The impact of adjuvant chemotherapy on breast cancer prognosis has been demonstrated in randomized trials, but its impact is unknown in real-world populations. The aim of this study was to evaluate ...the effect of adjuvant chemotherapy on the survival of breast cancer patients in an unselected population.
This prospective cohort study included 32,502 women treated at the Institut Curie between 1981 and 2008 for a first invasive breast cancer without metastasis. The patients were matched based on their propensity score to receive adjuvant chemotherapy.
The matching generated a subsample of 9,180 patients with an overlapping propensity score. In the group without chemotherapy, the overall survival (OS) rates at 5 and 10 years of follow-up were 87.6% (95% CI 86.7-88.6) and 75.0% (95% CI 73.6-76.5), respectively, versus 92.1% (95% CI 91.3-92.9) and 81.9% (95% CI 80.6-83.2), respectively, in the chemotherapy group. Distant disease-free survival (DDFS) was significantly improved in the five first years (absolute benefit of 3.5%). In a multivariate analysis, adjuvant chemotherapy was associated with better OS (HR = 0.75, 95% CI 0.69-0.83, p<0.0001) and DDFS (HR = 0.82, 95% CI 0.75-0.90, p<0.0001).
Adjuvant chemotherapy significantly improves OS and DDFS rates in an unselected population, in accordance with previous results reported by randomized trials.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Observational 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). Causal 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. In 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. Unmeasured 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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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).
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.
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Young age is a poor prognostic factor in early stage breast cancer (BC) but its value is less established in metastatic BC (MBC). We evaluated the impact of age at MBC diagnosis on overall survival ...(OS) across three age groups (<40, 40 to 60 and > 60 years(y)).
ESME MBC database is a national cohort, collecting retrospective data from 18 participating French cancer centers between January 01, 2008 and December 31, 2014.
Among 14 403 women included, 1077 (7.5%), 6436 (44.7%) and 6890 (47.8%) pts were <40, 40–60 and > 60 y respectively. Pts <40 had significantly more aggressive presentations than other age groups: more frequent HER2+ (25.7 vs 15.3% in >60y) and triple negative subtypes (27.4 vs 14.6% in >60y), and more frequent visceral involvement (36.3 vs 29.8% in >60y). At a median follow-up of 48 months, median OS differed across age groups: 38.8, 38.4 and 35.6 months for pts <40, 40–60 and > 60y, respectively (p < 0.0001). Compared to pts <40y, older pts had a statistically significant higher risk of death (all causes of death included), although of limited clinical value (HR = 1.1, IC 95%:1.01–1.20). There was a significant trend for better OS in pts <40y with HER2+ and luminal diseases. A possible explanation is a greater use of anti-Her2 therapies as first-line treatments: 86.6, 81.9 and 74.9% for pts <40, 40–60 and > 60y, respectively (p < 0.0001).
Although young age seems associated with more aggressive presentations at diagnosis of MBC, it has no deleterious effect on OS in this large series.
•Young age is a poor prognosis factor in early stage breast cancer.•Young age is associated with an aggressive presentation in metastatic breast cancer.•Young age had no impact on overall survivall in metastatic breast cancer.•Oppositely, older women (>60y) had a stightly poorer prognosis at the metastatic stage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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).
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.
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.
Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.
•This is the first large multicenter cohort reporting BMI’s effect on outcomes among patients with metastatic breast cancer.•Overweight or obese status does not negatively influence outcome of metastatic breast cancer patients, whatever the subtype.•Underweight is a strong negative independent prognostic factor on outcomes, whatever the subtype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Among metastatic breast cancer (MBC) patients, those with a triple-negative breast cancer phenotype (mTNBC) have the worst prognosis, but the benefit of chemotherapy beyond second line on outcome ...remains uncertain. The purpose of this study was to identify predictive factors of outcome after third- or fourth-line chemotherapy.
The ESME-MBC database is a French prospective real-life cohort with homogeneous data collection, including patients who initiated first-line treatment for MBC (2008–2016) in 18 cancer centers. After selection of mTNBC cases, we searched for independent predictive factors (Cox proportional-hazards regression models) for overall survival (OS) on third- and fourth-line chemotherapy (OS3, OS4). We built prognostic nomograms based on the main prognostic factors identified.
