PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy

Our plain-English summary of PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy, by B.K. Bitanihirwe, M. Meerang, M. Friess, et al (Journal of Thoracic Oncology, 2014).

The study

• Authors: B.K. Bitanihirwe, M. Meerang, M. Friess, A. Soltermann, L. Frischknecht, S. Thies, E. Felley-Bosco, M.S. Tsao, G. Allo, M. de Perrot, B. Seifert, H. Moch, R. Stahel, W. Weder, I. Opitz
• Journal: Journal of Thoracic Oncology
• Published: 2014;9(2):239-47
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: The prognostic significance of activity biomarkers within the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway was assessed in two independent cohorts of malignant pleural mesothelioma (MPM) patients uniformly treated with a multimodal approach. We specifically assessed expression signatures in a unique set of pre- and postchemotherapy tumor samples.

Methods: Biomarker expression was assessed in samples of two independent cohorts of 107 (cohort 1) and 46 (cohort 2) MPM cases uniformly treated with platinum-based induction chemotherapy followed by extrapleural pneumonectomy from two different institutions, assembled on tissue microarrays. Expression levels of phosphatase and tensin homologue (PTEN), phospho-mTOR, and p-S6 in addition to marker of proliferation (Ki-67) and apoptosis (cleaved caspase-3) were evaluated by immunohistochemistry and correlated with overall survival (OAS) and progression-free survival (PFS). To assess PTEN genomic status, fluorescence in situ hybridization was performed.

Results: Survival analysis showed that high p-S6 and Ki-67 expression in samples of treatment naïve patients of cohort 1 was associated with shorter PFS (p = 0.02 and p = 0.04, respectively). High Ki-67 expression after chemotherapy remained associated with shorter PFS (p = 0.03) and OAS (p = 0.02). Paired comparison of marker expression in samples before and after induction chemotherapy of cohort 1 revealed that decreased cytoplasmic PTEN and increased phospho-mTOR expression was associated with a worse OAS (p = 0.04 and p = 0.03, respectively).

Conclusions: These novel data reveal a prognostic significance of expression changes of PI3K/mTOR pathway components during induction chemotherapy if confirmed in other patient cohorts and support the growing evidence to target the PI3K/mTOR pathway in the treatment of MPM.

In plain English

This study examined tumor tissue from patients with malignant pleural mesothelioma, all treated with platinum-based chemotherapy followed by surgery called extrapleural pneumonectomy. It did not study asbestos exposure. Patients came from Zurich (107, treated 1999–2009) and Toronto (46, treated 2001–2011). The authors measured three PI3K/mTOR cell-growth pathway proteins (PTEN, p-mTOR, p-S6), a cell-division marker (Ki-67) and a cell-death marker (cleaved caspase-3), and compared them with survival. Tissue from before chemotherapy existed only for the Zurich group. In that group, high p-S6 and high Ki-67 before chemotherapy were associated with shorter progression-free survival. High Ki-67 after chemotherapy was associated with shorter progression-free and overall survival. Among 75 Zurich patients with paired samples, median overall survival was 19 months (95% CI 13–24) when cytoplasmic PTEN fell during chemotherapy versus 23 months (16–30) when it rose; among 66, it was 11 months (5–17) when p-mTOR rose versus 23 months (18–28) when it fell. The authors concluded these changes were prognostic factors and said larger cohorts were needed to confirm them. They noted few paired samples, tumor variability and a retrospective design as limitations.

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 observational study of tumor tissue samples (tissue microarrays stained by immunohistochemistry, plus FISH) from two hospital cohorts, with survival analysis
• Who was studied: Malignant pleural mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy. Cohort 1 had 107 patients at University Hospital Zurich, 1999–2009. Cohort 2 had 46 patients at Toronto General Hospital, 2001–2011. Pre-chemotherapy tissue was available only from cohort 1 (n = 87). Paired before-and-after samples were available for 86 cohort 1 patients.
• Exposure: Asbestos exposure was not assessed. The study examined tumor protein levels before and after platinum-based induction chemotherapy (mainly cisplatin with gemcitabine or pemetrexed) followed by extrapleural pneumonectomy.
• Main results:
  • Cohort 1, before chemotherapy: median progression-free survival was 16 months (95% CI 12–21) for low to moderate p-S6 versus 12 months (95% CI 5–18) for high p-S6 (n = 75; p = 0.02).
  • Cohort 1, before chemotherapy: median progression-free survival was 18 months (95% CI 13–23) for low to moderate Ki-67 versus 12 months (95% CI 10–13) for high Ki-67 (n = 74; p = 0.04).
  • Cohort 1, after chemotherapy: median progression-free survival was 16 months (95% CI 10–21) for low to moderate Ki-67 versus 14 months (95% CI 10–17) for high Ki-67 (n = 101; p = 0.03).
  • Cohort 1, after chemotherapy: median overall survival was 22 months (95% CI 17–27) for low to moderate Ki-67 versus 20 months (95% CI 15–25) for high Ki-67 (n = 101; p = 0.02).
  • Cohort 1, paired samples: median overall survival was 19 months (95% CI 13–24) when cytoplasmic PTEN decreased during chemotherapy versus 23 months (95% CI 16–30) when it increased (n = 75; p = 0.04). No association with progression-free survival was found.
  • Cohort 1, paired samples: median overall survival was 23 months (95% CI 18–28) when p-mTOR decreased versus 11 months (95% CI 5–17) when it increased (n = 66; p = 0.03). No association with progression-free survival was found.
  • In cohort 1, levels of PTEN, p-mTOR, p-S6 and Ki-67 were significantly reduced after chemotherapy. Cleaved caspase-3 was significantly increased (n = 74; p = 0.03).
  • Levels of PTEN, p-mTOR and cleaved caspase-3 measured before or after chemotherapy, taken on their own, were not significantly associated with overall or progression-free survival.
  • FISH testing of 20 cohort 1 patients (10 with high and 10 with low PTEN protein) found no PTEN gene deletion.
• The authors' conclusion: The authors concluded that changes in PTEN and p-mTOR levels during induction chemotherapy represent prognostic factors for overall survival in malignant pleural mesothelioma patients. They also said their data support the growing evidence for drugs that inhibit the PI3K/mTOR pathway.
• Limitations the authors state:
  • Fewer pre-chemotherapy samples meant fewer paired samples, which may have limited statistical power.
  • Because mesothelioma is heterogeneous, up to four tissue cores per patient may not represent the whole tumor.
  • Retrospective samples from different institutions introduce bias, and confounding variables could not be controlled.
  • The findings need validation in larger, multi-institutional cohorts.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Chemotherapy, Extrapleural Pneumonectomy (EPP), Biomarker, Pleural Mesothelioma, Ki-67, Apoptosis, Immunohistochemistry.

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)
• Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial) — S. Hasegawa, M. Okada, et al. (2016)
• Extrapleural pneumonectomy after induction chemotherapy: perioperative outcome in 251 mesothelioma patients from three high-volume institutions — O. Lauk, M.A. Hoda, et al. (2014)
• Extrapleural pneumonectomy for malignant pleural mesothelioma: outcomes of treatment and prognostic factors — T.D. Yan, M. Boyer, et al. (2009)
• Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience — G. Pasello, S. Nicotra, et al. (2011)
• Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma — M. Moriya, T. Yamada, et al. (2014)

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