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

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. [18F]fluorodeoxyglucose-positron emission tomography (18F-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) Ctrough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 µg/L (p = 0.02)). The optimal cut-off value to predict toxicity was Ctrough > 19.2 µg/L. GM Ctrough 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 (SULpeak high) at day 14. Patients with <11% versus >11% decrease in SULpeak 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 Ctrough. 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.

Female BRCA mutation carriers with a preference for prophylactic mastectomy are more likely to participate an educational-support group and to proceed with the preferred intervention within 2 years.

Women with a BRCA mutation face a complex choice between breast cancer surveillance and prophylactic mastectomy. We determined risk management preferences shortly after genetic test disclosure and mastectomy status after a median observation period of 2 years. The effect of an educational-support group on the realisation of risk management preference was explored. We included 163 newly disclosed BRCA mutation carriers with no history of cancer, whose breast cancer risk management preferences were recorded. All carriers were offered the opportunity to participate an educational-support group. Mastectomy status was checked after a median observation period of 2 years. Of the total sample, 27% had an initial preference for mastectomy and 48% attended an educational-support group. After a median observation period of 2 years, 30% of the total sample had undergone prophylactic mastectomy. Of the women with a preference for surveillance, 90% of educational-support group attendees and 88% of the other mutation carriers, were still under surveillance. The number of women with a preference for mastectomy who actually had a mastectomy performed, was significantly higher in the group that attended an educational-support group as compared to those who did not, 89% and 63% respectively (OR 4.8, P = 0.04). Strong predictors for prophylactic mastectomy within 2 years were younger age and prior preference for mastectomy (R (2) = 0.57). Nearly all BRCA mutation carriers proceed with their initial choice for surveillance or prophylactic mastectomy. The study provides presumptive evidence that educational-support group participants decide to undergo prophylactic mastectomy earlier than non-attendees.

Quantitative 19F MR spectroscopy at 3 T to detect heterogeneous capecitabine metabolism in human liver.

Chemotherapy in non-responding cancer patients leads to unnecessary toxicity. A marker is therefore required that can predict the sensitivity of a specific tumour to chemotherapy, which would enable individualisation of therapy. 19F MR spectroscopy (19F MRS) can be used to monitor the metabolism of fluorinated drugs. The aim of this study was to develop a method for quantified localised detection of fluorinated compounds in human liver. For this purpose, sensitivity-optimised localised 19F MRS methods at 3 T were used to detect MR signals from capecitabine, 5'DFUR, 5'DFCR and FBAL after oral intake of capecitabine. As the radio-frequency (rf) coil is made tuneable to 19F and 1H, the same localisation method is applied to obtain 1H MR signals of water and of the 19F metabolites. In addition, T1 measurements have been performed to correct for measurement-induced saturation effects. Finally, absolute tissue concentrations of capecitabine metabolites were obtained in vivo, which revealed a substantial spatial heterogeneity of these metabolites in human liver after chemotherapy.

Carbogen breathing differentially enhances blood plasma volume and 5-fluorouracil uptake in two murine colon tumor models with a distinct vascular structure.

For the systemic treatment of colorectal cancer, 5-fluorouracil (FU)-based chemotherapy is the standard. However, only a subset of patients responds to chemotherapy. Breathing of carbogen (95% O2 and 5% CO2) may increase the uptake of FU through changes in tumor physiology. This study aims to monitor in animal models in vivo the effects of carbogen breathing on tumor blood plasma volume, pH, and energy status, and on FU uptake and metabolism in two colon tumor models C38 and C26a, which differ in their vascular structure and hypoxic status. Phosphorus-31 magnetic resonance spectroscopy (MRS) was used to assess tumor pH and energy status, and fluorine-19 MRS was used to follow FU uptake and metabolism. Advanced magnetic resonance imaging methods using ultrasmall particles of iron oxide were performed to assess blood plasma volume. The results showed that carbogen breathing significantly decreased extracellular pH and increased tumor blood plasma volume and FU uptake in tumors. These effects were most significant in the C38 tumor line, which has the largest relative vascular area. In the C26a tumor line, carbogen breathing increased tumor growth delay by FU. In this study, carbogen breathing also enhanced systemic toxicity by FU.

Monitoring fluoropyrimidine metabolism in solid tumors with in vivo (19)F magnetic resonance spectroscopy.

(19)Fluorine magnetic resonance spectroscopy ((19)F MRS) offers unique possibilities for monitoring the pharmacokinetics of fluoropyrimidines in vivo in tumors and normal tissue in a non-invasive way, both in animals and in patients. This method may therefore be useful for predicting response to fluoropyrimidine-based therapy with or without the effects of modulating agents, and this may be of value for the individualization of anticancer therapy and the strategic development of new anticancer drugs. (19)F MRS has been very valuable in elucidating the basic aspects of fluoropyrimidine metabolism, especially in animal studies. Studies in humans have indicated its clinical potential, but widespread application has been hampered by the relatively low detection sensitivity of the method. The recent introduction of clinical MR scanners with magnetic fields above 1.5 T may stimulate increased clinical use of (19)F MRS.

19F-magnetic resonance spectroscopy in patients with liver metastases of colorectal cancer treated with 5-fluorouracil.

The purpose of this study was to examine the uptake and metabolism of 5-fluorouracil (5-FU) in human liver metastases. Patients with liver metastases of colorectal cancer were treated with 5-FU (500/600 mg/m)+folinic acid with or without trimetrexate. The clinical application of F-magnetic resonance spectroscopy (MRS) of 5-FU in a random group of patients (n=17) was investigated. MR spectra of all patients showed 5-FU and catabolite resonances, and fluoronucleotides were also seen in seven patients. A correlation was found between maximum levels of 5-FU catabolites as measured by F-MRS and response in a group with larger metastases. However, such correlation was not observed in a group with smaller metastases, probably because of a significant contribution of normal liver tissue to the MR spectra.

In vivo monitoring of capecitabine metabolism in human liver by 19fluorine magnetic resonance spectroscopy at 1.5 and 3 Tesla field strength.

In metastatic colorectal cancer the oral 5-fluorouracil (5FU) prodrug capecitabine is used with increasing frequency as an alternative to i.v. 5FU administration. The rate of conversion of capecitabine into 5'deoxy-5-fluorouridine has been related to tumor response, and 5FU catabolites have been associated with 5FU-related systemic toxicity. Here we demonstrate for the first time that capecitabine, its metabolites 5'deoxy-5-fluorocytidine and 5'deoxy-5-fluorouridine, and its catabolites 5-fluoro-ureido-propionic acid, alpha-fluoro-beta-alanine, and alpha-fluoro-beta-alanine-bile acid conjugate can be monitored in vivo by (19)fluorine magnetic resonance spectroscopy ((19)F MRS) in the liver of patients with metastatic colorectal cancer. Moreover, we demonstrate an improved signal-to-noise ratio and spectral resolution of the (19)F MRS spectra when measurements are performed at 3 T field strength as compared with measurements at the common clinical field strength of 1.5 T. We conclude that assessment of capecitabine metabolism in patients by (19)F MRS is a promising noninvasive tool for the prediction of its efficacy and toxicity, especially at the now currently available clinical field strength of 3 T.