Fluoroestradiol positron emission tomography reveals differences in pharmacodynamics of aromatase inhibitors, tamoxifen, and fulvestrant in patients with metastatic breast cancer

Abstract

Purpose: To determine, by molecular imaging, how in vivo pharmacodynamics of estrogen-estrogen receptor (ER) binding differ between types of standard endocrine therapy.

Experimental design: The ER has been a highly successful target for breast cancer treatment. ER-directed treatments include lowering ligand concentration by using aromatase inhibitors (AI) and blocking the receptor with agents like tamoxifen (TAM) or fulvestrant (FUL). We measured regional estrogen-ER binding by using positron emission tomography with (18)F-fluoroestradiol (FES PET) prior to and during treatment with AI, TAM, or FUL in a series of 30 metastatic breast cancer patients. FES PET measured in vivo estrogen binding at all tumor sites in heavily pretreated women with metastatic bone soft tissue-dominant breast cancer. In patients with uterus (n = 16) changes in uterine FES uptake were also measured.

Results: As expected, tumor FES uptake declined more markedly on ER blockers (TAM and FUL, average 54% decline) compared with a less than 15% average decline on estrogen-depleting AIs (P < 0.001). The rate of complete tumor blockade [FES standardized uptake value (SUV) ≤1.5] following TAM (5/5 patients) was greater than the blockade rate following FUL (4/11; 2-sided mid P = 0.019). Percent FES SUV change in the uterus showed a strong association with tumoral change (ρ = 0.63, P = 0.01).

Conclusions: FES PET can assess the in vivo pharmacodynamics of ER-targeted agents and may give insight into the activity of established therapeutic agents. Imaging revealed significant differences between agents, including differences in the efficacy of blockade by different ER antagonists in current clinical use.

Figure 1

Pre and post treatment images are shown in representative patients treated with ER- blocking (A. Tamoxifen, B. Fulvestrant) and estrogen lowering therapies (C. aromatase inhibitor.) Upper panels show coronal (i) and sagittal (ii) views pre-treatment, and lower panels show the same patient following treatment with coronal (iii), and sagittal views (iv). Tumor is shown with a solid arrow, uterus is shown with a dashed arrow. Liver (with diffuse uptake due to metabolism of FES) is shown with a thin line, and the bladder is denoted by a thin arrow.

1. Tumor in the upper spine shows baseline uptake and complete ER blockade in tumor and uterus following 21 days of TAM

2. Tumor in mediastinal nodes shows baseline uptake and incomplete ER blockade in tumor and uterus following 68 days of FUL.

3. Sternal tumor shows ER uptake, and no blockade in the tumor and uterus following 29 days of letrozole (AI).

Figure 1

Pre and post treatment images are shown in representative patients treated with ER- blocking (A. Tamoxifen, B. Fulvestrant) and estrogen lowering therapies (C. aromatase inhibitor.) Upper panels show coronal (i) and sagittal (ii) views pre-treatment, and lower panels show the same patient following treatment with coronal (iii), and sagittal views (iv). Tumor is shown with a solid arrow, uterus is shown with a dashed arrow. Liver (with diffuse uptake due to metabolism of FES) is shown with a thin line, and the bladder is denoted by a thin arrow.

1. Tumor in the upper spine shows baseline uptake and complete ER blockade in tumor and uterus following 21 days of TAM

2. Tumor in mediastinal nodes shows baseline uptake and incomplete ER blockade in tumor and uterus following 68 days of FUL.

3. Sternal tumor shows ER uptake, and no blockade in the tumor and uterus following 29 days of letrozole (AI).

Figure 1

Pre and post treatment images are shown in representative patients treated with ER- blocking (A. Tamoxifen, B. Fulvestrant) and estrogen lowering therapies (C. aromatase inhibitor.) Upper panels show coronal (i) and sagittal (ii) views pre-treatment, and lower panels show the same patient following treatment with coronal (iii), and sagittal views (iv). Tumor is shown with a solid arrow, uterus is shown with a dashed arrow. Liver (with diffuse uptake due to metabolism of FES) is shown with a thin line, and the bladder is denoted by a thin arrow.

1. Tumor in the upper spine shows baseline uptake and complete ER blockade in tumor and uterus following 21 days of TAM

2. Tumor in mediastinal nodes shows baseline uptake and incomplete ER blockade in tumor and uterus following 68 days of FUL.

3. Sternal tumor shows ER uptake, and no blockade in the tumor and uterus following 29 days of letrozole (AI).

Figure 2

Quantitative tumor and uterine FES SUV in patients undergoing AI, FUL, or TAM treatment are shown, with box and whisker plots superimposed. FES SUV values are shown at baseline (tumor site(s), A; uterus, B), and after 1–18 weeks of therapy (tumor site(s), C; uterus, D). Percent change between baseline and follow-up is shown for tumor site(s) (panel E) and the uterus (panel F). Two patients had baseline tumor uptake below the threshold for blockade (FES SUV ≤ 1.5) and are denoted by solid blue squares to track the effect of blocking therapy on tumors with low uptake. The FUL patient with low uptake and 4 additional patients (indicated by red plotting characters) took concomitant trastuzumab during endocrine therapy. Horizontal dashed lines indicate the FES SUV ≤ 1.5 threshold for tumor blockade (A, C) and a 0% change threshold for percent change in SUV (E, F).