Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study

Our plain-English summary of Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study, by B. Ghanim, T. Klikovits, M.A. Hoda, et al (British Journal of Cancer, 2015).

The study

• Authors: B. Ghanim, T. Klikovits, M.A. Hoda, G. Lang, I. Szirtes, U. Setinek, A. Rozsas, F. Renyi-Vamos, V. Laszlo, M. Grusch, M. Filipits, A. Scheed, M. Jakopovic, M. Samarzija, L. Brcic, D. Stancic-Rokotov, I. Kern, A. Rozman, G. Dekan, W. Klepetko, W. Berger, T. Glasz, B. Dome, B. Hegedus
• Journal: British Journal of Cancer
• Published: 2015;112(5):783-92
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM.

Methods: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98).

Results: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048).

Conclusion: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM.

In plain English

This retrospective study from several centres asked whether Ki67, a marker of dividing cells measured in tumour tissue, predicted survival in malignant pleural mesothelioma. The article did not examine asbestos exposure. A test group of 187 patients came from Croatia, Hungary and Austria, and a validation group of 98 patients came from Slovenia, all referred between 1994 and 2012. In the test group, patients whose tumours had more than 15% Ki67-positive cells had a median survival of 7.5 months, against 19.1 months for the rest (hazard ratio 2.3, confidence interval 1.7 to 3.2). After adjusting for age, sex, stage, histology and treatment in 149 patients, the hazard ratio was 2.1 (1.4 to 3.1). Ki67 predicted survival in the epithelioid subtype but not in the 31 non-epithelioid cases. Tumours sampled after induction chemotherapy had lower Ki67 levels. In the Slovenian group, using a 22% cutoff, median survival was 18.2 versus 9.1 months (p equal to 0.048). The authors concluded that Ki67 is useful to estimate prognosis in epithelioid mesothelioma. They noted that the surgery-alone subgroup was small.

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 multicentre study of archived tumour samples and clinical records, with a test cohort and an independent validation cohort
• Who was studied: 285 patients with histologically proven malignant pleural mesothelioma, referred between 1994 and 2012. The test cohort was 187 patients: 91 from Zagreb, Croatia; 42 from Budapest, Hungary; and 54 from Vienna, Austria. The validation cohort was 98 patients from Golnik, Slovenia. The test cohort was 147 male and 40 female; 156 had epithelioid and 31 had non-epithelioid (22 biphasic, 9 sarcomatoid) tumours.
• Exposure: Asbestos exposure was not studied. The factor examined was the Ki67 index (the percentage of tumour cells staining positive for the proliferation marker Ki67) in tumour tissue. It was compared with histology, stage, treatment, blood markers (CRP, fibrinogen, neutrophil-to-lymphocyte ratio) and a nuclear grading score.
• Main results:
  • Test cohort, unadjusted: patients with high Ki67 (above the median of 15%, n=92) had a median overall survival of 7.5 months (CI 5.2 to 9.8). Patients with low Ki67 (n=95) had 19.1 months (CI 11.7 to 26.5), p less than 0.001. The hazard ratio was 2.3 (CI 1.7 to 3.2).
  • Test cohort, adjusted for age, gender, stage, histology and treatment (149 patients with complete data): high Ki67 remained an independent prognostic marker (HR 2.1, CI 1.4 to 3.1, p less than 0.001). Histology and treatment were also independent; age, gender and stage were not.
  • By subtype: in epithelioid tumours, median survival was 22.9 months (CI 17.8 to 27.9) with low Ki67 versus 7.9 months (CI 5.3 to 10.4) with high Ki67, p less than 0.001. In non-epithelioid tumours, it was 4.9 months (CI 0 to 10.9) with low Ki67 versus 6.3 months (CI 2.4 to 10.2) with high Ki67, p equal to 0.630.
  • Ki67 index was not associated with histology, stage, age or sex. It was lower in patients sampled after induction chemotherapy (n=33, mean 10.5, s.d. 8.5) than in chemo-naive patients (n=124, mean 18.3, s.d. 13.9), p less than 0.001.
  • Slovenian validation cohort (n=98, median Ki67 22% used as cutoff): median survival was 18.2 months (CI 12.4 to 24.1) in the low Ki67 group (n=52) and 9.1 months (CI 5.4 to 12.9) in the high Ki67 group (n=46). The log rank p was 0.048.
  • In 65 patients with all blood markers available, the areas under the ROC curve were 0.70 for Ki67, 0.72 for neutrophil-to-lymphocyte ratio, 0.62 for fibrinogen and 0.71 for CRP.
  • When the two pathologists both scored the Hungarian cohort (n=41), their Ki67 scores correlated with a Pearson coefficient of 0.668.
• The authors' conclusion: The authors concluded that the Ki67 index is useful to estimate the prognosis of epithelioid malignant pleural mesothelioma. They added that it might also be a tool to evaluate the biological response after induction chemotherapy.
• Limitations the authors state:
  • Ki67 was not prognostic in the surgery-alone subgroup. The authors noted that this group was the smallest, which may have impaired the statistical analysis.

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: Epithelioid, Non-epithelioid, Pleural Mesothelioma, Prognosis, Overall Survival, Histology, Hazard Ratio, Chemotherapy.

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• Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma — A. Bilecz, P. Stockhammer, et al. (2020)
• Circulating fibrinogen is a prognostic and predictive biomarker in malignant pleural mesothelioma — B. Ghanim, M.A. Hoda, et al. (2014)
• 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)
• Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy — K. Schelch, M.A. Hoda, et al. (2014)

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