L’hormonorésistance acquise constitue l’un des défis majeurs dans le traitement du cancer du sein avancé exprimant le récepteur aux estrogènes (RE) et sans surexpression de HER2. Les mutations ...activatrices du gène
ESR1
affectant le domaine de liaison du ligand ont récemment été identifiées comme l’un des principaux mécanismes de résistance aux inhibiteurs de l’aromatase (IA). Ces mutations peuvent être recherchées sur des prélèvements histologiques ou sur ADN tumoral circulant, par PCR ou séquençage de nouvelle génération (NGS). Elles induisent une activation constitutionnelle du RE conduisant à une résistance acquise aux IA ; le tamoxifène, le fulvestrant et les thérapies ciblées anti-mTOR ou anti-CDK4/6 conservent leur efficacité. La place en pratique clinique de la détection des mutations du gène
ESR1
reste encore à définir.
Acquired endocrine resistance remains one of the main obstacles in the treatment of estrogen receptor (ER) positive, HER2 negative advanced breast cancer. Recently, activating
ESR1
gene mutations affecting the ligand-binding domain have been identified as a key mechanismin aromatase inhibitor (AI) resistance. These mutations can be detected on histological samples or circulating tumour DNA, using PCRbased assays or next-generation sequencing. They induce a constitutive activation of ER, leading to acquired resistance to AI; tamoxifen, fulvestrant and targeted therapies against mTOR or CDK4/6 retain their efficacy. The use of monitoring
ESR1
mutations in l practice is still to be defined.
For hormone receptor–positive (HR+) human epidermal growth factor receptor 2 (HER2-) negative metastatic breast cancer (MBC), international guidelines recommend endocrine therapy as first-line ...treatment, except in case of ‘visceral crisis’. In the latter case, chemotherapy is preferred. Few studies have compared these two strategies. We used the Epidemiological Strategy and Medical Economics (ESME) programme, UNICANCER, a large national observational database (NCT03275311), to address this question.
All patients who initiated treatment for a newly diagnosed HR+ HER2-negative MBC between January 2008 and December 2014 in any of the 18 French Comprehensive Cancer Centers participating to ESME were selected. Patients should be aromatase inhibitor (AI)–sensitive (no previous AI or relapse occurring more than 1 year after last adjuvant AI). Objectives of the study were evaluation of progression-free and overall survival (OS) according to the type of first-line treatment adjusted on main prognostic factors using a propensity score.
Six thousand two hundred sixty-five patients were selected: 2733 (43.6%) received endocrine therapy alone, while 3532 (56.4%) received chemotherapy as first-line therapy. Among the latter, 2073 (58.7%) received maintenance endocrine therapy. Median OS was 60.78 months (95% confidence interval CI, 57.16–64.09) and 49.64 months (95% CI, 47.31–51.64; p < 0.0001) for patients receiving endocrine therapy alone and chemotherapy ± maintenance endocrine therapy, respectively. However, this difference was not significant after adjusting on the propensity score (hazard ratio: 0.943, 95% CI 0.863–1.030, p = 0.19).
In this large retrospective cohort of patients with AI-sensitive metastatic luminal BC, OS was similar, whether first-line treatment was chemotherapy or endocrine therapy. In agreement with international guidelines, endocrine therapy should be the first choice for first-line systemic treatment for MBC in the absence of visceral crisis.
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.
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).
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.
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.
•OS of HER2+ MBC patients keeps improving over time Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference.•This effect seems timely related to the release of drugs demonstrated to improve survival in clinical trials.•OS gains observed in real life among HER2+ MBC patients are at least equivalent to those observed in clinical trials.•YOD had no sustained impact on OS among patients with TNBC and luminal MBC.•The impact of CDK4/6 inhibitors cannot yet be assessed in this cohort.
Bevacizumab combined with paclitaxel as first-line chemotherapy for patients with HER2-negative metastatic breast cancer (MBC) has led to mixed results in randomized trials, with an improvement in ...progression-free survival (PFS) but no statistically significant overall survival (OS) benefit. Real-life data could help in assessing the value of this combination.
This study aimed to describe the outcome following first-line paclitaxel with or without bevacizumab in the French Epidemiological Strategy and Medical Economics (ESME) database of MBC patients, established in 2014 by Unicancer. The primary and secondary end points were OS and PFS, respectively.
From 2008 to 2013, 14 014 MBC patient files were identified, including 10 605 patients with a HER2-negative status. Of these, 3426 received paclitaxel and bevacizumab (2127) or paclitaxel (1299) as first-line chemotherapy. OS adjusted for major prognostic factors was significantly longer in the paclitaxel and bevacizumab group compared with paclitaxel hazard ratio (HR) 0.672, 95% confidence interval (CI) 0.601–0.752; median survival time 27.7 versus 19.8 months. Results were consistent in all supportive analyses (using a propensity score for adjustment and as a matching factor for nested case–control analyses) and sensitivity analyses. Similar results were observed for the adjusted PFS, favoring the combination (HR 0.739, 95% CI 0.672–0.813; 8.1 versus 6.4 months).
In this large-scale, real-life setting, patients with HER2-negative MBC who received paclitaxel plus bevacizumab as first-line chemotherapy had a significantly better OS and PFS than those receiving paclitaxel. Despite robust methodology, real-life data are exposed to important potential biases, and therefore, results need to be treated with caution. Our data cannot therefore support extension of current use of bevacizumab in MBC.
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.
Purpose
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.
Methods
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.
Results
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).
Conclusion
In this large database, few older MBC patients were enrolled in a trial compared with younger ones.
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.
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).
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).
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.
•T1/T2 N0 de novo metastatic breast cancer (MBC) represented 6% of all de novo MBC.•Metastatic diagnosis in this population implied an unrecommended workup.•These patients were younger with oligometastatic disease and had a better prognosis.•Locoregional therapy prior to diagnosis in this population did not change survival.
The Time to First Metastatic Recurrence (TFMR) could be considered as an indirect reflection of the tumour growth kinetics which plays an important role in cancer. Molecular subtypes such as ...expression of estrogen receptor are known predictive factors of TFMR. The CinéBreast study aimed to identify predictive factors of the time to TFMR.
The French Epidemiological Strategy and Medical Economics (ESME) Metastatic Breast Cancer (MBC) Database (NCT03275311) was used, which contains data from a cohort of metastatic breast cancer patients from 2008 to 2016 using retrospective data collection. It is a national multi-centre database. The impact of TFMR on overall survival (OS) since first metastasis was also evaluated.
Among 16 702 patients recorded in the ESME MBC database, 10 595 had an initially localised breast cancer with hormone receptor (HR) and HER2 status available, with a metastatic recurrence. Median follow up was 56 months. Median TFMR was 59 months (<24: 20%, 24–60: 31%, 60–120: 25%, >120: 24%). HER2+ and TNBC were respectively 4 times and 12 times (p < 0.0001) more likely to have a recurrence within 2 years when compared to the luminal subgroup. Short TFMR and HR-/HER2-subtype significantly correlated with a poor OS in multivariate analysis.
Some patients with MBC (20% in HER2+, 10% in ER+/HER2-and <5% in the ER-/HER2-) were long-term survivors in all 3 subgroups.
In this large-scale real-life data study, patients with a TNBC metastatic recurrence had a shorter TFMR. Short TFMR significantly correlated with worse overall survival.
•ESME is a large-scale real-life database of 16 702 metastatic breast cancer patients.•A short time to first metastatic recurrence is associated with poor overall survival.•Triple-negative tumours were more likely to recur early than HR+ and HER2+ tumours.
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