The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma

Our plain-English summary of The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma, by D.J. Pinato, F.A. Mauri, T. Lloyd, et al (British Journal of Cancer, 2013).

The study

• Authors: D.J. Pinato, F.A. Mauri, T. Lloyd, V. Vaira, C. Casadio, R.L. Boldorini, R. Sharma
• Journal: British Journal of Cancer
• Published: 2013;108(3):621-8
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Recent preclinical studies identified Axl, a tyrosine kinase receptor implicated in tumour progression and epithelial-to-mesenchymal transition, as a putative therapeutic target in malignant pleural mesothelioma (MPM), an invariably fatal malignancy with limited treatment options. Here, we studied the expression of Axl and its ligand Gas-6 (growth arrest signal-6) in primary specimens of MPM, correlating their expression levels with tumour phenotype and clinical outcomes.

Methods: Two independent cohorts of consecutive patients diagnosed with MPM were studied: a derivation cohort composed of 63 cases and a validation set of 35 cases. Clinical variables including patients' demographics, tumour stage, histotype, performance status (PS), Axl and Gas-6 staining were tested for predicting overall survival (OS) using univariate and multivariate analyses.

Results: In the derivation cohort, Axl (P=0.001) but not Gas-6 overexpression (P=0.35) emerged as a univariate prognostic factor for OS, together with stage (P=0.05), PS (P<0.001) hypoalbuminaemia (P<0.001) and anaemia (P<0.001). Multivariate analyses confirmed Axl overexpression (P=0.01), PS (P=0.01), hypoalbuminaemia (P<0.001) and anaemia (P=0.04) as independent predictors of OS. The prognostic role of Axl overexpression was externally validated in an independent cohort (P=0.03).

Conclusion: Overexpression of Axl is found in the majority of MPM specimens and influences patient's survival independently from other established prognostic factors. Such information may support patient selection for future trials.

In plain English

This study measured two proteins, Axl and Gas-6, in tumour tissue from patients with malignant pleural mesothelioma and tested links with survival. Asbestos exposure was not studied, though it was documented for 27 of 63 patients in the main group. The authors stained archived samples from 63 consecutive patients diagnosed in 2001 to 2011 at Imperial College NHS Trust, London, then checked results in 35 patients from Novara, Italy. In the London group, 74% of tumours had high Axl. Patients with low Axl (called Axl-negative by the authors) lived a median of 3.7 months (95% CI 1.7 to 5.9), compared with 14.8 months (95% CI 5.8 to 23.7) for those with high Axl. This link held after adjusting for factors including performance status (general fitness), low albumin and anaemia. In the Italian group the figures were 8.0 months (95% CI 4.9 to 11.1) versus 15.0 months (95% CI 7.0 to 23.0). Gas-6 levels showed no statistically significant link with survival. The authors concluded that Axl expression predicted longer survival in both groups. They mentioned a relatively small sample size.

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 tumour specimens from more than one centre. Protein staining (immunohistochemistry) was compared with survival in a main (derivation) group and a separate validation group.
• Who was studied: Derivation group: 63 consecutive patients with malignant pleural mesothelioma diagnosed 2001 to 2011 at Imperial College NHS Trust, London (84% male, median age 65). Validation group: 35 core biopsy samples from patients diagnosed 2005 to 2010 at Maggiore della Carità University Hospital, Novara, Italy.
• Exposure: The factor studied was the level of the proteins Axl and Gas-6 in tumour tissue, not asbestos. In the derivation group, asbestos exposure was documented in 27 of 63 patients (43%), not documented in 20 (32%) and unknown in 16 (25%). No fiber types or doses were reported.
• Main results:
  • In the derivation group, Axl staining scores (histoscores) ranged from 0 to 300, with a median of 150. 74% of tumours were classed as high Axl expression, defined as a histoscore of 150 or more.
  • In the derivation group, median overall survival was 3.7 months (95% CI 1.7 to 5.9) for patients whose tumours the authors call Axl-negative. It was 14.8 months (95% CI 5.8 to 23.7) for Axl-positive cases. The negative and positive groups (16 and 47 patients) match the low and high groups defined by the histoscore cutoff.
  • In the derivation group, the hazard ratio for Axl-positive versus Axl-negative tumours was 0.3 (95% CI 0.2 to 0.6, P = 0.001) in the unadjusted analysis. After adjustment for other factors it was 0.3 (95% CI 0.2 to 0.8, P = 0.01).
  • Other independent predictors of worse survival in the derivation group were:
• Performance status of 2 or more (hazard ratio 3.0, 95% CI 1.3 to 7.0).
• Albumin below 35 g per litre (hazard ratio 5.0, 95% CI 2.3 to 11.5).
• Haemoglobin below 12 (hazard ratio 2.1, 95% CI 1.0 to 4.3).
  • Gas-6 levels showed no statistically significant association with survival in the derivation group (hazard ratio 0.7, 95% CI 0.4 to 1.4, P = 0.35). The authors report the same for the validation group (P = 0.78).
  • In the 35-patient validation group, median overall survival was 15.0 months (95% CI 7.0 to 23.0) for patients with elevated Axl. It was 8.0 months (95% CI 4.9 to 11.1) for patients with Axl-negative tumours. The hazard ratio was 0.3 (95% CI 0.2 to 0.7). The P-value is printed as 0.003 in the text but as 0.03 in the abstract.
  • Epithelial tumours had higher Axl levels (median score 180, range 0 to 300) than non-epithelial mesotheliomas (median 0, range 0 to 300), with P = 0.03.
  • In a subgroup of 20 specimens, Axl levels were higher in slowly growing tumours (median 180) than in fast-growing tumours (median 80), with P = 0.03. Axl and Gas-6 showed no significant association with VEGF-A, a marker of blood-vessel growth.
  • hTERT is a marker of unlimited cell growth. In 10 Axl-negative and 10 Axl-positive samples, hTERT was found in 3 of the 10 Axl-negative samples and in none of the Axl-positive samples. This difference was not statistically significant (P = 0.06).
• The authors' conclusion: The authors concluded that Axl expression in mesothelioma tumour cells predicted longer overall survival in two independent groups of patients. They suggested that testing Axl in diagnostic biopsies may improve survival prediction in routine practice.
• Limitations the authors state:
  • The authors acknowledge a relatively small sample size. They argue that the number of deaths and the external validation support the reliability of their analysis.
  • The authors say the hTERT findings on Axl and cell ageing (senescence) should be treated as preliminary because they were not statistically significant.
  • The authors attribute the lack of a survival link for tumour cell type (histotype) to the large share of epithelioid cases (over 80%).

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Performance Status, Overall Survival.

Related studies

• Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma — W.B. Ou, C. Hubert, et al. (2011)
• Soluble AXL is ubiquitously present in malignant serous effusions — K. Flem Karlsen, E. McFadden, et al. (2019)
• Proteoglycans in human malignant mesothelioma. Stimulation of their synthesis induced by epidermal, insulin and platelet-derived growth factors involves receptors with tyrosine kinase activity — A. Syrokou, G.N. Tzanakakis, et al. (1999)
• Receptor tyrosine kinase and downstream signalling analysis in diffuse malignant peritoneal mesothelioma — F. Perrone, G. Jocollè, et al. (2010)
• Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism — R. El Bezawy, M. De Cesare, et al. (2017)
• Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma — H. Kohno, V.J. Amatya, et al. (2010)

Browse more research in British Journal of Cancer, or return to medical research.