Ki67 Tumor Expression Predicts Treatment Benefit Achieved by Macroscopic Radical Lung-Preserving Surgery in Pleural Mesothelioma-A Retrospective Multicenter Analysis

Our plain-English summary of Ki67 Tumor Expression Predicts Treatment Benefit Achieved by Macroscopic Radical Lung-Preserving Surgery in Pleural Mesothelioma-A Retrospective Multicenter Analysis, by S. Hintermair, S. Iser, A. Varga, et al (Cancers, 2024).

The study

• Authors: S. Hintermair, S. Iser, A. Varga, M. Biesinger, T. Bohanes, A. Celik, M. Sayan, A. Kankoç, N. Akyurek, B. Öğüt, E. Stubenberger, B. Ghanim
• Journal: Cancers
• Published: 2024;16(10)
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM), linked to asbestos-induced inflammation, carries a poor prognosis. Therapy ranges from therapy limitation to aggressive multimodality treatment. Given the uncertainty about treatment benefits for patients, this study aimed to assess the role of Ki67 as a prognostic and predictive parameter in PM. Ki67 was measured in the specimens of 70 PM patients (17 female, 53 male) from two centers and correlated to overall survival (OS) and therapy outcome. The median OS was 16.1 months. The level of Ki67 expression was divided into low (≤15%) and high (>15%). A low value of Ki67 expression was associated with a longer OS (Ki67 ≤ 15%: 31.2 (95% CI 6.5-55.8) months vs. Ki67 > 15%: 11.1 (95% CI 7.7-14.6) months, p = 0.012). The 5-year survival represents 22% in the low Ki67 expression group, in contrast to 5% in the high Ki67 expression group. We found a significant interaction term of Ki67 with multimodality treatment (p = 0.031) translating to an OS of 48.1 months in the low expression Ki67 group compared to 24.3 months in the high Ki67 expression group when receiving surgery within multimodality therapy. Therefore, Ki67 stands out as a validated prognostic and, most importantly, novel predictive biomarker for treatment benefits, particularly regarding surgery within multimodality therapy.

In plain English

This retrospective study reviewed 70 pleural mesothelioma patients treated 2008 to 2021 in Krems, Austria, and Ankara, Turkey, without studying asbestos exposure. Ki67, a marker of dividing cells, was low (15% or less) in 33 patients, high in 37. Median overall survival was 16.1 months (95% CI 9.4 to 22.9): 31.2 months (95% CI 6.5 to 55.8) with low and 11.1 months (95% CI 7.7 to 14.6) with high Ki67 (p = 0.012). Among 60 epithelioid patients, medians were 36.8 months (95% CI 15.3 to 58.2) with low and 12.3 months (95% CI 8.9 to 15.7) with high Ki67. In 10 non-epithelioid patients (3 low, 7 high): 7.4 months (95% CI 4.6 to 10.2) and 7.8 months (95% CI 0.0 to 18.3), not significantly different (p = 0.732). Adjusted for age, sex, stage and treatment in epithelioid patients, Ki67 was not significant; multimodality treatment was. A Ki67-treatment interaction was significant (p = 0.031); with multimodality treatment including surgery, medians were 48.1 (low Ki67) and 24.3 months (high). The authors concluded Ki67 is prognostic and predictive in epithelioid pleural mesothelioma.

