The Predictive Value of ERCC1, RRM1, and Thymidylate Synthase in Advanced Malignant Pleural Mesothelioma Patients Treated with Platinum-Based Chemotherapy

Our plain-English summary of The Predictive Value of ERCC1, RRM1, and Thymidylate Synthase in Advanced Malignant Pleural Mesothelioma Patients Treated with Platinum-Based Chemotherapy, by N.I. Wahba, O. Khorshid, F. Abo Elkasem, et al (Asian Pacific Journal of Cancer Prevention, 2023).

The study

• Authors: N.I. Wahba, O. Khorshid, F. Abo Elkasem, A. Bahnassy, R. Gaafer
• Journal: Asian Pacific Journal of Cancer Prevention
• Published: 2023;24(1):195-205
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: A rare yet severe neoplasia called malignant pleural mesothelioma (MPM) typically manifests itself in advanced stages. Despite some improvements in the treatment of patients with MPM, this malignancy continues to have a detrimental prognosis . The primary goal of the present study was to assess the associatin between ERCC1, RRM1, and thymidylate synthase (TS) expression and disease outcome in patients with malignant pleural mesothelioma (MPM) treated with either pemetrexed plus cisplatin or gemcitabine plus cisplatin.

Methods: This prospective cohort study was done on ninety-one advanced MPM patients. The patients received either pemetrexed plus platinum (55 of 91) or gemcitabine plus platinum chemotherapy (36 of 91). Tissue biopsy was taken at time of diagnosis. Immunohistochemistry was used to assess the levels of ERCC1, RRM1, and TS transcription in tissue biopsies (paraffin embedded).

Results: Based on the findings, 70% of patients with low expression of TS had low expression of ERCC1, and 68% of patients with high expression of TS had high expression of ERCC1, suggesting a significat association between ERCC1 expression and TS expression (p=0.005). However, there was no relation between ERCC1 and RRM1 expression patterns (p= 0.296). In patients underwen platinum-based theraphy (n 91), a significant correlation was detected between low ERCC1 median High-scoring and longer progression time (TTP;9.6 v 5.3 months;P< .001) or overall survival (OS) (OS;18.1 v 9.1 months; P<0.001). A significant correlation was found between low TS protein expression and longer time progression (TTP; 11.8 v 5.4 months; P< .001) or OS (OS; 19.8 v 8.5 months; P <0.001) in patients undergoing pemetrexed plus platinum chemotherapy (n 55). Low RRM1 expression was accompanied by high progression free survival (TTP; 10.6 v 3.8 months) and OS (OS; 20.6 v 8.6 months) in patients receiving gemcitabine plus platinum chemotherapy. Based on the multivariate test results, the independent variables significantly affecting OS were tumor stage (HR: 2.3; 95% CI: 1.1-4.9; p= 0.021) and ERCC1 (HR: 2.7; 95% CI: 1.7-4.3; p < 0.001).

Conclusion: Decreased TS protein expression can be indicative of greater responsivness to pemtrexed and of longer TTP and OS in individuals with advanced MPM (locally progressed or metastatic) who are receiving pemetrexed-based chemotheraphy. Low ERCC1 expressions in individuals with advanced MPM can predict increased PFS and OS, as well as a better responsivness to platinum-based chemotherapy. In patients with progressed MPM receiving gemcitabine plus cisplatin chemotherapy, lower RRM1 expression was associated with a better prognosis, longer PFS, and longer OS.

In plain English

This study, from the National Cancer Institute in Cairo, Egypt, followed 91 patients with advanced malignant pleural mesothelioma who had not previously received chemotherapy. Fifty-five received pemetrexed plus cisplatin; 36 received gemcitabine plus cisplatin. Tumor biopsies taken at diagnosis were stained for three proteins: ERCC1 in all 91 patients, TS in the pemetrexed group and RRM1 in the gemcitabine group. The article does not report asbestos exposure. Median survival for the whole group was 12.7 months, and eight patients were alive at the end of follow-up. Patients with low ERCC1 had a median survival of 18.1 months, against 9.1 months with high ERCC1. In the pemetrexed group the figures were 19.8 months with low TS and 8.5 months with high TS. In the gemcitabine group they were 20.6 months with low RRM1 and 8.6 months with high RRM1. In a multivariate analysis, tumor stage and ERCC1 were independently associated with survival. The authors concluded that low ERCC1 can predict longer survival and better response to platinum-based chemotherapy. They drew similar conclusions for TS with pemetrexed and RRM1 with gemcitabine.

