MPM is a highly aggressive pleural tumor associated with asbestos exposure. The ability to analyze entire genomes opens the door to identification of new treatments.
RAMES is a ongoing phase II study to evaluate the efficacy and the safety of the addition of ramucirumab to gemcitabine as the second-line treatment in 160 pts with MPM. We designed a custom panel covering 1040 amplicons spanning 33 genes frequently altered in MPM. To establish the genetic asset of MPMs we used an amplicon-based next generation sequencing approach.
To date, 40 FFPE mesothelioma cancer tissues were successfully sequenced A total of 2930 variants passing quality filters were detected. Focusing on potentially functional alterations, polymorphisms and non-coding variants were excluded, leaving 143 alterations in 23 of the analyzed genes. Of these, 59.4% (85/143) were missense mutations, 22.4% (32/143) lead to frameshift alteration of the gene sequence, 13.3% (19/143) were splice variants, while the remaining 4.9% (7/143) were start loss, stop gain alterations and deletion. 97.5% of patients (39/40) displayed at least one mutation, while the average number of mutations per sample was 3.6 (range 0-8), confirming the high mutational load of these tumors. The most frequently altered genes identified were PIK3CA (62.5%), RDX (40%), MXRA5 (20%), BAP1 (15%), NF2 (15%). Molecular analyses have been correlated with Histology and Stage (thoracic vs extrathoracic MPM). We found the following NF2, PIK3CA, RDX altered genes in 9 biphasic tumor and MXRA5, NF2, PIK3CA, RDX, CUL1, BAP1, NF2, TAOK1 altered genes in 31 ephitelioid tumor. We observed a significant correlation between mutations in RDX gene (23.1%) and extrathoracic MPM. CUL1 and RDX genes were found in pts with progression free survival ≥6 months from prior treatment.
This preliminary data supports the generation of a genetic signature based on tumor mutational status useful to discriminate MPM with different clinico-pathological features and possible correlation with treatment choice.
Clinical trial identification
Legal entity responsible for the study
AUSL-IRCCS Reggio Emilia.
Has not received any funding.
All authors have declared no conflicts of interest.