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

Our plain-English summary of Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients, by S. Cedrés, S. Ponce-Aix, P. Iranzo, et al (Clinical & Translational Oncology, 2020).

The study

• Authors: S. Cedrés, S. Ponce-Aix, P. Iranzo, A. Callejo, N. Pardo, A. Navarro, A. Martinez-Marti, S. Gómez-Abecia, A.C. Zucchiatti, I. Sansano, A.B. Enguita, J.M. Miquel, C. Viaplana, R. Dienstmann, L. Paz-Ares, E. Felip
• Journal: Clinical & Translational Oncology
• Published: 2020;22(8):1390-1398
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This retrospective study examined tumor samples from 159 consecutive patients with malignant pleural mesothelioma collected from 2005 to 2017 at two hospitals in Spain. The authors stained the tumors for four DNA mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). All 158 samples with enough tissue were positive for all four proteins. This included samples from the 22 patients who received immunotherapy in clinical trials. About half the patients (52%) had previous asbestos exposure, and the authors found no difference in survival by asbestos exposure, gender or smoking. Median survival for the whole group was 15 months (95% confidence interval 13.5 to 18.8 months). Survival was longer in patients with better performance status (general fitness), the epithelioid tumor type, and a lower blood neutrophil-to-lymphocyte ratio. Patients given immunotherapy had a median survival of 25.9 months versus 14.5 months for the others, a difference that was not statistically significant (p = 0.086). The authors concluded that MMR protein staining is not a candidate marker that warrants further exploration in this disease. They noted that staining cannot detect every MMR defect.

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: Retrospective study of archival tumor samples using immunohistochemistry (protein staining), with clinical outcomes collected from patient records
• Who was studied: 159 consecutive cases of malignant pleural mesothelioma collected from 2005 to 2017 at Vall d'Hebron University Hospital and University Hospital Doce de Octubre, Spain; median age 69, 71% male. 22 patients received immunotherapy in clinical trials.
• Exposure: The study's focus was tumor expression of MMR proteins, not asbestos. Asbestos exposure history was recorded as a patient characteristic: yes in 83 of 159 (52.2%, Table 1). No fiber types, jobs or doses are given.
• Main results:
  • In all 158 patients with enough tissue, tumors were positive for MLH1, MSH2, MSH6 and PMS2; no patient had MMR deficiency.
  • In the subgroup treated with immunotherapy, all samples were also MMR-positive.
  • Median survival for the entire group was 15 months (95% CI 13.5 to 18.8 months).
  • By tumor type, median survival was 18.4 months for epithelioid, 4.6 months for sarcomatoid and 14.9 months for not otherwise specified (p less than 0.001).
  • By performance status, median survival was 28.2 months for PS 0, 13.7 months for PS 1 and 2.3 months for PS 2 (p less than 0.001).
  • Patients with a neutrophil-to-lymphocyte ratio below 5 survived a median of 18.4 months, versus 9.4 months for those above 5 (p less than 0.001).
  • Survival did not differ by gender, smoking or asbestos exposure.
  • Among the 22 immunotherapy patients, 58% had a response or stable disease for more than 6 months; progression-free survival was 5.7 months (2.1 to 26.1 months).
  • Overall survival was 25.9 months for immunotherapy patients versus 14.5 months for patients without immunotherapy; p = 0.086, not statistically significant at the study's 0.05 threshold.
  • In the multivariable analysis, performance status (ECOG) and tumor type remained significant prognostic factors for survival.
• The authors' conclusion: The authors concluded that MMR protein expression assessed by immunohistochemistry in malignant pleural mesothelioma is not a candidate marker that warrants further exploration.
• Limitations the authors state:
  • Immunohistochemistry has diagnostic limits; for example, it cannot always detect loss of proteins caused by certain mutations.
  • No tumor samples from immunotherapy patients were available for sequencing-based (NGS) microsatellite instability testing.
  • Because no patient had MMR deficiency, the authors could not evaluate whether MMR status relates to immunotherapy outcomes.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, checkpoint inhibitors, Biomarker, Microsatellite Instability (MSI-H), Immunohistochemistry, Immunotherapy, Chemotherapy, Clinical Trial.

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