BACKGROUND:Demonstration of trial emulation ability to benchmark randomised controlled trials (RCTs) from real-world data (RWD) is required to increase confidence in the use of routinely collected data for decision making in oncology. METHODS:To assess the frequency with which emulation findings align with RCTs regarding effect size on overall survival (OS) in metastatic breast cancer (MBC), 8 of 13 pre-selected pivotal RCTs in MBC were emulated using data from 32,598 patients enrolled in the French ESME-MBC cohort between January 1, 2008 and December 31, 2021. Adjustment methods and confounders were selected a priori for each emulation; stabilized weight was the reference method to mitigate confounding. Concordance in OS hazard ratios with associated 95 % confidence intervals between RCTs and emulations were assessed used predefined metrics based on statistical significance, estimates, and standardized differences. RESULTS:The effect sizes were consistent with RCT results in 7 out of the 8 emulations; 4 emulations achieved full statistical significance agreement; 5 emulations had a point estimate included in the RCT CI (estimate agreement); 6 emulations reported no significant differences between RCT and emulation (standardized difference agreement). Discrepancies related to residual confounders and significant shifts in prescription practices post-drug approval may arise in some cases. CONCLUSION:Target trial emulation from RWD combined with appropriate adjustment can provide conclusions similar to RCTs in MBC. In oncology, this methodology offers opportunities for confirming the impact on long-term survival, for expanding indications in patients excluded from RCTs and for comparative effectiveness in single-arm trials using external control arms.

Trial emulation applies RCT methodology to observational data, allowing estimation of long-term OS by mimicking existing RCTs. We emulated eight major RCTs in MBC to validate this approach using the ESME-MBC data. We selected the emulated RCTs based on feasibility regarding power and key confounders among 13 pre-selected pivotal RCTs since 2000. Emulation was combined with appropriate adjustment using Stabilized Inverse Probability of Treatment Weight as the reference method, and alternative methods as sensitivity analyses. The RWD and RCT results were compared using three predefined agreement metrics. Table: 237POS estimates and agreement metricsEmulation sample sizeHazard Ratio [95% Confidence Interval]AgreementRCTAdjusted RWDSAEASDPALOMA-3 (palbociclib)1, 1390.81 [0.64-1.03]0.81 [0.69-0.95]✓✓PALOMA-2 (palbociclib)2, 4130.96 [0.78-1.18]0.81 [0.72-0.92]✓✓MONALEESA-2 (ribociclib)1, 0030.76 [0.63-0.93]0.55 [0.39-0.79]✓✓CLEOPATRA(pertuzumab)1, 0620.68 [0.56-0.84]0.44 [0.36-0.55]✓EMILIA (T-DM1)8360.68 [0.55-0.85]0.64 [0.52-0.77]✓✓✓RIBBON-1 (bevacizumab4, 7031.11 [0.86-1.43]1.16 [1.07-1.25]✓✓AVADO (bevacizumab)8731.03 [0.70-1.33]0.96 [0.77-1.20]✓✓✓BOLERO-2 (everolimus)9040.89 [0.73-1.10]1.25 [1.06-1.47]SA, Full statistical significance agreement = when RWD and RCT HRs and CIs are on the same side of the null; EA, Estimate agreement = when the RWD HR falls within the 95% CI of the RCT; SD, Standardized difference agreement = difference in effect size between RCT and RWD relative to their standard deviation, achieved when the null hypothesis of no difference is not rejected, i.e. |z| ≤ 1.96. Open table in a new tab SA, Full statistical significance agreement = when RWD and RCT HRs and CIs are on the same side of the null; EA, Estimate agreement = when the RWD HR falls within the 95% CI of the RCT; SD, Standardized difference agreement = difference in effect size between RCT and RWD relative to their standard deviation, achieved when the null hypothesis of no difference is not rejected, i.e. |z| ≤ 1.96. These 8 emulations provide important insight into the real-world efficacy of major MBC drugs released in the past 15 years. Discrepancies may arise from residual confounding and drastic changes in prescription practices following drug approval. This approach provides opportunities to tackle challenges in demonstrating comparative effectiveness by applying external control arms.