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 multicenter study (two centers) of patient records and tumor Ki67 measurements, correlated with overall survival
• Who was studied: 70 patients with histologically proven pleural mesothelioma (53 male, 17 female; median age 66 years, range 42 to 88). 38 were from University Hospital Krems, Austria, and 32 from Gazi University, Ankara, Turkey. The observation period was 2008 to 2021. 60 had epithelioid and 10 had non-epithelioid tumors.
• Exposure: Asbestos exposure was not studied. The study looked at Ki67 tumor expression, split into low (15% or less) and high (above 15%), and at treatment. Multimodality treatment was defined as cisplatin/pemetrexed chemotherapy, cytoreductive surgery (pleurectomy/decortication or tumor debulking) and additive radiotherapy. It was compared with other options (chemotherapy, immunotherapy, radiotherapy, best supportive care).
• Main results:
  • 33 patients (47.1%) had low-Ki67 tumors and 37 patients (52.9%) had high-Ki67 tumors.
  • Median overall survival for the whole cohort of 70 was 16.1 months (95% CI 9.4 to 22.9; range 0.2 to 124 months).
  • Whole cohort: median overall survival was 31.2 months (95% CI 6.5 to 55.8) with Ki67 of 15% or less, versus 11.1 months (95% CI 7.7 to 14.6) with Ki67 above 15% (p = 0.012).
  • 5-year survival was 22% in the low Ki67 group and 5% in the high Ki67 group. This figure appears only in the article's abstract.
  • Epithelioid subgroup (30 low, 30 high Ki67): median overall survival was 36.8 months (95% CI 15.3 to 58.2) with low Ki67, versus 12.3 months (95% CI 8.9 to 15.7) with high Ki67 (p = 0.012).
  • Non-epithelioid subgroup (3 low, 7 high Ki67): Ki67 showed no significant influence on median overall survival. Median survival was 7.4 months (95% CI 4.6 to 10.2) with low Ki67 and 7.8 months (95% CI 0.0 to 18.3) with high Ki67 (p = 0.732).
  • Whole cohort: patients given multimodality therapy had a median overall survival of 26.1 months, versus 6.7 months for those given other treatment (p less than 0.001). More low-Ki67 patients (24 of 43) than high-Ki67 patients (19 of 43) were in the multimodality group.
  • Multivariate model in 60 epithelioid patients (age, sex, stage, treatment, Ki67): Ki67 was not statistically significant (HR 1.62, 95% CI 0.77 to 3.40, p = 0.205).
  • In the same model, multimodality treatment versus other treatment independently influenced the risk of earlier death (HR 0.31, 95% CI 0.12 to 0.82, p = 0.019).
  • Epithelioid patients (n = 60): the interaction between Ki67 and multimodality versus other therapy was significant (p = 0.031).
  • Epithelioid patients, median overall survival by group: low Ki67 with multimodality, 48.1 months; high Ki67 with multimodality, 24.3 months; high Ki67 with other treatment, 7.2 months; low Ki67 with other treatment, 1.4 months.
• The authors' conclusion: The authors concluded that Ki67 is a reproducible prognostic and predictive factor in epithelioid pleural mesothelioma. They wrote that it seems a promising biomarker for selecting patients for multimodality treatment. They added that high Ki67 combined with clinical parameters could help identify patients less likely to benefit from surgery within multimodality therapy.
• Limitations the authors state:
  • Therapies changed over the study period, and the authors did not relate these changes to when patients were treated. They say this can bias the analysis.
  • Because the data were retrospective, nuclear grading (recommended under the 2021 WHO classification) could not be included.
  • Immunotherapy was not available when the study began in 2008, so drugs could not be compared in relation to Ki67 and survival.
  • Ki67 was measured before treatment in some patients and after treatment in others, and the relationship between these values was not analyzed.
  • The authors could not reproduce Ki67's independent prognostic value from their earlier study. They attribute this most likely to the smaller number of patients.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Inflammation, Prognosis, Overall Survival, Multimodal Therapy, Biomarker.

Related studies

• Pretreatment serum C-reactive protein levels predict benefit from multimodality treatment including radical surgery in malignant pleural mesothelioma: a retrospective multicenter analysis — B. Ghanim, M.A. Hoda, et al. (2012)
• How successful is lung-preserving radical surgery in the mesothelioma and radical surgery-trial environment? A case-controlled analysis — Y. Shahin, J. Wellham, et al. (2011)
• Does surgery improve survival of patients with malignant pleural mesothelioma?: a multicenter retrospective analysis of 1365 consecutive patients — P. Bovolato, C. Casadio, et al. (2014)
• Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma — N. Kumar, D. Alrifai, et al. (2019)
• Combined epirubicin and interleukin-2 regimen in the treatment of malignant mesothelioma: a multicenter phase II study of the Italian Group on Rare Tumors — S. Bretti, A. Berruti, et al. (1998)
• Surgery as part of radical treatment for malignant pleural mesothelioma — D.A. Waller, S. Tenconi (2017)

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