Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane

Abstract

Background Treating breast cancer patients with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. Objective We investigated whether everolimus exposure and early metabolic response are predictors for toxicity and effectiveness in these patients. Patients and Methods We performed pharmacokinetic assessments 14 and 35 days after starting treatment. [ 18 F]fluorodeoxyglucose-positron emission tomography (18 F-FDG-PET) was performed at baseline, and 14 and 35 days after the start of the therapy. We recorded toxicity, defined as dose interventions within 3 months, and progression-free survival (PFS). Results Among 44 evaluable patients, the geometric mean (GM) C trough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 μg/L (p = 0.02)). The optimal cutoff value to predict toxicity was C trough > 19.2 μg/L. GM C trough of patients with and without progressive disease (PD) within 3 months was not significantly different (12.0 versus 15.2 μg/L (p = 0.118)). In 28 evaluable patients, PD within 3 months could best be predicted using the percentage decrease in peak standardized uptake value normalized by lean body mass of the lesion with highest FDG uptake (SUL peak high) at day 14. Patients with <11% versus >11% decrease in SUL peak high at day 14 had a median PFS of 90 days versus 411 days, respectively (p = 0.0013) and more frequently had PD within 3 months: 70 vs 11%, respectively. Conclusions Our results show that everolimus toxicity is related to everolimus C trough. No relation was observed between everolimus exposure and treatment effectiveness. An early FDG-PET can identify patients at high risk of nonresponse. These results warrant further validation. Clinicaltrials.gov identifier: NCT01948960.

Prospective Study of Drug-induced Interstitial Lung Disease in Advanced Breast Cancer Patients Receiving Everolimus Plus Exemestane

“…No correlation was seen between everolimus trough concentration and the development of (suspected) ILD, whereas other everolimus-related toxicities have been related to trough concentration [14,28]. This observation is in line with other studies that have indicated that the development of ILD is not exposure-related [44,45].…”

“…Everolimus plus exemestane is a valuable treatment option for patients with advanced breast cancer (ABC), but ILD is amongst the most common high-grade adverse events and is a frequent cause of treatment discontinuation [14][15][16][17]. In the BOLERO-2 trial, 10% of patients required everolimus dose interruption or reduction because of ILD [18].…”

“…In other ILDs, plasma biomarkers such as surfactant protein A (SP-A), surfactant protein D (SP-D), CC16, CCL18, YKL-40, lactate dehydrogenase (LDH), and cancer antigen (CA) 15-3 correlate with pulmonary inflammation [22][23][24][25][26][27]. Previous studies have demonstrated that a high everolimus trough concentration is associated with a higher risk of toxicity [14,28]. Increased FDG-avidity in the lungs on FDG-PET scans has been reported in several patients with drug-induced ILD such as bleomycin, rituximab, etoposide, and paclitaxel, mostly as diffuse bilateral FDG-accumulation [29][30][31][32][33][34][35].…”

Early Changes in [18F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts

“…A phase I study in breast, endometrial, and ovarian cancer evaluated [ 18 F]FDG as a biomarker after therapy with an mTOR inhibitor (temsirolimus) and pegylated liposomal doxorubicin and [ 18 F]FDG PET was able to predict early response [ 13 ]. Another clinical study, where breast cancer patients were treated with everolimus and exemestane, early [ 18 F]FDG PET 14 days after the start of therapy could identify patients at high risk of nonresponse [ 14 ]. These results contradict a preclinical investigation, in which everolimus inhibited tumor growth in relative insensitive (human colon and cervical) and sensitive (human melanoma and lung cancer) mTOR cancer models; tumor [ 18 F]FDG uptake after 2 and 7 days of treatment was only reduced in sensitive cell lines.…”

Early Changes of the Standardized Uptake Values (SUVmax) Predict the Efficacy of Everolimus-Exemestane in Patients with Hormone Receptor-Positive Metastatic Breast Cancer

“…Regarding breast cancer patients treated with everolimus, only one study assessed the role of FDG-PET in predicting outcome and toxicity in mBC patients treatment with everolimus, suggesting that poor decrease in metabolic activity after 14 days of treatment can identify a subgroup of patients with a shorter PFS compared to the subgroup with a significantly lower metabolic activity [ 21 ].…”