Mutational Profiling of Malignant Mesothelioma Revealed Potential Therapeutic Targets in EGFR and NRAS

Our plain-English summary of Mutational Profiling of Malignant Mesothelioma Revealed Potential Therapeutic Targets in EGFR and NRAS, by J.E. Kim, D. Kim, Y.S. Hong, et al (Translational Oncology, 2018).

The study

• Authors: J.E. Kim, D. Kim, Y.S. Hong, K.P. Kim, Y.K. Yoon, D.H. Lee, S.W. Kim, S.M. Chun, S.J. Jang, T.W. Kim
• Journal: Translational Oncology
• Published: 2018;11(2):268-274
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pemetrexed and platinum (PP) combination chemotherapy is the current standard first-line therapy for treatment of malignant mesothelioma (MM). However, a useful predictive biomarker for PP therapy is yet to be found. Here, we performed targeted exome sequencing to profile somatic mutations and copy number variations in 12 MM patients treated with PP therapy. We identified 187 somatic mutations in 12 patients (65 synonymous, 102 missense, 2 nonsense, 5 splice site, and 13 small coding insertions/deletions). We identified somatic mutations in 23 genes including BAP1, TP53, NRAS, and EGFR. Interestingly, rare NRAS p.Q61K and EGFR exon 19 deletions were observed in 2 patients. We also found somatic chromosomal copy number deletions in CDKN2A and CDKN2B genes. Genetic alteration related to response after PP therapy was not found. Somatic mutation profiling in MM patients receiving PP therapy revealed genetic alterations in potential therapeutic targets such as NRAS and EGFR. No alterations in genes with potential predictive role for PP therapy were found.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

In plain English

This retrospective study from Asan Medical Center in Seoul, Korea, examined tumor genes in malignant mesothelioma patients treated with pemetrexed and platinum chemotherapy. Of 51 patients given this as first-line treatment between 1990 and 2012, tumors from 15 were sequenced for 505 cancer-related genes; 12 passed quality checks. From the start of chemotherapy, the 51 patients had median progression-free survival of 7.5 months (95% CI, 3.9 to 11.0) and median overall survival of 17.8 months (95% CI, 9.6 to 26.0). The results reported 32 somatic (tumor-acquired) mutations in coding regions, in 9 of 12 tumors; the abstract gives 187, a difference the article does not explain. BAP1 and TP53 were each mutated in 2 of 12 cases. Deletions of the CDKN2A and CDKN2B genes were also found. Two pleural mesothelioma patients each carried a rare change, NRAS Q61K or an EGFR exon 19 deletion, which the authors called potential drug targets. No genetic change was linked to how well the chemotherapy worked. The authors noted the small sample and that asbestos exposure and smoking histories could not be collected.

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 using targeted next-generation (exome) sequencing of archived tumor tissue, with review of clinical outcomes
• Who was studied: 98 malignant mesothelioma patients diagnosed and treated at Asan Medical Center, Seoul, Korea, between January 1990 and December 2012. Of these, 51 received first-line pemetrexed and platinum therapy. Tumor samples from 15 were sequenced, and 12 passed quality control. The 51 treated patients had pleural (28), peritoneal (21) or pleural and pericardial (2) disease.
• Exposure: Asbestos exposure was not studied. The authors could not collect patients' occupational asbestos exposure or smoking histories. The study examined tumor gene changes in patients treated with pemetrexed and platinum chemotherapy.
• Main results:
  • Among the 51 patients given first-line pemetrexed and platinum therapy, median progression-free survival was 7.5 months (95% CI, 3.9-11.0 months) and median overall survival was 17.8 months (95% CI, 9.6-26.0 months). Both were measured from the start of chemotherapy.
  • In the 12 sequenced tumors, the Results section reported 32 somatic mutations in coding regions, found in 9 cases. No mutation was detected in 3 cases.
  • The article's abstract instead reports 187 somatic mutations in the 12 patients. The article does not reconcile this with the 32 reported in the Results.
  • BAP1 and TP53 were the most frequently mutated genes, each in 2 of 12 cases (16.7%).
  • Copy number deletions of the CDKN2A and CDKN2B genes were identified. No gene rearrangements were found in any of the 12 cases.
  • An NRAS Q61K mutation and an EGFR exon 19 deletion were each found in malignant pleural mesothelioma, in separate patients. The authors described these as potential therapeutic targets.
  • No genetic alteration was found to be related to response to pemetrexed and platinum therapy.
• The authors' conclusion: The authors concluded that they found no predictive marker for response to pemetrexed and platinum therapy. They did find potential actionable targets (NRAS Q61K mutation and EGFR exon 19 deletion), and they called for further studies with more patients.
• Limitations the authors state:
  • Only 12 tumor samples were included in the mutation profiling. The authors attributed this to the rarity of mesothelioma, the timescale of the therapy, and limited usable preserved tissue.
  • Because clinical data were collected retrospectively, smoking history and occupational asbestos exposure could not be collected.
  • Tumor samples could not be compared with matched normal tissue from the same patients.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, EGFR, Pemetrexed (Alimta), Chemotherapy, First-line Therapy, Biomarker, Somatic Mutation, BAP1.

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