MiR-193b-3p and miR-132-3p as prognostic biomarkers of survival in pleural mesothelioma patients treated with first-line bevacizumab plus pemetrexed-platinum chemotherapy in the IFCT-0701 MAPS phase 3 trial

Our plain-English summary of MiR-193b-3p and miR-132-3p as prognostic biomarkers of survival in pleural mesothelioma patients treated with first-line bevacizumab plus pemetrexed-platinum chemotherapy in the IFCT-0701 MAPS phase 3 trial, by G. Levallet, C. Creveuil, A. Léger-Vigot, et al (Translational Oncology, 2025).

The study

• Authors: G. Levallet, C. Creveuil, A. Léger-Vigot, S. Brosseau, C. Danel, A. Scherpereel, S. Lantuejoul, J. Mazières, L. Greillier, C. Audigier-Valette, E. Bergot, D. Moro-Sibilot, O. Molinier, H. Léna, I. Monnet, F. Morin, V. Gounant, G. Zalcman
• Journal: Translational Oncology
• Published: 2025;61:102520
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We investigated whether angiogenesis-related microRNAs (miRNAs) predict survival in patients with pleural mesothelioma (PM) treated with bevacizumab plus pemetrexed-platinum chemotherapy in the Mesothelioma Avastin Cisplatin Pemetrexed Study ('MAPS', NCT00651456) phase 3 trial phase III trial (NCT00651456). Twelve miRNAs were measured in FFPE samples from 236 of the 448 MAPS trial patients (50.8 %), normalized to RNU48. Overall survival (OS) and progression-free survival (PFS) were analyzed by miRNA expression using univariate and multivariate models adjusted for clinical covariates. Internal validation was performed by bootstrapping. Interaction tests assessed the predictive value of each miRNA with respect to treatment arm. Low miR-193b-3p expression was associated with longer OS in PM patients, as shown in both univariate and multivariate analyses (adjusted HR = 0.87 [0.81-0.93], p < 0.001; bootstrap inclusion fraction [BIF]: 81.3 %), with both treatment arms analyzed together. It also predicted longer PFS (adjusted HR = 0.91 [0.85-0.97], p = 0.0042). Interaction tests revealed that for four miRNAs (miR-155-5p, miR-29c-5p, miR-132-3p, and miR-100-5p), lower expression levels were associated with greater efficacy of the bevacizumab/cisplatin/pemetrexed combination. Notably, the interaction between treatment arms and miR-132-3p expression was statistically significant (p = 0.004). In the IFCT-GFPC-0701 MAPS trial, low miR-193b-3p expression demonstrated significant independent prognostic value, being associated with longer OS and PFS. Additionally, low expression of miR-155-5p, miR-29c-5p, miR-132-3p, and miR-100-5p showed independent predictive value for improved survival in the bevacizumab plus chemotherapy arm. Thus, a simple qRT-PCR assay of these four miRNAs may help identifying PM patients most likely to benefit from bevacizumab.

Copyright © 2025. Published by Elsevier Inc.