Background: Real-world data studies usually consider biases related to measured confounders. We emulate a target trial implementing study design principles of randomized trials to observational studies; controlling biases related to selection, especially immortal time; and measured confounders. Methods: This comprehensive analysis emulating a randomized clinical trial compared overall survival in patients with HER2-negative metastatic breast cancer (MBC), receiving as first-line treatment, either paclitaxel alone or combined to bevacizumab. We used data from 5538 patients extracted from the Epidemiological Strategy and Medical Economics-MBC cohort to emulate a target trial using advanced statistical adjustment techniques including stabilized inverse-probability weighting and G-computation, dealing with missing data with multiple imputation, and performing a quantitative bias analysis for residual bias due to unmeasured confounders. Results: Emulation led to 3211 eligible patients, and overall survival estimates achieved with advanced statistical methods favored the combination therapy. Real-world effect sizes were close to that assessed in the existing E2100 randomized clinical trial (hazard ratio = 0.88, P = .16), but the increased sample size allowed to achieve a higher level of precision in real-world estimates (ie, reduced confidence intervals). Quantitative bias analysis confirmed the robustness of the results with respect to potential unmeasured confounding. Conclusion: Target trial emulation with advanced statistical adjustment techniques is a promising approach to investigate long-term impact of innovative therapies in the French Epidemiological Strategy and Medical Economics-MBC cohort while minimizing biases and provides opportunities for comparative efficacy through the synthetic control arms provided.

Abstract Background Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification). Methods We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan–Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman’s correlation coefficient. Analyses were conducted by tumor subtype. Results 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8–6.2) for HR-/HER2 − subtype to 13.3 months (36% CI 12.7–14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR − /HER2 − mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies. Conclusions Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates.

OBJECTIVE:To study the cyclic fertilin peptide effects on preimplantation human embryogenesis. Cyclic fertilin peptide reproduces the structure of the binding site of the sperm Fertilin β (also named A Disintegrin and Metalloprotease 2: ADAM2) disintegrin domain. It binds to the oocyte membrane and increases sperm-oocyte fusion index in human and fertilization rate in mouse, providing healthy pups. It also improves human oocyte maturation and chromosome segregation in meiosis I and binds to human embryo blastomeres, suggesting that it has a membrane receptor.DESIGN:Thawed human embryos at the 3 to 4 cells stage were randomly included in a dose-response study with cyclic fertilin peptide. Inner cell mass (ICM), trophectoderm (TE), and total cell numbers were evaluated in top- and good-quality blastocysts.SETTING:The study was performed in an academic hospital and research laboratory.PATIENT(S):Human embryos donated for research. This project was approved by the French "Agence de la Biomédecine."INTERVENTION(S):Immunofluorescence and tissue-specific gene expression analysis, using Clariom D microarrays, were performed to study its mechanism of action.MAIN OUTCOME MEASURE(S):Cyclic fertilin peptide improves blastocyst formation by almost 20%, the concentration of 1 μM being the lowest most efficient concentration. It significantly increases twice the TE cell number, without modifying the ICM. It increases the in vitro hatching rate from 14% to 45%.RESULT(S):Cyclic fertilin peptide stimulates TE growth. In the ICM, it induces transcriptional activation of intracellular protein and vesicle-mediated transport.CONCLUSION(S):Cyclic fertilin peptide dramatically improves human embryo development potential. It could be used to supplement culture medium and improve the in vitro human embryo development. Starting supplementation immediately after fertilization, instead of day 2, could significantly upgrade assisted reproductive technology outcome.

Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. It is well-known that de novo metastatic HER2+ breast cancer patients have better outcomes that women with metastatic relapse. This could be related both to a lead time bias, as well as to an ATRESS (adjuvant therapy-related shortening of survival) phenomenon [1]. Indeed, cancer treatments induce increased both clonal selection, as well as globally tumor resistance and agressivity [2]. However, there is relatively limited real-world information on the impact of adjuvant and neoadjuvant anti-HER2 targeted treatments on patterns of recurrence and outcomes of HER2+ MBC. Thus, the purpose of this study was to determine how and how long anti-HER2 targeted treatment in early setting impact outcomes of patients with HER2+ recurring BC. Methods: Since 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2017 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to 1st metastasis [TTM]) in patients with HER2+ MBC pretreated with trastuzumab in the (neo)adjuvant setting (aT) compared with trastuzumab-naïve patients and patients with de novo HER2+ MBC. Multivariate analyses adjusted for baseline demographic, prognostic factors, adjuvant treatment received and time to MBC. Results: Among the 23698 pts of the ESME database, 4145 were women treated in 1st line of a HER2+ MBC: 1716 pts (41%) had de novo and 2429 pts (59%) recurrent and 65% had Hormone Receptor (HR) + MBC; 53%, 26% and 21% had respectively 1, 2, or > 2 metastatic sites (64% visceral and 11% brain). With a median follow-up of 60.7 m, median OS is 42.4 m (95% CI: 40.1-45.0) for patients who relapsed. OS is significantly longer in de novo MBC: 64.7 m (95% CI: 60.2-73) (HRadjusted=0.68, 95% CI: 0.62-0.76, p < 0.0001). Among pts with recurrent MBC, 56% (1343) had received adjuvant trastuzumab (aT). As 1st-line therapy for MBC, 86 % of pts received HER2-targeted agents (74% T-based, 24% T-pertuzumab-based). Median TTM was 46.9 months (m): 57.6 m in HR+ and 30.2 m in HR-. Among pts with HR- diseases, 38% relapsed during the first 2 years of follow-up and 30% after 4 years (14.8%% and 56.9% in HR+ respectively). Among pts with recurrent MBC, crude median OS is inferior in pts who received aT, as compared to those who did not: 37.2 m (95% CI: 34.4-40.3) vs. 53.5 m (95% CI: 47.6-60.1), but this difference does not persist after adjustment for age, performans status, disease-free interval and number and type of metastatic sites in the multivariate model (HR=1.05, 95% CI: 0.91-1.22). A short disease-free interval (6-24 months compared to >48) remains, however, a strong adverse prognostic factor (HR=2.1, 95% CI: 1.82-2.50). Conclusions: The receipt of adjuvant trastuzumab does not predict for worse outcomes when adjusted to the other prognostic factors, among patients who relapsed during the 2008-2017 period. An ATRESS phenomenon is not suggested, although we cannot rule it out for those who relapsed within the initial 2 years. The much better prognosis of de novo MBC may be largely linked to lead time biases. Citation Format: Fanny Le Du, Matthieu Carton, Mahasti Saghatchian, David Perol, Barbara Pistilli, Etienne Brain, Delphine Loirat, Laurence Vanlemmens, Thomas Vermeulin, Christelle Levy, Anthony Goncalves, Mony Ung, Marie Robert, Anne Jaffre, Mathieu Robain, Suzette Delaloge, Véronique Dieras. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-09.

Dans les essais cliniques randomisés (ECR) en cancérologie, la survie globale (SG) est reconnue comme le critère majeur d'évaluation le plus objectif et reproductible, pour évaluer l'efficacité des traitements. Dans le cancer du sein métastatique (CSm), la survie sans progression (SSP) et le temps jusqu'à progression (TJP) sont des critères intermédiaires fréquemment utilisés, considérés comme alternatifs à la SG, bien que non validés comme critères de substitution. Les données de vie réelle (DVR) sont une source d'information majeure complémentaire aux données générées via les ECR. Ces DVR permettent d'investiguer de multiples critères d'évaluation de l'efficacité thérapeutique et leur association avec la SG, offrant ainsi l'opportunité de s'intéresser à des populations peu représentées dans les ECR (e.g. : cancers rares, sujets âgés) ou hétérogènes. La SG à partir de DVR a déjà été rapportée, en revanche, les données restent rares quant aux SSP et TJP observées en vie réelle. L'objectif de ce travail est de décrire les SG, SSP et TJP en vie réelle dans une large cohorte de femmes atteintes d'un CSm, et d'estimer l'association individuelle entre SSP et SG. Le programme ESME CSm (NCT03275311) est une initiative soutenant la centralisation de DVR décrivant la prise en charge de femmes initiant le traitement d'un CSm à partir de 2008 dans l'un des 18 centres de Lutte Contre le Cancer. Toutes les femmes diagnostiquées entre le 01/01/2008 et 31/12/2017 et ayant reçu au moins une ligne de traitement étaient éligibles. Ont été exclues, les femmes ayant un historique de cancer du sein bilatéral avant le diagnostic métastatique. Les critères (SG, SSP, TJP) ont été décrits selon la méthode de Kaplan-Meier selon le type de traitement reçu en première ligne métastatique (1L) pour chaque profil immunohistochimique de cancer du sein, défini selon l'expression des récepteurs hormonaux [statut RH+/RH-] et l'expression de la protéine (ou amplification du gène) HER2 [statut HER2+/HER-]. Les coefficients de corrélation de Spearman résumant l'association au niveau individuel entre SSP et SG ont été estimés. Parmi les 20 033 femmes incluses dans la population d'analyse, l'âge médian était de 60 ans. La médiane de suivi était 62,3 mois (IC95% 61,3-63,5). La SSP médiane sous traitement de 1L variait de 6,0 mois (IC95% 5,8-6,2) pour les tumeurs de type RH-/HER2-, appelées cancers triple négatif (TN), à 13,3 mois (IC95% 12,7-14,3) pour les tumeurs de type RH+/HER2+. Une grande variabilité a été observée concernant l'association de la SSP avec la SG (coefficients de corrélation 0,33 à 0,81). Chez les 17 635 femmes ayant progressé en 1L, le TJP médian variait de 3,0 mois (IC95% 2,8-3,2) chez les patients avec un CSm de type TN à 4,8 mois (IC95% 4,3-5,4) chez les patientes avec un CSm RH-/HER2+. Notre étude décrit, à partir de DVR, les critères alternatifs à la SG fréquemment utilisés (SSP, TJP) pour évaluer l'efficacité des traitements dans le CSm selon les modalités de traitement de 1L et pour chaque sous-type de cancer du sein. Ces résultats pourront fournir les valeurs de référence lors de la mise en œuvre et/ou l'interprétation d'essais cliniques. L'association individuelle entre SSP et SG varie selon le type de traitement et le profil moléculaire. Ces données permettront de générer des hypothèses quant aux propriétés de substitution à la SG de la SSP, à valider ultérieurement par des méta-analyses d'ECRs. Mots clés Données de vie réelle ; cancer du sein ; survie ; critères d'évaluation Déclaration de liens d'intérêts Les auteurs n'ont pas précisé leurs éventuels liens d'intérêts

