B28
Altered tissue 3-Deoxy-3-[18F]Fluorothymidine Pharmacokinetics in human breast cancer following Capecitabine treatment detected by positron emission tomography
Laura M Kenny1, Kaiyumars B Contractor1, Justin Stebbing1, Adil Al-Nahhas2, Carlo Palmieri1, Sami Shousha3, R Charles Coombes1, Eric O Aboagye1
1Imperial College London, UK, 2Imperial College Healthcare NHS Trust, London, UK, 3Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
Background
Pre-clinical models used by our group have demonstrated that thymidylate synthase (TS) inhibition leads to redistribution of the nucleoside transporter, ENT1, to the cell membrane and hence increases the tissue uptake of [18F]fluorothymidine (FLT).
Method
In this study we assessed, for the first time, the altered pharmacokinetics of FLT in patients following TS inhibition. We analyzed 10 lesions from 6 breast cancer patients by positron emission tomography (PET) before and after treatment with capecitabine.
Results
Whereas drug treatment did not alter tumour delivery pharmacokinetic variables or blood flow, tumour FLT retention variables increased with drug treatment in all but one patient. The baseline average standardized uptake value (SUV) at 60 min, rate constant for the net irreversible transfer of radiotracer from plasma to tumour (Ki) and unit impulse response function (IRF) at 60 min were 11.11 x 10-5 m2/ml, 4.38 x 10-2 ml plasma/min/ml tissue and 4.93 x 10-2 /min, respectively. At 1 h after capecitabine, the SUV was 13.55 x 10-5 m2/ml (p=0.004), Ki 7.40 x 10-2 ml plasma/min/ml tissue (p=0.004) and IRF 7.40 x 10-2 /min (p= 0.002).
Conclusion
FLT pharmacokinetics did not change in normal tissues suggesting that the effect was largely restricted to tumour (p=0.55). In summary, we have identified FLT-PET retention parameters that could be used in future early clinical studies to measure the pharmacodynamics of TS inhibitors, as well as for identifying patients who are unlikely to benefit from TS inhibition.
