Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma

Jason M. Foster, Uppala Radhakrishna, Venkatesh Govindarajan, Joseph H. Carreau, Zoran Gatalica, Poonam K Sharma, Swapan K. Nath, Brian W. Loggie

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Article number88
JournalWorld Journal of Surgical Oncology
Volume8
DOIs
StatePublished - Oct 13 2010

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Mutation
Malignant Mesothelioma
Survival
COS Cells
Mesothelioma
Missense Mutation
Catalytic Domain
Neoplasms
Erlotinib Hydrochloride

All Science Journal Classification (ASJC) codes

  • Oncology
  • Surgery

Cite this

Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma. / Foster, Jason M.; Radhakrishna, Uppala; Govindarajan, Venkatesh; Carreau, Joseph H.; Gatalica, Zoran; Sharma, Poonam K; Nath, Swapan K.; Loggie, Brian W.

In: World Journal of Surgical Oncology, Vol. 8, 88, 13.10.2010.

Research output: Contribution to journalArticle

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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.",
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AU - Radhakrishna, Uppala

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AU - Gatalica, Zoran

AU - Sharma, Poonam K

AU - Nath, Swapan K.

AU - Loggie, Brian W.

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N2 - 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.

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