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. 2020 Oct 13;12(10):2948.
doi: 10.3390/cancers12102948.

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

Maria Pagano  1 , Luca Giovanni Ceresoli  2 , Paolo Andrea Zucali  3   4 , Giulia Pasello  5 , Marina Garassino  6 , Federica Grosso  7 , Marcello Tiseo  8   9 , Hector Soto Parra  10 , Francesca Zanelli  1 , Federico Cappuzzo  11 , Francesco Grossi  12 , Filippo De Marinis  13 , Paolo Pedrazzoli  14   15 , Roberta Gnoni  1 , Candida Bonelli  1 , Federica Torricelli  16 , Alessia Ciarrocchi  16 , Nicola Normanno  17 , Carmine Pinto  1
Affiliations

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

Maria Pagano et al. Cancers (Basel). .

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).

Keywords: BAP1; chemotherapy; gene expression profile; malignant pleural mesothelioma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Ramucirumab Mesothelioma clinical trial (RAMES) study design. MPM, malignant pleural mesothelioma, PD, progressive disease, TTP, time to progression, OS, overall survival, PFS, progression-free survival, ORR, overall response rate, QoL, quality of life.
Figure 2
Figure 2
(A) Mutational profile. (B) Number of gene mutations per patients.
Figure 3
Figure 3
Gene mutations and histotype. * Statistically significant (ACTG1 p = 0.027, RAPGEF6 p = 0.035).
Figure 4
Figure 4
(A) Gene mutations and first-line chemotherapy PFS. (B) Gene mutations and first-line chemotherapy ORR. * Statistically significant (BAP1 p = 0.04).
Figure 5
Figure 5
Gene expression-based clustering shows four molecular subgroups. Clustering of MPM cases based on the mutational status. Waterfall plot summarizing the gene variants detected in each patient (columns). Colored squares indicate mutation types. Upper histograms represent for each patient the estimated number of mutations per MB, based on 90.875 bps covered by the panel. Colored line at the bottom indicates patients classified in different genetic clusters.
See this image and copyright information in PMC

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