Background The efficacy and added benefit of platinum-based chemotherapy (PtCT) for metastatic breast cancer (MBC) remain unclear in patients with and without germline BRCA1 or BRCA2 mutations (g BRCA1/2 m and g BRCA1/2 wt, respectively). Methods We selected from the French national real-world multicentre ESME cohort (2008–2016) all patients with HER2-negative MBC with known g BRCA1/2 status at first-line chemotherapy initiation. Using multivariable Cox models, we compared the outcome (progression-free (PFS) and overall survival (OS)) of first-line PtCT and non-PtCT regimens based on the patients’ g BRCA1/2 status and tumour subtype. Results Patients who received PtCT had more aggressive tumour features. In the multivariable analysis, first-line PtCT was associated with better adjusted PFS and OS in g BRCA1/2 m carriers ( N = 300), compared with non-PtCT (HR 0.54, 95% CI 0.4–0.73, P < 0.001, and HR 0.70, 95% CI 0.49–0.99, P = 0.047, respectively). Conversely, outcomes were similar in g BRCA1/2 wt patients ( N = 922) treated with PtCT and non-PtCT, whatever the tumour subtype. Landmark analyses at months 3 and 6 post treatment initiation supported these results. Conclusions In this pre-PARP inhibitor real-world cohort, PFS and OS were better after PtCT than non-PtCT in patients with g BRCA1/2 m, but not in those with g BRCA1/2 wt. These results emphasise the need of early g BRCA1/2 testing in patients with MBC. Clinical trial number NCT03275311.

