Molecular comparison of glycolytic and DNA synthesis pathways in human breast cancer before and after treatment with an aromatase inhibitor: Implications for FDG and FLT PET

Objectives FDG is useful in assessing treatment response but flare responses have been described in hormonal therapies of breast cancer. FLT has also been applied in this setting. To better understand molecular mechanisms associated with aromatase inhibitor therapy, we used a gene array technique to compare the glycolytic and DNA synthesis pathway messages before and soon after treatment with the aromatase inhibitor, Letrozole, at the cellular level to help inform choice of radiotracers.

Methods A public microarray database was used (Gene Expression Omnibus: GSE5462). We analyzed data from 52 breast cancer patients before and after taking Letrozle for 10 to 14 days (clinical reponse:36 and no response: 16). 14,500 well-characterized human genes were measured before and after 10-14 days of treatment. The raw data were normalized with RMA software. Changes in gene expression were analyzed by Spotfire software to evaluate messages related to the glycolytic pathway (FDG uptake) and DNA synthesis (FLT uptake). ROC analysis was performed using SPSS for change in message at 10-14 days vs. final pathological response post-completion of therapy (90 days).

Results Thymidylate synthetase (TYMS), thymidine kinase 1 (TK1), and Ki67 mRNA levels decreased after Letrozole (p< 0.001). The glucose transporter 1(SLC2A1) and Hexokinase 1 (HK1) also decreased but the p values were borderline. ROC analysis demonstrated that drop in TYMS (0.668 ± 0.084; 95%CI 0.505-0.832) and TK1 (0.639 ± 0.081; 95%CI 0.481-0.797) had better detection of early response than Ki 67 (0.542 ± 0.081; 95%CI 0.382-0.701), SLC2A1 (0.595 ± 0.079; 95%CI 0.442-0.749), or HK1 (0.446 ± 0.093; 95%CI 0.263-0.629).

Conclusions Letrozole appears to have more substantial early effects on the DNA synthetic pathway than on glycolysis in this pre-clinical study. These molecular findings suggest FLT PET may have advantages over FDG to assess the early response to Letrozole , though clinical validation is essential.