One Third of Malignant Pleural Mesothelioma Shows High Immunohistochemical Expression of MSLN or CXCR4 Which Indicates Potent Candidates for Endo-Radiotherapy

Our plain-English summary of One Third of Malignant Pleural Mesothelioma Shows High Immunohistochemical Expression of MSLN or CXCR4 Which Indicates Potent Candidates for Endo-Radiotherapy, by T. Hager, S. Borchert, M. Wessolly, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: T. Hager, S. Borchert, M. Wessolly, A. Mathilakathu, E. Mairinger, J. Kollmeier, T. Mairinger, B. Hegedus, K. Greimelmaier, J. Wohlschlaeger, K. Herrmann, F.D. Mairinger
• Journal: International Journal of Molecular Sciences
• Published: 2023;24(7)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a mainly asbestos-related tumour associated with a very poor prognosis. Therapeutic approaches include multimodal therapy and chemotherapeutics, with cisplatin being the drug of choice, but response rates of only up to 14% indicate very poor outcomes. Effective treatment options are lacking. Besides the diagnostic usage of radioligands in positron emission tomography (PET)/computed tomography (CT), the endo-radioligand therapy with Lu177 has been proven as a powerful tool in cancer therapy. Mesothelin (MSLN) and C-XC chemokine receptor 4 (CXCR4) are membrane-bound proteins, expressed in certain cancers, and thus are promising targets for endo-radiotherapy. A significant portion of high MSLN- or CXCR4-expressing tumors within the MPM may open the field for this sophisticated treatment approach in the near future. Formalin-fixed, paraffin-embedded (FFPE) tumour specimens from 105 patients suffering from MPM and treated at the Lung Cancer Centre of Essen and at the Helios Klinikum Emil von Behring Berlin were screened. The tumour samples were arranged in tissue microarrays. We immunohistochemically stained the tumour samples against MSLN and CXCR4. The protein expressions of the stainings were scored by a pathologist by using a semiquantitative method. The data obtained were correlated with the clinical outcome. Overall, 77.1% of the analysed tumours showed CXCR4 protein expression (25.7% of them at high expression level (Score 3)). 48.6% of all samples showed an overall strong staining (Score ≥ 2), 59% of the investigated tumours showed MSLN protein expression (10.5% of them at high expression (Score 3)), and 36.2% of all samples showed an overall strong staining (Score ≥ 2). Our results show significant tissue expression levels, for both CXCR4 and MSLN protein, in a major portion of clinical MPM samples. One-third of patients showed outstanding immunoexpression of at least one of these markers, making them interesting candidates for radioligand-based PET/CT diagnostics and follow-up and furthermore may profit from endo-radiotherapy.

In plain English

This retrospective study examined stored tumour tissue from 105 patients with malignant pleural mesothelioma treated in Essen (2006 to 2009) or Berlin (2002 to 2009), Germany. The authors stained the samples for two cell-surface proteins, mesothelin (MSLN) and CXCR4, which are possible targets for imaging and radioactive drug treatment. They scored staining from 0 to 3. Asbestos exposure was not studied. CXCR4 was found in 81 tumours (77.1%), with 27 (25.7%) at the highest score. MSLN was found in 62 tumours (59.0%), with 11 (10.5%) at the highest score. CXCR4 levels were not significantly linked to survival. Among epithelioid tumours, low MSLN staining was associated with shorter overall survival: the low group had a hazard ratio of 3.74 (95% CI 1.46 to 9.56). MSLN was not significantly associated with progression-free survival under platinum-based therapy, though 1-year progression-free survival was 47.6% in the high group versus 18.6% in the low group. Public gene data from 87 patients showed a similar MSLN pattern. The authors concluded that one third of patients showed outstanding expression of one of these markers, making them candidates for such diagnostics and treatment.