Introduction L'essai contrôlé randomisé (ECR) constitue le gold standard pour estimer l'effet causal d'un traitement, en garantissant par l'allocation aléatoire et le strict respect du protocole d’étude un contrôle élevé des différents biais. En complémentarité des ECR, les données de vie réelle (DVR) peuvent être intéressantes dans certaines situations comme dans les tumeurs rares ou lorsque la survie globale (OS) n'est pas évaluable en critère principal dans l'ECR. La mise en œuvre d’étude à partir de DVR nécessite cependant un cadre et des méthodes spécifiques afin de contrôler du mieux possible les biais. Parmi ces méthodes, l’émulation d'essai a récemment été proposée par Hernàn et Robins. L'objectif est d’évaluer la faisabilité de l'approche par émulation à partir de DVR, via l’évaluation de l'effet de l'addition du bevacizumab (BVZ) au paclitaxel (P) sur la survie de patientes atteintes de cancer du sein métastatique (CSM) HER2-négatif. Méthodes L'approche par émulation consiste à appliquer les concepts de design des ECR aux données observationnelles, en définissant sept éléments-clés d'un protocole : (1) les critères d’éligibilité (2) les stratégies thérapeutiques (3) la procédure d'attribution (4) la période de suivi (5) le critère de jugement (6) l'effet causal d'intérêt (intention de traiter/per-protocole) et (7) le plan d'analyse. Ce travail a été basé sur l’étude de phase III E2100 (P+BVZ versus P), qui démontrait l'amélioration de la survie sans progression lors de l'addition du BVZ au P en première ligne de traitement (L1) dans le CSM HER2-négatif, mais sans bénéfice statistiquement significatif en OS. Nous avons tout d'abord émulé le protocole d'E2100 à partir de la base nationale en vie réelle ESME afin d'estimer l'effet en vie réelle sur l'OS de cette combinaison (P+BVZ) ; les patients présentant les critères d’éligibilité et ayant initié le P ou le BVZ en L1 dans le mois précédent ou les quatre mois suivant le diagnostic ont été inclus. Puis une analyse utilisant des méthodes de contrôle des biais basées sur le score de propension, telles que la pondération inverse aux probabilités d’être traité (IPTW), a été réalisée. L'OS était définie comme le temps depuis le t0 (i.e. date minimale où tous les critères d’éligibilité sont respectés pour un patient) jusqu’à la date de décès ou la date des dernières nouvelles. Résultats La cohorte émulée à partir de la base ESME (période d'inclusion 2008-2017 et suivi jusqu'au 04/2020) comprenait 3795 patients : 2256 dans le groupe P+ BVZ et 1539 dans le groupe P. Avant ajustement, les médianes d'OS étaient de 28,8 mois (P+BVZ) versus 23,4 mois (P) dans la cohorte émulée (HR 0,85, IC 95% 0,77–0,90), contre 26,7 mois (P+BVZ) versus 25,2 mois (P) (HR 0,88, p=0,16) dans l'essai E2100. Après ajustement par IPTW, permettant d’équilibrer les caractéristiques des groupes dans la cohorte émulée (différence des moyennes standardisées <0,1 atteinte pour chaque covariable), l'estimation du HR était similaire à 0,85 (IC 95% 0,78–0,92). Conclusion La cohérence dans les estimations de l'effet des traitements à l’étude souligne l'intérêt de l'approche par émulation dans l'analyse des DVR issues de large bases hospitalières. Ces résultats nécessitent cependant une interprétation prudente au vu des différences constatées dans les mesures de précision des estimations, ainsi que la réalisation d'analyses de sensibilité. Ce travail contribuera à la rédaction de recommandations sur l'utilisation de l’émulation d'essais cliniques en oncologie. Mots clés Cancer du sein métastatique; Efficacité; Données de vie réelle; Données de vie réelle; Émulation d'essai clinique; Biais de confusion Déclaration de liens d'intérêts AA rapporte une bourse doctorale dans le cadre d'un contrat CIFRE (Centre Léon Bérard, UNICANCER, UMR CNRS 5558, Roche). DP rapporte des honoraires (Laboratoire Roche) en dehors du contexte de ce travail et de la communication qui lui est reliée. BBHY, MG et RC sont des salariés du Laboratoire Roche. Les autres auteurs n'ont rien à déclarer.

