Thibaut Sanglier

Les bases de données des plans d’assurance maladie permettent de reconstruire l’évolution des patients dans le système de soins sans influencer le comportement du prescripteur ou du patient. Les troubles dépressifs sont largement étudiés en population générale, ils ont cependant fait l’objet d’une attention tardive chez le sujet âgé. Malgré les singularités de la dépression chez les sujets âgés, les traitements demeurent efficaces dans cette population. L’objectif de ce travail était d’utiliser une base de données de remboursements afin de comparer la prise en charge de la dépression chez les sujets âgés de 65 ans et plus et les adultes plus jeunes. Nous avons comparé 6 316 sujets dépressifs âgés à 25 264 sujets dépressifs adultes plus jeunes, en termes d’initiation et de durée de traitement antidépresseur. Comparé à l’échantillon plus jeune, notre échantillon de sujets âgés est apparu sous-traité alors que les sujets âgés initiant un traitement semblaient mieux y adhérer. La présence de comorbidités favorisait l’initiation d’un traitement sans être associé à une durée de traitement différente. De plus, une amélioration du remboursement des médicaments dans notre population fut concomitante d’un allongement de la durée de traitement chez les sujets âgés. Ces résultats, supportés par d’autres études plus classiques, suggèrent que la déviation ? de données collectées à des fins autres que la recherche épidémiologique est une approche permettant d’étudier des cohortes de patients en conditions réelles de prescription, de décrire des groupes spécifiques de patients et de mesurer des expositions médicamenteuses ainsi que de potentiels impacts de politiques de santé.

Analysis of single arm trials complemented with external comparator arms (ECAs) may be used to support evidence of effectiveness of novel therapies in oncology research when a randomized trial is unavailable or unfeasible. However, the intention-to-treat effect, which is a common target of estimation in ECA studies, is difficult to interpret when there are differences in adherence between the trial and ECA. This paper describes an approach to estimation of per-protocol effects in ECA studies using the target trial emulation framework for study design and analysis based on the results from an exploratory case study (TBASEL). We highlight challenges, potential solutions and future opportunities from the perspectives of protocol specification, data suitability and analysis, to help guide future implementations of per-protocol effects in ECAs.

Importance: Brain metastases portend poor prognosis in patients with metastatic breast cancer (MBC). Designing treatment and prevention clinical trials requires knowledge of brain metastases incidence with each line of therapy. Objectives: We assessed the prevalence and cumulative incidence of brain metastases in a large MBC patient cohort by subtype and line of therapy, and the impact of HER2-low expression on prevalence. Design, Setting and Outcomes: We analyzed brain metastases prevalence in patients with MBC in a nationwide electronic health record-derived de-identified database. The primary outcome was first diagnosis of brain metastases. We estimated prevalence and incidence of brain metastases by MBC subtype, including HER2-low and therapy line. We used the cumulative incidence function to estimate brain metastases risk in patients without brain metastases at initiation of systemic therapy. All P-values are 2-sided, and a P-value ≤.05 indicates statistical significance. Results: Among 18 075 patients with MBC, 1102 (6.1%) had at least 1 brain metastasis at first-line therapy initiation. For the remaining 16 973 patients, cumulative incidence of brain metastases at 60 months was 10% in patients with hormone receptor-positive (HR+)/HER2− disease, 23% for HR+/HER2+ disease, 34% for HR−/HER2+ disease, and 22% for triple-negative breast cancer (TNBC). HER2-low expression within HR+/HER2− and TNBC subtypes had no impact on brain metastases incidence. Brain metastases prevalence increased per line of therapy for patients with all breast cancer subtypes. Conclusions: Brain metastases incidence increases per line of therapy for every MBC subtype. The HER2-low biomarker does not impact brain metastases incidence within historical subtypes.

