Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy

Our plain-English summary of Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy, by F.D. Mairinger, J. Schmeller, S. Borchert, et al (Oncotarget, 2018).

The study

• Authors: F.D. Mairinger, J. Schmeller, S. Borchert, M. Wessolly, E. Mairinger, J. Kollmeier, T. Hager, T. Mairinger, D.C. Christoph, R.F.H. Walter, W.E.E. Eberhardt, T. Plönes, J. Wohlschlaeger, B. Jasani, K.W. Schmid, A. Bankfalvi
• Journal: Oncotarget
• Published: 2018;9(32):22254-22268
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a biologically highly aggressive tumor arising from the pleura with a dismal prognosis. Cisplatin is the drug of choice for the treatment of MPM, and carboplatin seems to have comparable efficacy. Nevertheless, cisplatin treatment results in a response rate of merely 14% and a median survival of less than seven months. Due to their role in many cellular processes, methallothioneins (MTs) have been widely studied in various cancers. The known heavy metal detoxifying effect of MT-I and MT-II may be the reason for heavy metal drug resistance of various cancers including MPM.

Methods: 105 patients were retrospectively analyzed immunohistochemically for their MT expression levels. Survival analysis was done by Cox-regression, and statistical significance determined using likelihood ratio, Wald test and Score (logrank) tests.

Results: Cox-regression analyses were done in a linear and logarithmic scale revealing a significant association between expression of MT and shortened overall survival (OS) in a linear (p=0.0009) and logarithmic scale (p=0.0003). Reduced progression free survival (PFS) was also observed for MT expressing tumors (linear: p=0.0134, log: p=0.0152).

Conclusion: Since both, overall survival and progression-free survival are negatively correlated with detectable MT expression in MPM, our results indicate a possible resistance to platin-based chemotherapy associated with MT expression upregulation, found exclusively in progressive MPM samples. Initial cell culture studies suggest promoter DNA hypomethylation and expression of miRNA-566 a direct regulator of copper transporter SLC31A1 and a putative regulator of MT1A and MT2A gene expression, to be responsible for the drug resistance.

In plain English

This retrospective study examined tumor samples from 105 patients with malignant pleural mesothelioma treated at centres in Essen (2006 to 2009) and Berlin (2002 to 2009), Germany. All patients received platinum-based chemotherapy (cisplatin or carboplatin). The authors stained pre-treatment samples for metallothionein, a metal-binding protein. Twenty-one tumors (20.0%) showed metallothionein. All 21 came from the 54 patients whose disease progressed. None of the other 51 tumors stained. The article calls them stable or responding, though its counts give 49 such patients and 2 unassessed. A formal test of the link with progression was not statistically significant (p=0.078). Metallothionein-positive tumors were associated with shorter overall survival (linear p=0.0009, logarithmic p=0.0003) and shorter progression-free survival. None of the 21 positive patients lived beyond three years, versus approximately 35% with negative tumors. In laboratory tests, all three mesothelioma cell lines had metallothionein. The two with strong, mainly cytoplasmic staining showed less, later cell death after cisplatin. The authors concluded that metallothionein expression may predict resistance to platinum-based chemotherapy. They noted that the study included few non-epithelioid cases. The article did not report patients' asbestos exposure.

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 archived tumor samples (immunohistochemistry and survival analysis), with additional cell-line experiments and analysis of public gene data (TCGA)
• Who was studied: 105 patients with malignant pleural mesothelioma (84 men, 21 women; 96 epithelioid, 5 biphasic, 4 sarcomatoid) treated in Essen (2006 to 2009) and Berlin (2002 to 2009), Germany; survival data available for 100
• Exposure: Not an asbestos exposure study. The factor studied was tumor metallothionein (MT-1 and MT-2) protein expression in patients given platinum-based chemotherapy (cisplatin or carboplatin)
• Main results:
  • 21 of 105 tumors (20.0%) showed metallothionein expression
  • All 21 metallothionein-positive tumors were among the 54 progressive tumors. None of the other 51 stained, a group the article calls remissive or stable, although its response counts give 42 stable, 7 partial response and 2 not assessed
  • Response counts among the 105 patients were 42 stable disease, 7 partial response, 54 progressive disease and 2 not assessed
  • The association between metallothionein expression and tumor progression or remission under platin-based chemotherapy was not statistically significant (p=0.078 and p=0.089)
  • Metallothionein expression was significantly associated with shortened overall survival (linear p=0.0009, logarithmic p=0.0003)
  • Metallothionein-expressing tumors had reduced progression-free survival (linear p=0.0134, log p=0.0152)
  • About 35% of patients with MT-negative tumors survived 3 years; none of the 21 MT-positive patients was alive beyond that time
  • Among epithelioid tumors only, metallothionein expression was also associated with shortened overall survival (linear p=0.0016, logarithmic p=0.0011)
  • Metallothionein expression was rare in epithelioid, more frequent in biphasic and most frequent in sarcomatoid tumors (p=0.0039)
  • All three mesothelioma cell lines showed detectable metallothionein, while the fibroblast line was negative
  • In cell culture, NCI-H2052 and NCI-H2452, with strong mainly cytoplasmic metallothionein, showed a delayed and weaker apoptotic response to cisplatin than MSTO-211H, which had weak mainly nuclear staining
  • In TCGA gene data, mRNA expression and methylation levels of metallothionein genes were not significantly associated with overall survival, except the MT1DP pseudogene
• The authors' conclusion: The authors concluded that immunohistochemical metallothionein expression was significantly correlated with poor overall and progression-free survival under platin-based chemotherapy, suggesting a possible role as a predictor of resistance to platin-based chemotherapy
• Limitations the authors state:
  • Only a small number of biphasic and sarcomatoid cases were included
  • The TCGA data set had no data on response to therapy or progression-free survival
  • Another study found no significant association between metallothionein expression and survival in mesothelioma, in contrast to these results

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Pleura, Prognosis, Cisplatin, Carboplatin, Median Overall Survival, Statistical Significance.

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• Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro — S. Borchert, M. Wessolly, et al. (2019)
• Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy — R.F. Walter, C. Vollbrecht, et al. (2016)
• Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma — S. Borchert, P.M. Suckrau, et al. (2020)
• Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53 — R.F.H. Walter, R. Werner, et al. (2018)
• Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma — F.D. Mairinger, R.F. Walter, et al. (2014)

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