Identification of single nucleotide polymorphism of PI3k-AKT-TOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.

Abstract

2007 Background: Although new therapeutic options are available, an early diagnosis of central nervous system (CNS) metastasis may be needed to improve the prognosis. The PI3k-Akt-mTor pathway has been shown to be relevant in the development of CNS metastasis. Our aim was to identify risk-associated single nucleotide polymorphisms (SNP) of the PI3K Akt-mTOR pathway in the development of CNS metastasis in patients with metastatic breast cancer. Methods: We performed a secondary analysis in a subpopulation of patients from the GENEOM study (NCT00959556). In this previous study, blood samples were collected from 914 breast cancer patients treated by chemotherapy in the neoadjuvant, adjuvant or metastatic setting for genomic analysis. We identified CNS metastatic patients (both leptomeningeal and parenchymal) and non-CNS metastatic patients (no neurological symptoms or normal brain MRI before death or during 5-years metastatic period). Based on the literature, 88 SNPs of the PI3K-Akt-mTOR pathway were analyzed, including AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). Results: Of the 342 patients with metastases in the GENEOM cohort, 100 patients with CNS metastasis (parenchymal lesions only, n = 51; leptomeningeal lesions only, n = 18; both, n = 31) and 107 patients without CNS metastasis were included. Negative hormonal status (p = 0.002) and presence of vascular emboli on breast cancer samples (p = 0.006) were associated with CNS metastasis. In univariate analysis, genotypes CC of AKT1 rs3803304, AA of AKT2 rs3730050, CC of AKT2 rs8100018, TT of PDK1 rs1168690, GG of PDK1 rs11904366 and GG of PI3KR1 rs251408 were associated with CNS metastasis at the p < 0.05 threshold. Only genotype TT of PI3KR1-rs706716 was statistically associated with CNS metastasis after Bonferroni correction (p = 0.0003, < 0.00085). Conclusions: PI3KR1-rs706716 is associated with CNS metastasis in metastatic breast cancer patients, in addition to negative hormonal status and presence of vascular emboli and could be combined in a composite score to predict the risk of and to detect early CNS metastasis in this population.