L'essai contrôlé randomisé (ECR) constitue le gold standard pour estimer l'effet causal d'un traitement, en garantissant par l'allocation aléatoire et le strict respect du protocole d'étude un contrôle élevé des différents biais. En complémentarité des ECR, les données de vie réelle (DVR) peuvent être intéressantes dans certaines situations comme dans les tumeurs rares ou lorsque la survie globale (OS) n'est pas évaluable en critère principal dans l'ECR. La mise en œuvre d'étude à partir de DVR nécessite cependant un cadre et des méthodes spécifiques afin de contrôler du mieux possible les biais. Parmi ces méthodes, l'émulation d'essai a récemment été proposée par Hernàn et Robins. L'objectif est d'évaluer la faisabilité de l'approche par émulation à partir de DVR, via l'évaluation de l'effet de l'addition du bevacizumab (BVZ) au paclitaxel (P) sur la survie de patientes atteintes de cancer du sein métastatique (CSM) HER2-négatif. L'approche par émulation consiste à appliquer les concepts de design des ECR aux données observationnelles, en définissant sept éléments-clés d'un protocole : (1) les critères d'éligibilité (2) les stratégies thérapeutiques (3) la procédure d'attribution (4) la période de suivi (5) le critère de jugement (6) l'effet causal d'intérêt (intention de traiter/per-protocole) et (7) le plan d'analyse. Ce travail a été basé sur l'étude de phase III E2100 (P+BVZ versus P), qui démontrait l'amélioration de la survie sans progression lors de l'addition du BVZ au P en première ligne de traitement (L1) dans le CSM HER2-négatif, mais sans bénéfice statistiquement significatif en OS. Nous avons tout d'abord émulé le protocole d'E2100 à partir de la base nationale en vie réelle ESME afin d'estimer l'effet en vie réelle sur l'OS de cette combinaison (P+BVZ) ; les patients présentant les critères d'éligibilité et ayant initié le P ou le BVZ en L1 dans le mois précédent ou les quatre mois suivant le diagnostic ont été inclus. Puis une analyse utilisant des méthodes de contrôle des biais basées sur le score de propension, telles que la pondération inverse aux probabilités d'être traité (IPTW), a été réalisée. L'OS était définie comme le temps depuis le t0 (i.e. date minimale où tous les critères d'éligibilité sont respectés pour un patient) jusqu'à la date de décès ou la date des dernières nouvelles. La cohorte émulée à partir de la base ESME (période d'inclusion 2008-2017 et suivi jusqu'au 04/2020) comprenait 3795 patients : 2256 dans le groupe P+ BVZ et 1539 dans le groupe P. Avant ajustement, les médianes d'OS étaient de 28,8 mois (P+BVZ) versus 23,4 mois (P) dans la cohorte émulée (HR 0,85, IC 95% 0,77–0,90), contre 26,7 mois (P+BVZ) versus 25,2 mois (P) (HR 0,88, p=0,16) dans l'essai E2100. Après ajustement par IPTW, permettant d'équilibrer les caractéristiques des groupes dans la cohorte émulée (différence des moyennes standardisées <0,1 atteinte pour chaque covariable), l'estimation du HR était similaire à 0,85 (IC 95% 0,78–0,92). La cohérence dans les estimations de l'effet des traitements à l'étude souligne l'intérêt de l'approche par émulation dans l'analyse des DVR issues de large bases hospitalières. Ces résultats nécessitent cependant une interprétation prudente au vu des différences constatées dans les mesures de précision des estimations, ainsi que la réalisation d'analyses de sensibilité. Ce travail contribuera à la rédaction de recommandations sur l'utilisation de l'émulation d'essais cliniques en oncologie. Cancer du sein métastatique; Efficacité; Données de vie réelle; Données de vie réelle; Émulation d'essai clinique; Biais de confusion AA rapporte une bourse doctorale dans le cadre d'un contrat CIFRE (Centre Léon Bérard, UNICANCER, UMR CNRS 5558, Roche). DP rapporte des honoraires (Laboratoire Roche) en dehors du contexte de ce travail et de la communication qui lui est reliée. BBHY, MG et RC sont des salariés du Laboratoire Roche. Les autres auteurs n'ont rien à déclarer.