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 laboratory study of archived tumour tissue (immunohistochemistry on tissue microarrays) with survival analysis, plus analysis of public TCGA genetic data
• Who was studied: 105 patients with malignant pleural mesothelioma (84 male, 21 female; mean age at diagnosis 65, range 34 to 82). Tumour types were 96 epithelioid, 5 biphasic and 4 sarcomatoid. Patients were treated in Essen (2006 to 2009) or at Helios Klinikum Emil von Behring, Berlin (2002 to 2009). Survival data were available for 102 patients. TCGA data from 87 malignant pleural mesothelioma patients were also analysed.
• Exposure: Asbestos exposure was not studied: no fibre types, jobs or doses were reported. The article mentions asbestos only as background. What was measured was tumour protein expression of MSLN and CXCR4, scored 0 to 3 by the share of positive tumour cells (Score 1 about 1 to 10%, Score 2 11 to 50%, Score 3 more than 50%).
• Main results:
  • CXCR4: 81 of 105 tumours (77.1%) showed expression. 30 (28.6%) were Score 1, 24 (22.9%) Score 2 and 27 (25.7%) Score 3. In all, 48.6% of samples scored 2 or higher.
  • MSLN: 62 tumours (59.0%) showed expression. 24 (22.9%) were Score 1, 27 (25.7%) Score 2 and 11 (10.5%) Score 3. In all, 36.2% of samples scored 2 or higher.
  • CXCR4 was not significantly associated with tumour characteristics, including progression under platinum chemotherapy (p = 0.326). Score 3 CXCR4 staining was seen only in progressive cases. Only 4 of 54 progressive cases (7.4%) stained negative.
  • No significant influence of CXCR4 expression on overall survival was observed (p = 0.715, HR 0.94, 95% CI 0.67 to 1.31). No significant influence on progression-free survival was observed either (p = 0.494, HR 1.11, 95% CI 0.82 to 1.50). Grouping into high versus low expression was also not significant.
  • Low MSLN expression was associated with shortened overall survival (continuous: p = 0.012, HR 0.62, 95% CI 0.42 to 0.91). When grouped high versus low, the low-expressing group had a higher risk of dying earlier (p = 0.003, HR 3.74, 95% CI 1.46 to 9.56).
  • MSLN-negative tumours had a 3-year overall survival rate of 14.4% and a median survival of about 11.5 months. Tumours with strong MSLN expression had a 3-year overall survival rate of 65.3% and a median survival of 44.8 months.
  • MSLN expression was not significantly associated with progression-free survival under platinum-based therapy (continuous: p = 0.206, HR 0.80, 95% CI 0.58 to 1.13; grouped: p = 0.146, HR for low group 1.74, 95% CI 0.82 to 3.68).
  • The authors noted a clear separation between the MSLN groups in the first two years. The 1-year progression-free survival rate was 47.6% for the high group versus 18.6% for the low group. Median progression-free survival was 10.1 versus 7.3 months.
  • Biphasic and sarcomatoid subtypes showed significantly shortened overall survival (p = 0.0036). Only epithelioid tumours were then considered for the survival analysis.
  • In the TCGA gene data (87 patients), low MSLN gene expression was associated with shortened overall survival (p = 0.008, HR 0.64, 95% CI 0.49 to 0.86). CXCR4 gene expression had no significant influence (p = 0.174).
• The authors' conclusion: The authors concluded that both CXCR4 and MSLN were expressed in a major portion of the mesothelioma samples. They stated that one third of patients showed outstanding expression of one or the other marker, making them candidates for radioligand-based PET/CT diagnostics and follow-up and for endo-radiotherapy.
• Limitations the authors state:
  • Biphasic and sarcomatoid cases were few. A separate subgroup analysis of them was not reasonable because of the small numbers.
  • Classification of mesothelioma is surgically based only, which creates problems in classifying patients who did not have resection.
  • For 5% of patients, surgical treatment status could not be assigned because the data were anonymized.

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, Prognosis, Multimodal Therapy, Cisplatin, Mesothelin, Lung Cancer.

Related studies

• The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma — T. Li, H. Li, et al. (2011)
• Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity — L. Brcic, A. Mathilakathu, et al. (2021)
• Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter — K. Tan, K. Kajino, et al. (2010)
• Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study — A. Mathilakathu, S. Borchert, et al. (2021)
• Expression status of candidate genes in mesothelioma tissues and cell lines — O. Melaiu, E. Melissari, et al. (2015)
• High SUVmax on FDG-PET indicates pleomorphic subtype in epithelioid malignant pleural mesothelioma: supportive evidence to reclassify pleomorphic as nonepithelioid histology — K. Kadota, S.S. Kachala, et al. (2012)

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