Assessment of ¹⁸F-FLT PET to predict treatment response in HER2+ breast cancer xenografts

Objectives Changes in tumor size may not provide the most sensitive response assessment to targeted therapies. Thus, imaging methods that can quantify early molecular changes are of interest. This study evaluated the utility of ¹⁸F-FLT PET to predict treatment response before changes in tumor size with HER2+ human xenografts sensitive and resistant to the HER2 antibody trastuzumab.

Methods Trastuzumab-sensitive (BT474) xenografts were established in female athymic mice to determine the time point at which tumor volumes became statistically different. Once tumors reached ≥250 mm³, mice were treated with trastuzumab (10 mg/kg; n=4) or vehicle (n=4) twice per week. A second cohort included mice with BT474 (8 treated, 5 control) and trastuzumab-resistant (HR6; n=8) xenografts. For the second cohort, a ¹⁸F-FLT PET scan was acquired at each time point, and the maximum standardized uptake value normalized to muscle (SUL_max) was calculated.

Results In the first cohort with treated and control BT474 xenografts, significant differences in tumor volume were observed on days 4, 5, 7, and 8. Thus, time points for the second cohort were baseline and days 1 and 4. Significant differences were observed on days 1 and 4 between the treated and control mice with BT474 xenografts, whereas a significant difference between treated mice with BT474 and HR6 tumors was only observed on day 4 (see table).

Conclusions The detected SUL_max change in the BT474 tumors differentiated treated vs. control animals before changes in tumor size occured. However, treatment-induced SUL_max changes in the BT474 and HR6 xenografts occurred only when tumor size changes were also evident. Thus, these findings suggest that ¹⁸F-FLT PET can only predict response before changes in tumor size in trastuzumab-sensitive HER2+ xenografts. In an attempt to validate these imaging findings, histology and western blot analyses of tumor lysates are ongoing.

Research Support NCI 5R01CA138599, P50CA098131, P30CA068485