Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma

Our plain-English summary of Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma, by J.M. Foster, U. Radhakrishna, V. Govindarajan, et al (World Journal of Surgical Oncology, 2010).

The study

• Authors: J.M. Foster, U. Radhakrishna, V. Govindarajan, J.H. Carreau, Z. Gatalica, P. Sharma, S.K. Nath, B.W. Loggie
• Journal: World Journal of Surgical Oncology
• Published: 2010;8:88
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: There is a paucity of information about the molecular perturbations involved in MPM tumor formation. We previously reported that EGFR-TK mutations in MPM were predictive of achieving optimal surgical cytoreduction, but the status of EGFR pathway activation potential of these mutations was not known. Here we present the mutant EGFR activating potential and the matured survival data of the EGFR mutant(mut+) relative to wild type EGFR(mut-) mesothelioma.

Methods: Twenty-nine patients were evaluated and their tumors were probed for mutations in the catalytic TK-domain. Twenty-five patients were treated with cytoreductive surgery and complete clinical data was available for comparison of the mut+ and mut- groups. A COS-7 cell expression model was used to determine mutation activating profiles and response to erlotinib.

Results: Functional mutations were found in 31%(9/29) of patients; 7 of these mutations were novel and another was the L858R mutation. All missense mutations were found to be activating mutations and responsive to erlotinib. Of the 25 patients managed surgically, there were 7 mut+ and 18 mut-. Two of 7 (29%) mut+ developed progressive disease and died with a median follow-up time of 22 months; while 13/18 (72%) mut- developed progressive disease and 10/18 (56%) died with median TTP of 12 months and median survival of 14 months.

Conclusions: The novel EGFR mutations identified are activating mutations responsive to erlotinib. The mut+ subset have a 'relative' improved outcome. Erlotinib may have a role in MPM and exploration for mutations in a larger patient cohort is warranted.

In plain English

This laboratory and clinical study examined tumor samples from 29 consecutive patients with newly diagnosed malignant peritoneal mesothelioma (mesothelioma of the abdominal lining). The patients were seen at Creighton University Medical Center, Omaha, between January 2003 and July 2006. The article does not discuss asbestos exposure. The authors searched the tumors for mutations in one part of the EGFR gene, the tyrosine kinase domain. They found eight different mutations, seven of them not previously described. One of these, L831H, appeared in two tumors. None of the mutations were found in the same patients' normal tissue. The mutations were placed into laboratory-grown COS-7 cells and stimulated with epidermal growth factor (EGF). All showed increased EGFR activity, but without EGF there was little or no activation. The drug erlotinib reduced the activity. Of 25 patients treated with surgery plus heated chemotherapy inside the abdomen, 2 of 7 patients with mutations had died. Among the 18 without mutations, 10 had died, and their median survival was 14 months. The authors concluded the mutations were activating and linked to a 'relative' improvement in outcome. They expected more patients with mutations to progress with longer follow-up and called for study of a larger group.

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: Laboratory analysis of tumor samples for EGFR gene mutations, cell-culture experiments testing the mutations, and an exploratory survival comparison in surgically treated patients
• Who was studied: 29 consecutive patients with newly diagnosed malignant peritoneal mesothelioma at Creighton University Medical Center, Omaha, January 1, 2003 to July 31, 2006. Of these, 25 were treated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy.
• Exposure: Not asbestos. The factor studied was mutation status of the EGFR gene tyrosine kinase domain (exons 18 to 24), plus laboratory exposure of mutant-carrying cells to the drug erlotinib.
• Main results:
  • Eight different EGFR mutations were found in the 29 tumors. Seven were novel. The eighth, L858R, had previously been identified in non-small cell lung cancer.
  • Each mutation appeared once, except L831H, which was found in two separate tumors.
  • The mutations were somatic: they were not present in the same patients' normal tissue.
  • No amplification of the EGFR or ERBB2 genes was found in any specimen.
  • In COS-7 cells exposed to EGF, all eight mutant forms of EGFR showed increased activation (phosphorylation), peaking at 15 minutes. The authors interpreted this as showing the mutations were activating.
  • The activation depended on EGF: without EGF stimulation there was little or no activation of any of the mutant forms.
  • Erlotinib reduced EGFR activation in cells carrying each of the eight mutations, in a dose-dependent manner.
  • Among surgically treated patients with EGFR mutations, median survival had not been reached. Of these patients, 2 of 7 (29%) had died of disease progression, with a median follow-up of 22 months.
  • Among surgically treated patients without mutations (wild type), 10 of 18 (56%) had died of disease progression, with median survival of 14 months. Their time to progression was 12 months, and 13 of 18 (72%) developed progressive disease.
  • In patients with mutations, median time to progression had not been reached.
  • Three-year overall survival and disease-free survival were 71% and 71% in the mutation group, compared with 44% and 21% in the wild type group. The text gives no p-value for this comparison.
• The authors' conclusion: The authors concluded that they had identified novel activating EGFR mutations in malignant peritoneal mesothelioma, associated with optimal resectability and prolonged survival. They described the improved outcome as 'relative'.
• Limitations the authors state:
  • The authors stated that with longer follow-up more patients with mutations will likely develop progressive disease, so the improvement is only 'relative'.
  • The authors called for a larger cohort and for testing pleural mesothelioma.

Topics

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

Medical terms in this study, explained in our Lexicon: EGFR, Peritoneal Mesothelioma, Cytoreductive Surgery, Mesothelioma, Median Overall Survival.

Related studies

• Patients with peritoneal mesothelioma lack epidermal growth factor receptor tyrosine kinase mutations that would make them sensitive to tyrosine kinase inhibitors — N. Kalra, A. Ashai, et al. (2012)
• Mutation analysis of the EGFR gene and downstream signalling pathway in histologic samples of malignant pleural mesothelioma — R. Mezzapelle, U. Miglio, et al. (2013)
• Low frequency of EGFR mutations in pleural mesothelioma patients, Cologne, Germany — V. Schildgen, O. Pabst, et al. (2015)
• Epidermal growth factor receptor mutations in malignant pleural and peritoneal mesothelioma — Y. Enomoto, T. Kasai, et al. (2012)
• Synergistic anticancer activity of arsenic trioxide with erlotinib is based on inhibition of EGFR-mediated DNA double-strand break repair — K. Kryeziu, U. Jungwirth, et al. (2013)
• Characterization of DNA hypermethylation in two cases of peritoneal mesothelioma — R. Hama, Y. Watanabe, et al. (2012)

Browse more research in World Journal of Surgical Oncology, or return to medical research.