Date Published: July 20, 2017
Publisher: Public Library of Science
Author(s): Tomas Pascual, María Apellániz-Ruiz, Cristina Pernaut, Cecilia Cueto-Felgueroso, Pablo Villalba, Carlos Álvarez, Luis Manso, Lucia Inglada-Pérez, Mercedes Robledo, Cristina Rodríguez-Antona, Eva Ciruelos, Daotai Nie.
Metastatic 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.
Blood 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.
We 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).
CYP3A4*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.
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. Although 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.
The BOLERO-2 trial demonstrated a clinically meaningful improvement in PFS with everolimus plus exemestane therapy in patients with ER–positive/HER2-negative advanced breast cancer [10,11].Despite these encouraging results, not all patients benefit from everolimus, and an optimal target patient population for this drug is yet to be defined. Moreover, the benefits of treatment with everolimus come with an increased incidence of mTOR inhibitor-associated toxicities. Thus, there is an urgent need for biomarkers that can predict response to everolimus and better define the ideal target patient group.