Mutational Profile of Malignant Pleural Mesothelioma (MPM) in the Phase II RAMES Study

Our plain-English summary of Mutational Profile of Malignant Pleural Mesothelioma (MPM) in the Phase II RAMES Study, by M. Pagano, L.G. Ceresoli, P.A. Zucali, et al (Cancers, 2020).

The study

• Authors: M. Pagano, L.G. Ceresoli, P.A. Zucali, G. Pasello, M. Garassino, F. Grosso, M. Tiseo, H. Soto Parra, F. Zanelli, F. Cappuzzo, F. Grossi, F. De Marinis, P. Pedrazzoli, R. Gnoni, C. Bonelli, F. Torricelli, A. Ciarrocchi, N. Normanno, C. Pinto
• Journal: Cancers
• Published: 2020;12(10)
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer. Data are not available in prospective trials on correlations between genetic alterations and outcomes of therapies. In this study, we assessed the genetic profile of MPM patients (pts) in tissue samples. Patients and Methods: From December 2016 to July 2018 (end of enrolment), 164 pts were enrolled. We evaluated by targeted sequencing the mutational profile of a panel of 34 genes: ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6. Genetic profiling was correlated with clinical and pathological variables. Results: Overall, 110 pts (67%) from both treatment arms had samples available for molecular analysis. Median age was 63 years (45-81), 25.5% (n = 28) were females, and 74.5% (n = 82) were males. Tumor histotype was 81.8% (n = 90) epithelioid and 18.2% (n = 20) non-epithelioid; 28.5% of the tumors (n = 42) were stage IV, 71.5% (n = 68) were stage III. Targeted sequencing of tissue specimens identified 275 functional somatic mutations in the 34 genes analyzed. The number of mutated genes was positively associated with higher stage and metastatic disease (p = 0.025). RDX (42%), MXRA5 (23%), BAP1 (14%), and NF2 (11%) were the most frequently mutated genes. Mutations in RAPGEF6 (p = 0.03) and ACTG1 (p = 0.02) were associated with the non-epithelioid subtype, and mutations in BAP1 (p = 0.04) were related to progression-free survival (PFS) > 6 months. Conclusions: In the Ramucirumab Mesothelioma clinical trial (RAMES), mutation of the gene BAP1 is related to a prolonged PFS for patients treated with platinum/pemetrexed regimens (p = 0.04).

In plain English

This report analyzed tumor tissue from patients with malignant pleural mesothelioma in RAMES, an Italian randomized Phase II trial testing ramucirumab added to gemcitabine as second-line treatment. Of 164 patients enrolled from December 2016 to July 2018, 110 had tissue available. The tissue was taken at diagnosis, when all had stage III or IV disease, and was tested for mutations in 34 genes. The authors compared the mutations with how patients did on first-line platinum/pemetrexed chemotherapy. Asbestos exposure was self-reported by 53 of 110 patients (48.2%). No fiber types were given. The study found 275 functional somatic mutations. RDX (42%), MXRA5 (23%), BAP1 (14%) and NF2 (11%) were the most often mutated genes. Mutations did not differ significantly by asbestos exposure status. More mutated genes went with higher tumor stage (p = 0.025). RAPGEF6 and ACTG1 mutations were more frequent in sarcomatoid and biphasic tumors than in epithelioid tumors. BAP1 mutations were associated with longer progression-free survival after first-line chemotherapy (p = 0.04). The authors concluded that BAP1 showed a possible prognostic role. They noted limits, including the restricted gene panel and the lack of matched normal tissue.

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: Genetic (targeted sequencing) analysis of tumor tissue from patients in a multicenter, double-blind, randomized Phase II trial, correlated with outcomes of first-line chemotherapy; first-line progression-free survival was collected retrospectively
• Who was studied: 110 of 164 patients with Stage III and IV malignant pleural mesothelioma enrolled in the RAMES trial at 26 Italian oncology centers, December 2016 to July 2018; median age 63 (range 45 to 81), 82 males and 28 females; 90 epithelioid, 16 biphasic, 4 sarcomatoid
• Exposure: Self-reported asbestos exposure: 53 (48.2%) exposed, 52 (47.3%) not exposed, 5 (4.5%) unknown; no fiber types or jobs reported. All patients had received first-line cisplatin or carboplatin plus pemetrexed.
• Main results:
  • 275 functional somatic mutations were found in the 34 genes; the most frequently mutated were RDX (42%), MXRA5 (23%), BAP1 (14%) and NF2 (11%)
  • In 10% of patients no mutations were found in the genes tested
  • No significant differences in gene mutations were found according to asbestos exposure status
  • The number of mutated genes was positively associated with higher tumor stage (p = 0.025)
  • The average number of somatic mutations was 1.6 in patients with first-line progression-free survival of 6 months or less and 2.2 in those with more than 6 months (p = 0.032)
  • RAPGEF6 (p = 0.035) and ACTG1 (p = 0.027) alterations were more frequent in sarcomatoid and biphasic tumors than in epithelioid tumors
  • BAP1 variants were associated with longer progression-free survival after first-line platinum/pemetrexed (p = 0.04)
  • Median first-line progression-free survival for the 110 patients was 5.75 months (95% CI 4.75 to 6.76)
  • Four molecular clusters were identified, but clinical characteristics, including asbestos exposure, did not differ significantly among them
• The authors' conclusion: The authors concluded that BAP1 showed a possible prognostic role in first-line treatment with platinum/pemetrexed regimens
• Limitations the authors state:
  • Only a restricted panel of genes was tested
  • Because most mutations were present at low frequency, they could not be confirmed by Sanger sequencing
  • Tumors could not be compared with matched normal tissue
  • Whether BAP1 mutations were inherited or arose in the tumor could not be determined
  • Overall survival data were not yet mature
  • CUL1 and DHFR variants were too infrequent for statistical significance

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, BAP1, CDKN2A, Epithelioid, Non-epithelioid, Somatic Mutation, Progression-Free Survival, Ramucirumab.

Related studies

• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)
• Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study — A. Marabelle, M. Fakih, et al. (2020)
• Trabectedin in Malignant Pleural Mesothelioma: Results From the Multicentre, Single Arm, Phase II ATREUS Study — D. Cortinovis, F. Grosso, et al. (2021)
• Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors — R. Bahleda, M.C. Le Deley, et al. (2018)
• Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials — G.L. Ceresoli, B. Castagneto, et al. (2008)
• Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma — G.L. Ceresoli, P.A. Zucali, et al. (2013)

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