Abstract Background: Platinum-based chemotherapy regimens (PtCT) have been shown to increase treatment efficacy when combined to neoadjuvant standard of care treatment of triple negative breast cancers (TNBC). In the metastatic breast cancer (MBC) setting, preclinical and clinical data suggest that PtCT could be more efficient than non-platinum based ones (non-PtCT) among patients (pts) with germline BRCA1/2 mutations (gBRCAm). However, published data remain controversial on this topic, particularly for MBC. We evaluated the progression-free (PFS) and overall survival (OS) under first-line PtCT and non-PtCT among gBRCAm carriers in ESME, a nationwide real-life MBC database. Methods: ESME MBC database (NCT03275311), is a unique national cohort of all consecutive pts who initiated a first-line treatment for MBC between 2008 and 2016 in one of the 18 French Comprehensive Cancer Centers. Women with HER2- MBC and known hormone receptors (HR) and gBRCA1/2 (before or in the 6 first months of metastatic disease, gBRCAm / wild type / not tested) status, who received a first-line MBC CT were selected. Patients with other germinal mutations were considered as wild type. Primary objectives were OS and PFS under first-line CT (PtCT vs. non-PtCT) in the TNBC gBRCA1/2m population.Secondary objectives were OS and PFS during first-line CT (PtCT vs. non-PtCT) in the TNBC wild-type and “not tested” population, as well as among the HR+/HER2- pts.To avoid guarantee time bias related to oncogenetic testing, analyses were performed at baseline (CT initiation) and different landmark time points (3-month or 6-month after CT initiation). Thus, BRCA status was defined according to oncogenetic testings performed before the landmark time, and patients who progressed or censored before the landmark time were excluded. Results: 10,164 pts (2,794 TNBC; 7,370 HR+/HER2-) were included in this analysis. Pts who received PtCT were significantly younger, affected by a gBRCA1/2m, had a high histological grade and/or TNBC tumor, with more frequent visceral and central nervous system spreading than non PtCT ones. Median follow-up was 51.1 months [95%CI 49.6; 52.6]. All reported results were based on the gBRCA status defined at CT initiation and on multivariable analysis adjusted on age at MBC diagnosis, de novo MBC status, type and number of metastases. In the gBRCA1/2m TNBC population (N=132), PtCT was independently associated with a better PFS compared to non-PtCT (HR=0.56, 95%CI 0.38-0.84, p=0.005), without significant difference in OS (HR=0.79, 95%CI 0.51-1.23, p=0.29).No difference was seen in wild-type BRCA1/2 TNBC pts (N=269) according to the CT regimen, while, in the larger population of untested TNBC (N=2,393), PtCT was associated with worse OS (HR=1.18, 95%CI 1.03-1.34, p=0.016) compared to non-PtCT regimens, without significant difference in PFS (HR=1.07, 95%CI 0.95-1.22, p=0.26). No significant difference was seen regarding PFS nor OS in gBRCA1/2m HR+/HER2- pts (N=124) and in the wild-type BRCA1/2 HR+/HER2- population.However, in the larger population of untested HR+/HER2- pts (N=6,836), PtCT was independently associated with worse OS (HR=2.15, 95%CI 1.79-2.59, p<0.001) and PFS (HR=1.57, 95%CI 1.33-1.86, p<0.001) compared to non-PtCT regimens. Results were similar in landmark analyses at 3-month or 6-month after CT initiation. Conclusions: This large-scale real-life analysis suggests higher efficacy of PtCT in term of PFS in gBRCA1/2m TNBC pts. The small sample size and post-1st line treatments may preclude observing a significant OS difference. PtCT appeared however associated with worse outcomes in untested TNBC and HR+/HER2- pts. These results emphasize the need for BRCA1/2 characterization before considering these regimens in the MBC setting. Citation Format: William Jacot, Amélie Lusque, Audrey Mailliez, Thibault De la Motte Rouge, Luc Cabel, Christelle Levy, Anne Patsouris, Isabelle Desmoulins, Lionel Uwer, Marianne Leheurteur, Mathieu Robain, Olivier Caron, Thomas Bachelot, Thomas Filleron, Jean-Sébastien Frenel, Suzette Delaloge. Efficacy of Platinum-based first-line chemotherapy among metastatic breast cancer (MBC) patients according to the germline BRCA1/2 mutational status: An analysis of the French ESME MBC database [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-11.

PurposeObservational studies using routinely collected data are faced with a number of potential shortcomings that can bias their results. Many methods rely on controlling for measured and unmeasured confounders. In this work, we investigate the use of instrumental variables (IV) and quasi-trial analysis to control for unmeasured confounders in the context of a study based on the retrospective Epidemiological Strategy and Medical Economics (ESME) database, which compared overall survival (OS) with paclitaxel plus bevacizumab or paclitaxel alone as first-line treatment in patients with HER2-negative metastatic breast cancer (MBC).Patients and methodsCausal interpretations and estimates can be made from observation data using IV and quasi-trial analysis. Quasi-trial analysis has the same conceptual basis as IV, however, instead of using IV in the analysis, a "superficial" or "pseudo" randomized trial is used in a Cox model. For instance, in a multicenter trial, instead of using the treatment variable, quasi-trial analysis can consider the treatment preference in each center, which can be informative, and then comparisons of results between centers or clinicians can be informative.ResultsIn the original analysis, the OS adjusted for major factors was significantly longer with paclitaxel and bevacizumab than with paclitaxel alone. Using the center-treatment preference as an instrument yielded to concordant results. For the quasi-trial analysis, a Cox model was used, adjusted on all factors initially used. The results consolidate those obtained with a conventional multivariate Cox model.ConclusionUnmeasured confounding is a major concern in observational studies, and IV or quasi-trial analysis can be helpful to complement analysis of studies of this nature.

