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Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients

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Abstract

Background

Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy.

Methods

Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort.

Results

MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1–26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5–18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil–lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001).

Conclusions

In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.

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Acknowledgements

We want to acknowledge the Cellex Foundation for providing facilities and equipment, and Spanish Cancer Association (AECC) for its support.

Funding

This work was supported by the Spanish Cancer Association (AECC) Scientific Foundation (GCB14-2170).

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Authors and Affiliations

  1. Medical Oncology Department, Vall d´Hebron University Hospital and Institute of Oncology, Barcelona, Spain

    S. Cedrés, P. Iranzo, A. Callejo, N. Pardo, A. Navarro, A. Martinez-Marti, R. Dienstmann & E. Felip

  2. CIBERONC, Madrid, Spain

    S. Ponce-Aix & L. Paz-Ares

  3. Medical Oncology Department, University Hospital Doce de Octubre, Madrid, Spain

    S. Ponce-Aix

  4. University Hospital Doce de Octubre, Madrid, Spain

    S. Gómez-Abecia

  5. Pathology Department, Vall d’Hebron University Hospital, Barcelona, Spain

    A. C. Zucchiatti

  6. Pathological Anatomy Department, University Hospital Doce de Octubre, Madrid, Spain

    I. Sansano & A. B. Enguita

  7. Vall d´Hebron Institute of Oncology, Barcelona, Spain

    J. M. Miquel

  8. Oncology Data Science (ODysSey) Group, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

    C. Viaplana & R. Dienstmann

  9. H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation I+12, Madrid, Spain

    L. Paz-Ares

  10. H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    L. Paz-Ares

  11. Medical School, Complutense University, Madrid, Spain

    L. Paz-Ares

  12. Servicio de Oncología, Hospital Vall D´Hebron, Paseo Vall d´Hebron 119-129, 08035, Barcelona, Spain

    S. Cedrés

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  1. S. Cedrés
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Correspondence to S. Cedrés.

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Approval for the use of the tissue in research was obtained from the ethical local committee from both hospitals.

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Cedrés, S., Ponce-Aix, S., Iranzo, P. et al. Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients. Clin Transl Oncol 22, 1390–1398 (2020). https://doi.org/10.1007/s12094-019-02275-9

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