PURPOSE: On the basis of the results from CLEOPATRA, pertuzumab plus trastuzumab and chemotherapy is the first-line standard of care for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, discrepancies have been reported between clinical trial and real-world outcomes. We report real-world outcomes for patients with HER2-positive MBC treated with first-line pertuzumab plus trastuzumab and a taxane in routine clinical practice in the United States. METHODS: A retrospective analysis was conducted using electronic health record-derived deidentified data from the Flatiron Health database. Patients were grouped according to the first taxane received (paclitaxel/nab-paclitaxel or docetaxel). Median real-world progression-free survival (rwPFS) and overall survival (rwOS) was estimated using Kaplan-Meier methodology. Subgroup analyses were conducted in patients treated with docetaxel who met CLEOPATRA's key eligibility criteria. RESULTS: We included 1,065 patients; 313 patients received paclitaxel/nab-paclitaxel and 752 received docetaxel. Patients who received paclitaxel/nab-paclitaxel were older, had a worse Eastern Cooperative Oncology Group Performance Status, and had more recurrent metastatic disease compared with the docetaxel group. After adjustment for potential confounders, similar median rwPFS (inverse probability of treatment weighted average treatment effect for the treated [IPTW-ATT] hazard ratio [HR], 1.09; 95% CI, 0.9 to 1.3; P = .365) and rwOS (IPTW-ATT HR, 1.23; 95% CI, 0.96 to 1.58; P = .101) was observed between treatment groups. In the subgroup of CLEOPATRA-eligible patients, median rwPFS and rwOS were 16.9 months and 57.8 months, respectively. CONCLUSION: There was no statistically significant difference in real-world outcomes between patients treated with paclitaxel/nab-paclitaxel and those treated with docetaxel. Selecting patients using key CLEOPATRA eligibility criteria resulted in rwPFS and rwOS similar to those observed in CLEOPATRA, highlighting the importance of ensuring similar patient populations when comparing clinical trial and real-world data.

Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patients with metastatic breast cancer (mBC) who received prior trastuzumab plus pertuzumab (H + P). However, these studies may have been biased toward pertuzumab-experienced patients with more aggressive disease. Using an electronic health record-derived database, patients diagnosed with mBC on/after 1 January 2011 who initiated T-DM1 in any treatment line (primary cohort) or who initiated second-line T-DM1 following first-line H ± P (secondary cohort) from 22 February 2013 to 31 December 2019 were included. The primary outcome was time from index date to next treatment or death (TTNT). In the primary cohort (n = 757), the percentage of patients with prior P increased from 37% to 73% across the study period, while population characteristics and treatment effectiveness measures were generally stable. Among P-experienced patients from the secondary cohort (n = 246), median time from mBC diagnosis to T-DM1 initiation increased from 10 to 14 months (2013–2019), and median TTNT increased from 4.4 to 10.2 months (2013–2018). Over time, prior H + P prevalence significantly increased with no observable impact on T-DM1 effectiveness. Drug approval timing should be considered when assessing treatment effectiveness within a sequence.

Background: Continuing trastuzumab beyond disease progression was one of the most important paradigm changes in Oncology and is recommended by all guidelines. The reason behind it is that metastatic breast cancer (MBC) progresses much faster when the HER2 pathway is not blocked. However, the amount and robustness of data supporting this recommendation is limited, leading to lack of approval and/or access to this therapeutic strategy in many countries. The present study aims to provide additional data supporting that continuing trastuzumab (Tras) + chemotherapy (CT) may substantially improve outcomes of patients with MBC. Methods: We conducted a retrospective cohort study, using an U.S Electronic Health Record-derived de-identified database (Flatiron Health). Patients with MBC who were previously treated with anti-HER2 therapies and initiated as third line treatment CT combined with trastuzumab-based therapy (Tras+CT) or CT alone (index date) from 01/01/12-31/12/20 were included. An intention-to-treat approach was used to estimate the direct average treatment effects (ATEs) of initiating Tras+CT versus CT only on the Hazard Ratios for overall survival (OS) and real world progression free survival (rwPFS). Potential sources of confounding were identified using directed acyclic graphs and included clinical characteristics at index date as well as prior duration of similar treatments. Propensity score of received Tras+Ct vs CT was estimated using covariate balancing propensity score methodology. ATE was estimated using inverse probability of treatment weighting (IPTW) for Cox-proportional hazard models. Hazard ratios 95% confidence intervals were estimated using empirical bootstrap. Results: Three hundred and thirty seven patients initiated either treatment strategy (median age 60 years old), of these 288 patients initiated Tras+CT (49% trastuzumab based regimens, 43% T-DM1 based regimens and 8% including newer agents) and 49 received CT only. The median OS and median rwPFS were 23 months and 6 months for Tras+CT treated patients and 11 months and 5 months for CT treated patients. In the weighted population the median OS and median rwPFS were 19 months and 6 months for Tras+CT treated patients and 10 months and 5 months for CT treated patients resulting in hazard ratios of 0.29 [0.15-0.54] and 0.69 [0.45-1.06] for OS and rwPFS respectively. Conclusion: Including trastuzumab-based therapy in addition to CT in the third line treatment (Trast+CT) was associated with markedly improved survival outcomes compared with CT only. This study represents how HER2 blockade is maintained in third line in the U.S. over the period of time covered by the study. Limitations of the study could be unmeasured confounding factors, and the potential channeling of patients with lower socio-economic status towards CT treatment only. The latter could be similar to what is happening to patients treated in countries where continuing trastuzumab beyond progression is not accessible. This study provides further and strong support for this treatment strategy that should be accessible to all MBC patients across the world. As next steps, these results will be confirmed using other real-world datasets from different countries, including countries without current access to trastuzumab beyond progression. Citation Format: Thibaut Sanglier, Ryan Ross, Tianlai Shi, Joao Mouta, Fatima Cardoso. Comparative effectiveness of initiating chemotherapy with or without trastuzumab based regimens as third line treatment for metastatic breast cancer [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 P2-13-22.