In the last years, tumor genomic testing has drastically changed the prognosis of patients especially in those treated for an advanced/metastatic nonsquamous non–small-cell lung cancer (NSCLC). Lung cancer is associated with older age. However considering the heterogeneity of this population it remains unclear whether older patients are screened in the same proportion as younger patients. This study aims to compare the proportion of molecular testing performed in advanced or metastatic nonsquamous NSCLC at diagnosis between patients aged ≥ 70 years old, and their younger counterparts.

BACKGROUND:Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. PATIENTS AND METHODS:We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2-; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). RESULTS:The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2- MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2- and TNBC cohorts, respectively, whatever YOD. CONCLUSION:OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed.

Background: Cisplatin-based chemotherapy administered concurrently to thoracic radiation therapy is the recommended treatment for fit patients with unresectable stage III NSCLC. The aim of this study was to describe patient profiles and clinical outcomes for the different treatment strategies in a real-word setting. Methods: The epidemio-strategy and medical economics (ESME) database for advanced and metastatic lung cancer is a French, national, multicenter, observational cohort. Out of 8514 Patients, 822 patients with unresectable locally advanced NSCLC in 2015-016 were selected (mean age, 65.3 years; male gender, 69%; performance status 0-1, 77%; smokers or former smokers, 89%). Results: Treatment was initiated for 736 (90%) of patients (concurrent chemoradiotherapy, n = 283; sequential chemoradiotherapy, n = 121; chemotherapy alone, n = 194; radiotherapy alone, n = 121; targeted therapy alone, n = 8; other, n = 9). Compared to the other treatment strategy groups, patients with radiotherapy alone appeared the most fragile (e.g. higher age, lower body weight or higher frequency of chronic obstructive pulmonary disease). OS rates at 12 and 24 months were 79.5% (95% CI, 73.4-84.3) and 55.3% (95% CI, 44.9-64.5) for concurrent chemoradiotherapy, and 64.3% (95% CI, 52.8-73.8) and 53.2 (95% CI, 33.2-69.6) for sequential chemoradiotherapy. Conclusions: Real-world evidence shows that concurrent chemoradiotherapy is administered to the most fit patients with non resectable locally-advanced NSCLC. Clinical outcomes are actually higher than those reported in landmark clinical trials, which suggests that an optimized and individualized selection of patients allows for prolonged survival. Long-term outcomes are similar after sequential or concurrent chemoradiotherapy.

Introduction: The estimated rate of de novo metastatic breast cancer (dnMBC) at the time of diagnosis is between 5 to 12%. International guidelines recommend metastatic work-up (MWU) only in women with advanced breast cancer. The purpose of this study was to describe the characteristics and prognosis of patients with dnMBC diagnosed without an initial indication for MWU. Methods: We conducted a retrospective, comparative study in dnMBC patients selected from the ESME-MBC cohort. Patients were treated in France between 2008 and 2016. We compared two populations: patients in whom dnMBC was diagnosed by staging although not indicated by guidelines (non-guideline staging [NGS]) and those in whom dnMBC was diagnosed by guideline staging (GS). Results: During the study period, 22,463 patients with MBC were included in the ESME cohort. Among them, 6698 were dnMBC patients. In 247 of these patients (6% of dnMBC and 1% of the overall population), dnMBC was diagnosed by non-guideline staging. Women in this group were significantly younger (57 vs. 59 years, p = 0.02) and had fewer metastatic sites at diagnosis than dnMBC-GS patients. The two groups were not significantly different in terms of the other characteristics. Overall survival (OS) and progression-free survival (PFS) were better in the dnMBC-NGS group than in the dnMBC-GS group. The impact on survival was confirmed by univariate and multivariate analysis (HR 1.83 [1.31-2.57], p < 0.01). Conclusion: This study provides the first description of a very specific population. These patients with dnMBC-NGS were younger and more likely to have oligometastatic disease with a better prognosis. (C) 2021 Elsevier Ltd. All rights reserved.

Background: High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC). Methods: The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers. Results: Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1–66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2–48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02–1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect. Conclusion: Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.