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

Our plain-English summary of 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, by W. Muñoz-Montaño, S. Muñiz-Hernández, A. Avilés-Salas, et al (BMC Cancer, 2021).

The study

• Authors: W. Muñoz-Montaño, S. Muñiz-Hernández, A. Avilés-Salas, R. Catalán, L. Lara-Mejía, S. Samtani-Bassarmal, A.F. Cardona, J. Mendoza-Desión, D. Hernández-Cueto, A. Maldonado, G. Baay-Guzmán, S. Huerta-Yepes, O. Arrieta
• Journal: BMC Cancer
• Published: 2021;21(1):892
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is a rare but aggressive neoplasia that usually presents at advanced stages. Even though some advances have been achieved in the management of patients with MPM, this malignancy continuous to impose a deleterious prognosis for affected patients (12-18 months as median survival, and 5-10% 5-year survival rate), accordingly, the recognition of biomarkers that allow us to select the most appropriate therapy are necessary.

Methods: Immunohistochemistry semi-quantitative analysis was performed to evaluate four different biomarkers (ERCC1, RRM1, RRM2, and hENT-1) with the intent to explore if any of them was useful to predict response to treatment with continuous infusion gemcitabine plus cisplatin. Tissue biopsies from patients with locally advanced or metastatic MPM were analyzed to quantitatively asses the aforementioned biomarkers. Every included patient received treatment with low-dose gemcitabine (250 mg/m2) in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks as first-line therapy.

Results: From the 70 eligible patients, the mean and standard deviation (SD) for ERCC1, RRM1, RRM2 and hENT-1 were 286,178.3 (± 219, 019.8); 104,647.1 (± 65, 773.4); 4536.5 (± 5, 521.3); and 2458.7 (± 4, 983.4), respectively. Patients with high expression of RRM1 had an increased median PFS compared with those with lower expression (9.5 vs 4.8 months, p = < 0.001). Furthermore, high expression of RRM1 and ERCC1 were associated with an increased median OS compared with their lower expression counterparts; [(23.1 vs 7.2 months for RRM1 p = < 0.001) and (17.4 vs 9.8 months for ERCC1 p = 0.018)].

Conclusions: ERCC1 and RRM1 are useful biomarkers that predict better survival outcomes in patients with advanced MPM treated with continuous infusion of gemcitabine plus cisplatin.

© 2021. The Author(s).

In plain English

This retrospective study looked at 70 patients with newly diagnosed stage III to IV malignant pleural mesothelioma treated in Mexico City from 2012 to 2017. All received low-dose gemcitabine by six-hour infusion plus cisplatin, or carboplatin if cisplatin was not tolerated. Prior asbestos exposure was reported in 51.4% of patients. The authors measured four tumor proteins (ERCC1, RRM1, RRM2, hENT-1), splitting patients into high and low groups at the median. Tissue was not always sufficient: RRM1 was measured in 28 patients, ERCC1 in 47. High RRM1 was linked to longer progression-free survival (9.5 vs 4.8 months; adjusted hazard ratio 0.11, 95% confidence interval 0.02 to 0.52). After adjustment, high ERCC1 was linked to a lower risk of death (hazard ratio 0.24, 95% confidence interval 0.07 to 0.79). The results section gives median overall survival of 23.1 vs 7.2 months for ERCC1 and 17.4 vs 9.8 months for RRM1; the abstract swaps these figures. hENT-1 showed no association with survival. The authors concluded that higher RRM1 and ERCC1 are associated with better survival. They noted a small sample, missing tissue and no established cut-off value.

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: Single-institution retrospective analysis of tumor biomarkers (immunohistochemistry) in relation to outcomes of first-line chemotherapy
• Who was studied: 70 newly diagnosed, chemotherapy-naive patients with locally advanced or metastatic (stage III to IV) malignant pleural mesothelioma, treated at the Thoracic Oncology Unit of the Instituto Nacional de Cancerología (INCan), Mexico City, January 2012 to December 2017
• Exposure: Low-dose gemcitabine 250 mg/m2 as a six-hour continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks, for up to 6 cycles. Patients with unacceptable toxicity to cisplatin received carboplatin instead, with the same gemcitabine dose. Tumor expression of ERCC1, RRM1, RRM2 and hENT-1 was measured by immunohistochemistry and divided into high and low groups at the median. Asbestos exposure was recorded only as present or absent, with no fiber type given.
• Main results:
  • Prior asbestos exposure was reported in 51.4% of the 70 patients
  • RRM1 could be measured in only 28 patients: 13 in the low-expression group and 15 in the high-expression group
  • ERCC1 could be measured in 47 patients: 23 in the low-expression group and 24 in the high-expression group
  • All 70 patients: overall response rate 47.1% (33/70), disease control rate 80% (56/70), no complete responses
  • Median progression-free survival for all patients was 7.6 months
  • Median overall survival for all patients was 14 months (95% CI 10.5 to 17.5)
  • High-RRM1 patients had longer median progression-free survival than low-RRM1 patients: 9.5 vs 4.8 months, p = 0.001
  • In multivariate analysis, high RRM1 was associated with a lower risk of progression: HR 0.11, 95% CI 0.02 to 0.52, P = 0.005
  • ERCC1 expression was not significantly associated with progression-free survival: 7.7 vs 7.3 months, p = 0.915
  • In unadjusted analysis, the Results section gives median overall survival of 17.4 vs 9.8 months for high vs low RRM1 (p = 0.018), and 23.1 vs 7.2 months for high vs low ERCC1 (p = 0.001). The article's abstract assigns these two comparisons the other way round.
  • In multivariate analysis, only a Karnofsky score above 80 (HR 0.16, 95% CI 0.04 to 0.75, p = 0.019) and high ERCC1 (HR 0.24, 95% CI 0.07 to 0.79, p = 0.020) were significantly associated with a lower risk of death
  • Asbestos exposure was not statistically significantly associated with overall survival in unadjusted analysis: HR 0.72, 95% CI 0.40 to 1.31, p = 0.283
  • No association was found between hENT-1 expression and survival
  • No grade 4 adverse events or treatment-related deaths were observed
• The authors' conclusion: The authors concluded that, in patients with advanced malignant pleural mesothelioma given first-line low-dose continuous-infusion gemcitabine plus cisplatin, higher RRM1 and ERCC1 expression are associated with better overall survival, and higher RRM1 also with longer progression-free survival
• Limitations the authors state:
  • Relatively small sample size
  • Not enough tissue to measure all four biomarkers in every patient
  • No established cut-off value exists for these biomarkers, which complicates interpretation and comparison with earlier studies

Topics

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

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Gemcitabine, Cisplatin, Prognosis, Median Overall Survival, Immunohistochemistry, First-line Therapy.

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)
• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma — O. Arrieta, D. López-Macías, et al. (2014)
• Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival — Z.G. Zimling, J.B. Sørensen, et al. (2012)
• The Predictive Value of ERCC1, RRM1, and Thymidylate Synthase in Advanced Malignant Pleural Mesothelioma Patients Treated with Platinum-Based Chemotherapy — N.I. Wahba, O. Khorshid, et al. (2023)
• Efficacy, Safety, and Cost-Minimization Analysis of Continuous Infusion of Low-Dose Gemcitabine Plus Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma — O. Arrieta, W. Muñoz-Montaño, et al. (2021)
• 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)

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