In plain English

This was a pre-planned, exploratory add-on analysis of the MAPS trial, in which 448 patients with pleural mesothelioma were randomly assigned to pemetrexed-cisplatin chemotherapy with or without bevacizumab. The authors measured twelve tumor microRNAs linked to blood-vessel growth in samples from 236 patients (171 for miR-132-3p). After adjusting for clinical factors, only miR-193b-3p remained linked to overall survival: median survival was 22.3 months (95% CI 16.5 to 28.0) with levels below the median and 13.5 months (9.3 to 17.6) above it. No microRNA was significantly linked to time without disease progression after multiple-testing correction. For miR-132-3p, the bevacizumab effect differed by level: above the median, median survival was 17.1 months (8.5 to 25.8) with bevacizumab versus 11.2 (8.9 to 13.6) without it; below it, 24.6 (19.1 to 30.1) versus 24.7 months (20.1 to 29.3). The authors said this should be confirmed in a separate randomized comparison of bevacizumab, or another anti-angiogenic drug, against a control group. Asbestos exposure was not studied. The abstract reports several results differently, including a progression link for miR-193b-3p; this summary follows the main text.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Pre-specified ancillary and exploratory biomarker analysis (Bio-MAPS) of tumor samples from a randomized phase 3 treatment trial (MAPS)
• Who was studied: Patients with pleural mesothelioma in the French MAPS trial, randomized from February 2008 to January 2014. There were 448 patients in total: 223 were assigned to pemetrexed plus cisplatin and bevacizumab, and 225 to pemetrexed plus cisplatin. The microRNA panel was successfully measured in 236 of the 448.
• Exposure: No asbestos exposure was measured. The study examined tumor expression of 12 angiogenesis-related microRNAs, selected from 20 candidates and measured by qRT-PCR in formalin-fixed paraffin-embedded tumor samples. These levels were studied in relation to treatment with pemetrexed-cisplatin with or without bevacizumab.
• Main results:
  • The twelve microRNAs were successfully assayed in 236 of 448 patients (50.8 %). Fewer samples were analyzed for some microRNAs, including miR-132-3p (171 of 448).
  • In univariate analyses (both treatment arms together), three microRNAs were associated with overall survival: miR-193b-3p, miR-210-3p and miR-21-5p.
  • For miR-193b-3p in univariate analysis: HR 0.89, 95% CI 0.84 to 0.95, corrected p = 0.0031, per 1-point increase in delta Ct.
  • Only miR-193b-3p remained significant after adjustment for minimization and clinical risk factors: adjusted HR 0.86, 95% CI 0.80 to 0.92, p less than 0.001, corrected c-index 0.66.
  • Patients were split at the median miR-193b-3p expression. Median overall survival was 13.5 months (95% CI 9.3 to 17.6) for patients with expression above the median, and 22.3 months (95% CI 16.5 to 28.0) for patients with low expression.
  • In bootstrap resampling of the multivariate analysis, miR-193b-3p was the most frequently selected microRNA, but in only 42 % of cases.
  • In the main text, none of the twelve microRNAs was significantly associated with progression-free survival in univariate analyses after Bonferroni-Holm correction, so no multivariate model was estimated. (The abstract reports a significant adjusted association for miR-193b-3p instead.)
  • Tests asked whether microRNA level changed the effect of bevacizumab on overall survival. Only miR-132-3p was significant after Bonferroni-Holm correction (Table 2: interaction p = 0.0043, corrected p = 0.030, n = 171).
  • In patients with high tumor miR-132 expression (above the median), median overall survival was 17.1 months (95% CI 8.5 to 25.8) in the bevacizumab arm. It was 11.2 months (95% CI 8.9 to 13.6) in the chemotherapy-alone arm.
  • In patients with low tumor miR-132 expression, median overall survival was 24.6 months (95% CI 19.1 to 30.1) in the bevacizumab arm. It was 24.7 months (95% CI 20.1 to 29.3) in the chemotherapy-alone arm.
  • The miR-132-3p interaction was significant in 40 % of 1000 bootstrapped samples.
  • No statistically significant interaction effect was found for progression-free survival.
  • MicroRNA expression was not correlated with the angiogenesis markers previously studied by immunohistochemistry in MAPS patients (CD34, VEGFR2, VE-statin, IGFR1, YAP/TAZ, amphiregulin).
• The authors' conclusion: In the main text, the authors concluded that only miR-193b-3p retained an independent prognostic effect on overall survival. They said the predictive value of miR-132-3p should be validated in an independent cohort of randomized patients comparing bevacizumab, or another anti-angiogenic agent, with a control arm. The abstract states broader conclusions: it names four predictive microRNAs and says a qRT-PCR assay may help identify patients likely to benefit from bevacizumab.
• Limitations the authors state:
  • Possible bias from sample loss: the microRNA study succeeded in only about half of the trial population, although the authors found no differences between patients with and without analyses.
  • Interaction tests had reduced statistical power, further reduced by multiple-testing correction, so predictive effects of other microRNAs may have been missed.
  • The biological role of miR-193b-3p in mesothelioma is unclear and needs further investigation.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Bevacizumab, Pemetrexed (Alimta), Chemotherapy, Angiogenesis, Mesothelioma, Cisplatin.

Related studies

• MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial — E. Maille, S. Brosseau, et al. (2019)
• A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT-0701 MAPS phase 3 trial — E. Maille, J. Levallet, et al. (2022)
• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort — S. Brosseau, C. Danel, et al. (2019)
• Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma — G.L. Ceresoli, P.A. Zucali, et al. (2013)
• Cost-effectiveness analysis of additional bevacizumab to pemetrexed plus cisplatin for malignant pleural mesothelioma based on the MAPS trial — M. Zhan, H. Zheng, et al. (2017)

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