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: Prospective cohort study measuring tumor protein markers by immunohistochemistry and relating them to treatment response and survival
• Who was studied: 91 chemotherapy-naive patients with advanced (locally advanced or metastatic), inoperable malignant pleural mesothelioma treated at the National Cancer Institute, Cairo, Egypt: 51 men and 40 women, mean age 54.4 years. Study dates are not given.
• Exposure: Not asbestos. The study looked at chemotherapy (pemetrexed plus cisplatin, n=55; gemcitabine plus cisplatin, n=36) and tumor levels of three proteins: ERCC1 (all patients), TS (pemetrexed group) and RRM1 (gemcitabine group). Asbestos exposure is not reported.
• Main results:
  • ERCC1 and TS levels were associated (p=0.005). In the pemetrexed group, 21 of 30 patients (70.0%) with low TS had low ERCC1, and 17 of 25 (68.0%) with high TS had high ERCC1. ERCC1 and RRM1 levels were not related (p=0.296).
  • Whole group (n=91): median follow-up 12.7 months (range 3.4-48.5); eight patients alive at end of follow-up; one-year overall survival 53.8%; median survival 12.7 months.
  • All 91 patients, low vs high ERCC1: median time to progression 9.6 vs 5.3 months; median overall survival 18.1 vs 9.1 months (p<0.001).
  • Pemetrexed plus cisplatin group (n=55), low vs high TS: median time to progression 11.8 vs 5.4 months (p<0.001); median overall survival 19.8 vs 8.5 months (p<0.001).
  • Gemcitabine plus cisplatin group (n=36), low vs high RRM1: median progression-free survival 10.6 vs 3.8 months; median overall survival 20.6 vs 8.6 months (Table 5 p=0.001).
  • Treatment response: high ERCC1 was associated with disease progression (p=0.019); 23 of the 36 patients whose disease progressed (63.9%) had high ERCC1. Low RRM1 was associated with better response in the gemcitabine group (Table 4 p less than 0.001). TS was also related to response in the pemetrexed group (p=0.047).
  • Multivariate analysis of overall survival: tumor stage (HR 2.3; 95% CI 1.1-4.9; p=0.021) and ERCC1 (HR 2.7; 95% CI 1.7-4.3; p<0.001) were independent factors.
  • Multivariate analysis of progression-free survival (Table 8): ERCC1 HR 2.25 (95% CI 1.42-3.56; p=0.001). Tumor stage (HR 6.77), surgery (HR 4.53) and residence (Helwan vs Shobra, HR 3.71) were also listed.
  • Overall survival was longer in women than men (median 18.3 vs 10.9 months, p=0.004), in non- or ex-smokers than current smokers (18 vs 10 months, p=0.008), and in the 15 patients who had surgery compared with the 76 who did not (25.8 vs 10.8 months, p=0.001).
• The authors' conclusion: The authors concluded that low ERCC1 can predict longer progression-free and overall survival and better response to platinum-based chemotherapy in advanced MPM. They concluded that low TS can indicate better response to pemetrexed and longer survival, and that lower RRM1 was associated with better prognosis and longer survival in patients receiving gemcitabine plus cisplatin.

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, Chemotherapy, Prognosis, Pemetrexed (Alimta), Cisplatin, Gemcitabine, Cohort Study, Biopsy.

Related studies

• Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery — L. Frischknecht, M. Meerang, et al. (2015)
• RRM1 and ERCC1 as biomarkers in patients with locally advanced and metastatic malignant pleural mesothelioma treated with continuous infusion of low-dose gemcitabine plus cisplatin — W. Muñoz-Montaño, S. Muñiz-Hernández, et al. (2021)
• Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients — T. Powrózek, D.M. Kowalski, et al. (2014)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)
• Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)
• Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience — G. Pasello, S. Nicotra, et al. (2011)

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