¹⁸F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice

Abstract

Breast cancers (BCs) with high human epidermal growth factor receptor type 2 (HER2) expression are most likely to respond to trastuzumab; however, the mechanisms of action of trastuzumab are complex and there are no established biomarkers to accurately monitor treatment outcome in individual patients. Therefore, our aim was to determine, in human BC xenografts in athymic mice treated with trastuzumab, whether there were any changes in 18 F-FDG uptake that were associated with response to the drug and that could have utility in monitoring response in patients. Methods: Baseline tumor uptake of 18 F-FDG was measured in mice with MDA-MB-361 HER2-overexpressing xenografts and MDA-MB-231 xenografts with low HER2 expression by small-animal PET imaging on day 0. Mice were treated with phosphate-buffered saline (PBS) or trastuzumab (4 mg/kg), and small-animal PET was repeated 2 d after treatment. Maintenance doses of trastuzumab (2 mg/kg) or PBS were administered on days 7 and 14, and mice were imaged again on days 9 and 16. Tumor uptake was measured as percentage injected dose per gram (%ID/g) by volume-of-interest analysis on days 0 (baseline), 2, 9, and 16, followed by biodistribution studies on day 16. Tumor growth was measured, and a tumor growth index was calculated. Results: The treatment of mice with trastuzumab, compared with control mice treated with PBS, resulted in a significant decrease in tumor uptake of 18 F-FDG in HER2-overexpressing MDA-MB-361 xenografts after 16 d of treatment (2.6 6 0.8 %ID/g vs. 4.6 6 1.8 %ID/g, respectively; P , 0.03) but not after 2 or 9 d of treatment (P 5 0.28-0.32). In contrast, there was no significant change in the tumor uptake of MDA-MB-231 xenografts with low HER2 expression during the entire course of therapy (4.4 6 1.7 %ID/g vs. 3.6 6 1.1 %ID/g, respectively; P 5 0.31). Trastuzumab treatment, compared with PBS treatment of controls, resulted in significant growth inhibition of MDA-MB-361 xenografts as early as 10 d from the initiation of treatment (tumor growth index, 0.7 6 0.2 vs. 1.7 6 0.3, respectively; P , 0.0005), whereas no tumor growth inhibition was observed for MDA-MB-231 xenografts (5.3 6 2.7 and 5.2 6 3.0; P 5 0.95). Conclusion: Changes in the tumor uptake of 18 F-FDG after therapy accurately identified responding and nonresponding human BC xenografts in athymic mice treated with trastuzumab; however, diminished glucose utilization did not precede changes in tumor volume.

Optical imaging of metabolism in HER2 overexpressing breast cancer cells

“…6A). These results are the first of its kind, but are consistent with an FDG-PET study of trastuzumab responsive and non-responsive breast cancer xenographs, demonstrating that HER2 inhibitors failed to reduce FDG uptake in those tumors whose growth was unaffected by trastuzumab [37]. Interestingly, the redox ratio of the trastuzumab and lapatinib resistant cells are different from the pre-treatment redox ratio value of responsive BT474 cells, p<0.001 (Fig.…”

Changes in 2-fluoro-2-deoxy-d-glucose incorporation, hexokinase activity and lactate production by breast cancer cells responding to treatment with the anti-HER-2 antibody trastuzumab

“…Generally, compared with pretreatment, responding tumors show decreased FDG uptake within a few days of starting chemotherapy. Two recent studies of human tumor xenografts [9,10] have produced conflicting findings regarding the effect of response to trastuzumab on FDG incorporation. McLarty et al [9] showed that treatment of MDA-MB-361 cells, which overexpress HER-2, exhibited a decline in FDG incorporation, whereas MDA-MB-231 cells, which do not overexpress HER-2, showed no change in FDG incorporation.…”

“…Two recent studies of human tumor xenografts [9,10] have produced conflicting findings regarding the effect of response to trastuzumab on FDG incorporation. McLarty et al [9] showed that treatment of MDA-MB-361 cells, which overexpress HER-2, exhibited a decline in FDG incorporation, whereas MDA-MB-231 cells, which do not overexpress HER-2, showed no change in FDG incorporation. However, in the study by Shah et al [10], FDG incorporation by trastuzumab-treated MMTV/HER-2 and BT474 cells was found not to accompany response.…”

Repeatability of 18F-FDG Uptake Measurements in Tumors: A Metaanalysis

“…In the research setting, PET is increasingly being used to study early changes of biologic effects during and after anticancer treatment (7)(8)(9)(10). The noninvasive nature of PET allows multiple serial measurements without interfering with biologic processes within the tumor and might obviate more invasive procedures, such as biopsy.…”