 85yo and more class), good ECOG Performance Status (PS 0–1) (OR 0.15 [95%CI 0.08–0.27] for the PS 2–4 class), HER2 + disease (OR 1.78 [95%CI 1.27–2.48]), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 [95%CI 3.13–8.18]), and period (OR 1.65 [95%CI 1.22–2.26] for 2012–2016, compared to 2008–2011). In this large database, few older MBC patients were enrolled in a trial compared with younger ones.