Abstract
PurposeMetastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis.Patients and methodsBlood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities), dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival.ResultsWe found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019). ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031), while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively). Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006).ConclusionsCYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.
Highlights
Breast cancer is a life-threatening disease and is the second leading cause of cancer death among women
Twelve single nucleotide polymorphisms (SNPs) in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities, dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival
We found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019)
Summary
Breast cancer is a life-threatening disease and is the second leading cause of cancer death among women. It has been estimated that in 2017 there will be 255,180 newly diagnosed breast cancer cases in the US, and approximately 40,610 women will die from breast cancer[1]. Metastatic breast cancer is diagnosed in only 5% of cases at presentation, nearly one third of breast cancer patients with non-metastatic tumors will eventually develop metastases [2]. Endocrine therapies that target estrogen receptor (ER) signaling pathways for ER-positive disease and HER2-targeted therapies for HER2-positive disease play a critical role in the treatment of most patients with breast cancer. For patients with ER-positive advanced breast cancer, endocrine therapy is the recommended initial treatment. Since most patients eventually develop resistance to these therapies, the guidelines recommend another endocrine agent when initial therapy fails [3]
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