Of the 22,266 MBC cases in the ESME cohort, 2903 were mTNBC, 1074 (37%) and 598 (20%) of which had received at least 3 or 4 lines of chemotherapy. PFS after first- and second-line chemotherapy (PFS1, PFS2) and number of metastatic sites ≥3 at baseline were identified by multivariate analysis as prognostic factors for both OS3 (HR = 0.76 95%CI0.66–0.88, HR = 0.55 95%CI0.46–0.65, HR = 1.36 95%CI1.14–1.62, respectively), and OS4 (HR = 0.76 95%CI0.63–0.91, HR = 0.56 95%CI0.45–0.7, HR = 1.37 95%CI1.07–1.74), respectively. In addition, metastasis-free interval was identified as a prognostic factor for OS3 (p = 0.01), while PFS3 influenced OS4 (HR = 0.75 95%CI0.57–0.98). Nomograms predicting OS3 and OS4 achieved a C-index of 0.62 and 0.61, respectively.
The duration of each previous PFS is a major prognostic factor for OS in mTNBC patients receiving third- or fourth-line chemotherapy. The clinical utility of nomograms including this information was not demonstrated.
•After 3rd- or 4th-line therapy, PFS remained linear in the majority of women with metastatic triple-negative breast cancer.•The duration of each previous PFS had an impact on the OS associated with subsequent lines.•PFS2 was more strongly predictive of outcome than PFS1 for third-line therapy.•PFS2 and PFS3 had an impact on outcome irrespective of PFS1 for fourth-line therapy.•The clinical utility of nomograms including duration of each previous PFS to predict OS was not sufficient.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
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.
Database registration
clinicaltrials.gov Identifier NCT03275311.
Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study ...aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.
ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008–31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor–positive and HER2-negative (HR+/HER2–, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR–/HER2–, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.
Median OS of the whole cohort was 37.22 months (95% confidence interval CI, 36.3–38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 95% CI, 0.97–1.00, P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2–, HER2+ and HR–/HER2– subcohorts was, respectively, 42.12 (95% CI, 40.90–43.10), 44.91 (95% CI, 42.51–47.90) and 14.52 (95% CI, 13.70–15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 95% CI, 0.88–0.94, P < .001), but not in HR+/HER2– nor HR–/HER2– subcohorts (hazard ratio 1.00 95% CI, 0.98–1.01, P = .80 and 1.00 95% CI, 0.97–1.02, P = .90, respectively).
The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.
•Overall survival (OS) of metastatic breast cancer patients has slightly improved over the past decade.•OS improvement was confined to Epidermal Growth Factor (HER)-2-overexpressing metastatic breast cancer patients.•The uptake of therapeutic innovations was lower than expected.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological ...Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC).
Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients’ characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2−, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours.
The median OS of the whole cohort was 39.5 months (95% confidence interval CI, 38.7–40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p < 0.0001) with a median OS of 43.3 (95% CI, 42.5–44.5) in HR+/HER2−; 50.1 (95% CI, 47.6–53.1) in HER2+; and 14.8 months (95% CI, 14.1–15.5) in triple-negative subgroups, respectively. Beyond performance status, the following variables had a constant significant negative prognostic impact on OS in the whole cohort and among subtypes: older age at diagnosis of metastases (except for the triple-negative subtype), metastasis-free interval between 6 and 24 months, presence of visceral metastases and number of metastatic sites ≥ 3.
The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients.
clinicaltrials.gov Identifier NCT032753.
•ESME provides a full picture of the real-life overall survival (OS) of women diagnosed with metastatic breast cancer from 2008 till 2016.•The median OS of the whole population over this 9-year period was 39.5 months (95% confidence interval, 38.7–40.3).•Prognostic factors on OS were age, tumour subtype, metastasis-free interval, presence of visceral metastases and number of metastatic sites.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses.
The kinetics of central nervous system (CNS) ...metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient's prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan-Meier method).
CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2-/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR- (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8-92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5-17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18-3.75, triple-negative and HER2-/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2-8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50-0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65-0.81) for HER2+/HR-, 4.4 months (HR = 1.55, 95% CI: 1.42-1.69) for triple-negative and 7.1 months for HER2-/HR+ patients (p <0.0001).
Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients.
NCT03275311.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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