Molecular profile in primary and metastatic breast cancer treated with Exemestane and Everolimus.

Background. The PI3K/Akt/ mTOR pathway plays a significant role in endocrine resistance breast cancer (BC). Everolimus (EVE) has been approved after BOLERO-2 study, which showed a significant increase of PFS thanks to EVE plus Exemestane (EXE), compared to EXE alone. Hortobagyi et al. performed Next Generation Sequencing on 227 BOLERO-2 samples of primary BC to study the potential correlation between genetic alterations and EVE efficacy: a greater incidence of mutations in PI3KCA, PTEN, CCND1 and FGFR1 was detected, but treatment effect was independent from the genetic status. The aim of this study was to evaluate the molecular profile of both primary and secondary lesions in 25 metastatic BC patients treated with EVE+EXE in Modena University Hospital since 2014. Materials and methods. Thirty-three DNA samples from 25 patients were examined, 13 from primary BC and 20 from metastatic lesions. In 8 patients both primary tumor and metachronous metastasis were evaluated. Genomic DNA samples from FFPE tissues was conducted using panel OncoCarta 2.0 on MassArray Sequenom platform that detect more than 150 single nucleotide variations from 18 genes (AKT1, BRAF, CTNNB1, FBX4, FBXW7, FGFR2/3, GNAQ, KIT, KRAS, MAP2K1/2, NRAS, PDGFR, PIK3CA, PTPN11, SOS1, TP53). Differences between mutational status of primary and metastatic BC have been evaluated using χ2 and Fisher tests. Results. The median age was 54 years (range 50-67). 70% of patients had visceral involvement, 62% received more than 3 previous therapies, and for 8% of them an AI constituted the last treatment before EVE. Overall, 11 DNA samples were mutated (33%). 5 mutations were detected in the primary lesion with a frequency of 3% (PI3KCA, FBX4, KIT, MAP2K1, FBXW7) - 6 mutations in the metastasis (BRAF, KIT, TP53, FBXW7, CTNNB1, PI3KCA, AKT). Notably, mutations were found exclusively in primary lesion or in metastatic site, while only in one case both primary and secondary cancer were mutated, even if in two different genes. No significant correlation with treatment efficacy was evidenced. Conclusions. The genes most frequently mutated in MBC were PI3KCA, AKT1 and FBXW7, even if the percentage of PIK3CA and AKT1 mutations was less than expected. No correlation between primary and metastatic mutational status was detected. Involving new patients maybe could be the way for more encouraging results.