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

Our plain-English summary of 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, by E. Maille, J. Levallet, F. Dubois, et al (International Journal of Cancer, 2022).

The study

• Authors: E. Maille, J. Levallet, F. Dubois, M. Antoine, C. Danel, C. Creveuil, J. Mazieres, J. Margery, L. Greillier, V. Gounant, D. Moro-Sibilot, O. Molinier, H. Léna, I. Monnet, E. Bergot, A. Langlais, F. Morin, A. Scherpereel, G. Zalcman, G. Levallet
• Journal: International Journal of Cancer
• Published: 2022;150(11):1889-1904
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The Hippo pathway effector YAP is dysregulated in malignant pleural mesothelioma (MPM). YAP's target genes include the secreted growth factor amphiregulin (AREG), which is overexpressed in a wide range of epithelial cancers and plays an elusive role in MPM. We assayed the expression of YAP and AREG in MPM pathology samples and that of AREG additionally in plasma samples of patients from the randomized phase 3 IFCT-0701 Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) using immunohistochemistry and ELISA assays, respectively. MPM patients frequently presented high levels of tumor AREG (64.3%), a high cytosolic AREG expression being predictive of a better prognosis with longer median overall and progression-free survival. Surprisingly, tumor AREG cytosolic expression was not correlated with secreted plasma AREG. By investigating the AREG metabolism and function in MPM cell lines H2452, H2052, MSTO-211H and H28, in comparison with the T47D ER+ breast cancer cell line used as a positive control, we confirm that AREG is important for cell invasion, growth without anchorage, proliferation and apoptosis in mesothelioma cells. Yet, most of these MPM cell lines failed to correctly execute AREG posttranslational processing by metalloprotease ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and extracell secretion. The favorable prognostic value of high cytosolic AREG expression in MPM patients could therefore be sustained by default AREG posttranslational processing and release. Thus, the determination of mesothelioma cell AREG content could be further investigated as a prognostic marker for MPM patients and used as a stratification factor in future clinical trials.

© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

In plain English

This was a preplanned, exploratory study (Bio-MAPS) within the IFCT-0701 MAPS phase 3 trial, which randomly assigned 448 patients with malignant pleural mesothelioma (2008 to 2014) to pemetrexed plus cisplatin with or without bevacizumab. Asbestos exposure was not examined. The authors measured the proteins amphiregulin (AREG) and YAP in tumor samples, and AREG in plasma. Median overall survival was 22.2 months (95% CI 17.9 to 24.5) for the 139 patients with AREG-positive tumors and 15.1 months (95% CI 13.2 to 16.8) for the 146 AREG-negative patients (adjusted hazard ratio 0.69, 95% CI 0.54 to 0.90). With AREG in the cell cytoplasm, median overall survival was 24.8 months (95% CI 19.6 to 35.6), against 15.9 months (95% CI 14.1 to 17.9) with nuclear AREG. High YAP expression was also associated with longer survival. Plasma AREG was detected in 42 of 373 patients and was not correlated with tumor AREG or survival. In laboratory tests, three of four mesothelioma cell lines released little AREG. The authors concluded that cytosolic tumor AREG could mark better prognosis; the underlying mechanism, they noted, remains elusive.

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: Preplanned, ancillary, exploratory biomarker study within a randomized phase 3 trial (Bio-MAPS), combined with laboratory experiments on mesothelioma and breast cancer cell lines
• Who was studied: Patients with malignant pleural mesothelioma in the IFCT-0701 MAPS trial: 448 randomized between February 13, 2008 and January 5, 2014. Tumor AREG was assessed in 306 of 448 (not interpretable in 21; 139 positive, 146 negative) and plasma AREG in 373 of 448. Lab work used mesothelioma cell lines H2452, H2052, MSTO-211H and H28, with the T47D breast cancer cell line as a control.
• Exposure: No asbestos exposure was studied. The factors examined were tumor AREG and YAP protein, measured by immunohistochemistry, and plasma AREG, measured by ELISA. Patients were treated with pemetrexed plus cisplatin, with or without bevacizumab.
• Main results:
  • Median overall survival was 22.2 months (95% CI 17.9-24.5) for patients with positive tumor AREG versus 15.1 months (95% CI 13.2-16.8) for patients with null AREG; adjusted HR 0.69 (95% CI 0.54-0.90), P = .0052.
  • Median progression-free survival was 8.8 months (95% CI 8.1-10.0) for AREG-positive patients versus 7.9 months (95% CI 6.6-8.6) for AREG-negative patients; adjusted HR 0.71 (95% CI 0.55-0.90), P = .0056.
  • Median overall survival was 24.8 months (95% CI 19.6-35.6) for patients with cytosolic tumor AREG versus 15.9 months (95% CI 14.1-17.9) when AREG was nuclear; HR 0.61 (95% CI 0.44-0.84), P = .003.
  • Median progression-free survival was 10.4 months (95% CI 8.4-13.3) for patients with cytosolic tumor AREG versus 8.2 months (95% CI 7.2-8.6) when AREG was nuclear; adjusted HR 0.60 (95% CI 0.40-0.88), P = .009.
  • Null tumor AREG was more frequent in patients with sarcomatoid or biphasic mesothelioma than in those with epithelioid mesothelioma (P = .0081).
  • AREG did not predict survival differently between the two treatment arms (interaction test P = .348 for overall survival and .865 for progression-free survival).
  • Median overall survival was 19.6 months (95% CI 15.9-24.5) for high YAP expression (H-score 300 or more) versus 14.1 months (95% CI 12.1-17.9) for intermediate YAP expression; adjusted HR 0.69 (95% CI 0.51-0.94), P = .02.
  • Median progression-free survival was 9.2 months (95% CI 8.2-10.6) for high YAP expression versus 7.3 months (95% CI 6.4-8.6) for intermediate YAP expression; adjusted HR 0.63 (95% CI 0.46-0.85), P = .003.
  • Plasma AREG was detected in 42 of 373 patients (11.26%).
  • Plasma AREG was not correlated with tumor AREG (r = .007, P = .91), nor with overall or progression-free survival.
  • In the H2452, H2052 and MSTO-211H cell lines, cellular and released AREG were both low (1 to 4 pg). This contrasted with the T47D control line, which released about three times more AREG into the medium than it kept in the cells. H28 was the only mesothelioma cell line that actively released AREG.
  • Silencing AREG in the four mesothelioma cell lines reduced their invasion capacity by almost half.
• The authors' conclusion: The authors proposed that cytosolic tumor AREG, determined by immunohistochemistry, could serve as a prognostic biomarker to identify mesothelioma patients with better prognosis. They suggested its favorable prognostic value could be sustained by faulty AREG processing and release.
• Limitations the authors state:
  • The biomarker study was ancillary and purely exploratory.
  • The basic mechanism behind AREG's prognostic influence remains elusive.
  • It remains to be established whether patients with high cytosolic AREG would specifically benefit from combination immunotherapy.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pathology, Mesothelioma, Cisplatin, Pemetrexed (Alimta), Immunohistochemistry, Prognosis, Progression-Free Survival.

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)
• 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 — G. Levallet, C. Creveuil, et al. (2025)
• 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)
• Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma — S. Inaguma, J. Lasota, et al. (2018)
• Loss of expression of BAP1 predicts longer survival in mesothelioma — M. Farzin, C.W. Toon, et al. (2015)

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