Abstract
BackgroundThere 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.MethodsTwenty-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.ResultsFunctional 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.ConclusionsThe 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.
Highlights
Discovering the molecular pathways and mutations active in cancer has resulted in the emergence of novel therapies, as well as, the development of objective predictors of clinical outcome and response to cancer therapies
Identification of surrogate markers that can predict response to CRS/IPHC and lead to novel therapeutic targets in mesothelioma prompted the pursuit of epidermal growth factor receptor (EGFR) mutations
We have previously reported that EGFR mutations occur in 31% of Malignant peritoneal mesothelioma (MPM), a rate similar to that reported in non small cell lung cancer (NSCLC) [20]
Summary
Discovering the molecular pathways and mutations active in cancer has resulted in the emergence of novel therapies, as well as, the development of objective predictors of clinical outcome and response to cancer therapies. A potential cancer type similar to NSCLC that might harbor functional EGFR mutations is malignant mesothelioma. We perform a high volume of CRS/IPHC for all forms of peritoneal surface malignancies Through this experience it is evident that many mesothelioma patients do not experience the long term benefits of this aggressive surgical intervention, but all must endure the associated morbidity and mortality. Since most patients who present with MPM are unresectable, achieving optimal resection is important because it represents the only reproducible (surrogate) factor that predicts long-term survival [14]. 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. We present the mutant EGFR activating potential and the matured survival data of the EGFR mutant(mut+) relative to wild type EGFR(mut-) mesothelioma
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