Introduction: Pts with HER2-positive metastatic BC (mBC) often develop CNS mets, which is associated with poor prognosis and negative impact on quality of life. Resistance to anti-HER2 treatment can lead to disease progression; furthermore, many therapies do not cross the blood-brain barrier, leading to an unmet need for effective CNS mets treatment. In this real world study, we explored the molecular profile and clinical features of pts with CNS and non-CNS mets to better understand tumor biology in these populations. Methods: This retrospective, cross-sectional, observational study evaluated pts with CNS mets or non-CNS mets at the time of HER2-positive mBC diagnosis using the Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-FMI CGDB). The database comprised de-identified data from ~280 US cancer clinics (~800 sites of care), and included pts with FMI comprehensive genomic profiling assays covering >300 cancer-related genes. Descriptive analyses were conducted for baseline demographic, clinical, and biomarker characteristics, as well as genetic alterations including single nucleotide variants (SNVs), copy number alterations (CNAs), and rearrangements. T-tests were used to compare continuous variables, chi-squared tests for categorical variables, and non-parametric tests for non-normal distributions. Results: Of 8204 pts with BC in the CGDB, 6111 females 18+ yrs were diagnosed with mBC on or after 1-1-2011, of whom 919 had HER2-positive mBC, and 314 had an FMI assay up to 120 days after mBC diagnosis. This study population included 45 pts with CNS mets and 269 pts with non-CNS mets (Table). FMI data were derived from the primary tumor (29% from breast) or a metastatic lesion (19%, 12%, and 4% from liver, lymph nodes, and brain, respectively). Pts with CNS vs non-CNS mets were significantly younger at initial and at mBC diagnosis (p=0.04). At mBC diagnosis, a higher percentage of pts with CNS vs non-CNS mets had ≥3 sites of mets (p=0.01) and mets sites in adrenal glands (p=0.01), while there was a trend toward lower rates of lung and liver mets (not significant [NS]). Pts with CNS mets were more likely to be hormone receptor-negative vs pts with non-CNS mets (NS). Missing data for HER2 results by IHC or FISH, tumor grade, and histology limited the interpretation of any observed differences. Pts with CNS vs non-CNS mets were more likely to have SNVs in TP53 (82% vs 64%, p=0.03) and CNAs in ERBB2 (60% vs 43%, pTP53 (82%) and PIK3CA (29%), followed by ERBB2, BRCA1, ESR1, CDH1, MLL2, and ATRX (ERBB2 (60%) and MYC (20%), followed by CCND1, FGF19, FGF3, FGF4, and CCNE1 (13% each). Rearrangements were rare and no clear differences were observed between pts with CNS and non-CNS mets. Conclusions: Despite its small sample size, our analysis is one of the largest real world genomic studies in HER2-positive pts with CNS mets to date. Pts with CNS mets at mBC diagnosis showed potential distinguishing clinical and genetic features, including younger age, a higher proportion with adrenal gland mets and ≥3 sites of mets, and a higher prevalence of SNVs in TP53 and CNAs in ERBB2. Cautious interpretation is needed due to the small sample, unique pt population, and heterogeneity in tissue location. Further analyses can help elucidate the biology of CNS mets in these pts with a high unmet need. Citation Format: Preet K. Dhillon, Peter Lambert, Thibaut Sanglier, Adam Knott, Eleonora Restuccia, Sanne L. de Haas, Chiara Lambertini. Clinical features and genetic alterations in patients (pts) with HER2-positive breast cancer (BC) and central nervous system (CNS) metastases (mets) in the real world [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 P3-13-04.