Abstract P3-07-40: Pharmacogenetic study of exemestane and everolimus in metastatic breast cancer patients progressing on prior non-steroidal aromatase inhibitors
Authors: Pascual-Martínez T , Apellániz-Ruiz M , Pernaut C , Cueto-Felgueroso C , Villalba P , Alvarez C , Manso L , Rodriguez-Antona C , Ciruelos EM 
Published: May 2016

Background: Activation of the mTOR pathway has been observed in patients (pts) with metastatic breast cancer (MBC) progressing on endocrine therapy. BOLERO-2 trial demonstrated a significant increase in progression free survival (PFS) obtained with everolimus (EVE) and exemestane (EXE) versus EXE alone in pts refractory to a prior non-steroidal aromatase inhibitors (NSAI). However, there is large interindividual variability in toxicity and efficacy profiles of EXE-EVE treatment. Single Nucleotide Polymorphisms (SNPs) have been proposed to explain some of these differences. The objective of this study was to perform a pharmacogenetic analysis to identify SNPs associated with EVE toxicity and activity.

Methods: This is a prospective unicentric clinical trial for postmenopausal pts with hormone receptor-positive, HER2 negative, MBC progressing on prior NSAI, treated with EXE-EVE.

Blood samples were obtained from all pts, and 12 SNPs in key genes involved in EXE pharmacokinetics (ABCB1, CYP2C8, CYP3A4, CYP3A5) and pharmacodynamics (AKT1, AKT2, FGFR4, PHLPP2, PIK3R1, RAPTOR) were genotyped. EVE pharmacokinetics data was available for a subset of 37 pts. The association between the SNPs and EVE pharmacokinetic parameters were analyzed using U-Mann-Whitney test. A selection of clinically relevant toxicities (non-infectious pneumonitis (NIP), mucositis, hyperglycemia and hematological) was analyzed using binary logistic regression. Cox regression was used to analyze the association of SNPs with time to treatment modifications (reduction or interruption) due to toxicity, PFS and OS.

Results: 90 patients with median age of 62 yrs were included. At data cut off, a total of 77 pts had discontinued treatment. Major reasons for discontinuation were: disease progression (80%), adverse events (17%) and death (2%). Number of prior chemotherapy lines: 0; 50%, 1;18%, 2;10%, ≥3; 22%. 76% of pts experienced at least one adverse event related to EVE.

CYP3A4 rs35599367 (CYP3A4*22 allele) heterozygous pts had higher EVE concentration in blood compared to wild type pts (P=0.019), in agreement with previous data.

Regarding EVE toxicities, ABCB1 SNP rs1045642 showed a higher risk of mucositis (HR=2.3, 95%CI=1.1-4.8, P=0.031; multivariable analysis), and PIK3R1 rs10515074 variant was inversely associated with hyperglycemia (HR=0.24, 95%CI=0.1-0.8, P=0.016; multivariable analysis). RAPTOR rs9906827 protected for NIP (HR=0.38, 95%CI=0.2-0.9, P=0.024; multivariable analysis). When analyzing the time to treatment modification due to any toxicity, we observed a trend for FGFR4 rs351855 and RAPTOR rs9906827 (HR=0.59, 95%CI=0.3-1.0, P=0.06 and HR=0.71, 95%CI=0.5-1.1, P=0.12; respectively, in multivariable analysis).

Regarding activity, RAPTOR rs9906827 was also associated with longer PFS (dominant model HR=0.48, 95%CI=0.3-0.8, P=0.006; multivariable analysis). No SNP was significantly associated with OS.

Conclusions: We found altered EVE pharmacokinetics for CYP3A4*22 carriers and protection for NIP and longer PFS for RAPTOR rs9906827. This study supports prospective trials for genetic testing prior to EXE-EVE therapy to stratify patients according to toxicity and efficacy risk profiles.

Citation Format: Pascual-Martínez T, Apellániz-Ruiz M, Pernaut C, Cueto-Felgueroso C, Villalba P, Alvarez C, Manso L, Rodriguez-Antona C, Ciruelos EM. Pharmacogenetic study of exemestane and everolimus in metastatic breast cancer patients progressing on prior non-steroidal aromatase inhibitors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-40.