Breast cancer patients treated with intrathecal therapy for leptomeningeal metastases in a large real-life database

M Carausu, M Carton, A Darlix, D Pasquier, M Leheurteur, M Debled, M A Mouret-Reynier, A Goncalves, F Dalenc, B Verret, M Campone, P Augereau, J M Ferrero, C Levy, J-D Fumet, C Lefeuvre-Plesse, T Petit, L Uwer, C Jouannaud, L Larrouquere, M Chevrot, C Courtinard, L Cabel, M Carausu, M Carton, A Darlix, D Pasquier, M Leheurteur, M Debled, M A Mouret-Reynier, A Goncalves, F Dalenc, B Verret, M Campone, P Augereau, J M Ferrero, C Levy, J-D Fumet, C Lefeuvre-Plesse, T Petit, L Uwer, C Jouannaud, L Larrouquere, M Chevrot, C Courtinard, L Cabel

Abstract

Background: Leptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high morbidity/mortality rates. Our study aimed to describe the largest-to-date real-life population of MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models.

Methods: The Epidemiological Strategy and Medical Economics (ESME) MBC database (NCT03275311) includes all consecutive patients who have initiated treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan-Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots.

Results: Of the 22 266 patients included in the database between 2008 and 2016, 312 received IT therapy and were selected for our analysis. Compared with non-IT-treated patients, IT-treated patients were younger at MBC relapse (median age: 52 years versus 61 years) and more often had lobular histology (23.4% versus 12.7%) or triple-negative subtype (24.7% versus 13.3%) (all P < 0.001). Median OS was 4.5 months [95% confidence interval (CI) 3.8-5.6] and 1-year survival rate was 25.6%. Significant prognostic factors associated with poorer outcome on multivariable analysis were triple-negative subtype (hazard ratio 1.81, 95% CI 1.32-2.47), treatment line ≥3 (hazard ratio 1.88, 95% CI 1.30-2.73), ≥3 other metastatic sites (hazard ratio 1.33, 95% CI 1.01-1.74) and IT cytarabine or thiotepa versus methotrexate (hazard ratio 1.68, 95% CI 1.28-2.22), while concomitant systemic therapy was associated with better OS (hazard ratio 0.47, 95% CI 0.35-0.62) (all P < 0.001). We validated two previously published prognostic scores, the Curie score and the Breast-graded prognostic assessment, both with C-index of 0.57.

Conclusions: MBC patients with LM treated with IT therapy have a poor prognosis. We could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used.

Keywords: breast cancer; cohort study; intrathecal therapy; leptomeningeal metastasis.

Conflict of interest statement

Disclosure MCapone reports personal fees (consulting, advisory) from Lilly, Novartis, GT1, Daiichi Sankyo and fees to the institution from AstraZeneca, Sanofi, Servier and AbbVie, outside the submitted work. All other authors have declared no conflicts of interest.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Flowchart of patients who received IT therapy in the ESME MBC database. ESME, Epidemiological Strategy and Medical Economics; MBC, metastatic breast cancer; IT, intrathecal.
Figure 2
Figure 2
Kaplan–Meier plots for overall survival (A) in all patients treated with IT therapy; (B) according to BC subtype (HR+/HER2− versus HER2+ versus TN, log-rank P < 0.0001); (C) according to IT agent (methotrexate versus cytarabine or thiotepa, log-rank P = 0.047). BC, breast cancer; CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IT, intrathecal; OS, overall survival; TN, triple negative.
Figure 3
Figure 3
Kaplan–Meier plots for overall survival according to (A) Curie score (0 versus 1 versus 2-3, log-rank P < 0.0001) and (B) Breast-GPA-designated risk groups (0.0-1.0 versus 1.5-2.0 versus 2.5-4.0, log-rank P = 0.00011). Patients were grouped in classes according to each score, as described in the ‘Materials and methods’ section. CI, confidence interval; GPA, graded prognostic assessment.

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