Abstract
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Objectives: 18F-fluoro-5α-dihydrotestosterone (FDHT) is a novel radiotracer for imaging the androgen receptor (AR) with PET. Most primary and metastatic breast cancer tumors express AR, and modulating AR signaling has become recognized as a potentially important therapeutic target for metastatic breast cancer. As part of a phase II clinical trial investigating a selective AR modulator (SARM), enobosarm, for estrogen receptor positive (ER+) metastatic breast cancer (G200802, GTx, Inc, NCT02463032) , a prospective imaging sub-study was designed to: 1) demonstrate the proof-of-principle that FDHT-PET can be used to non-invasively image the presence of AR expression in breast cancer; and, 2) to explore the potential of FDHT-PET as an imaging biomarker for evaluating response to SARM therapy. Methods: 11 post-menopausal women with ER+ metastatic breast cancer were enrolled in the imaging sub-study and underwent FDHT-PET/CT at baseline, and at 6 and 12 weeks after starting SARM therapy (n=10, 9 mg orally daily; n=1, 18 mg orally daily). PET/CT scans were obtained from the skull vertex to mid-thighs 45 minutes after the intravenous administration of 333 MBq (9 mCi) of FDHT. All FDHT-PET/CT scans were obtained on the same scanner for individual participants. Abnormal FDHT uptake in the tumor was qualitatively defined as uptake greater than background in a pattern consistent with metastatic breast cancer and quantified using SUVmax at baseline, 6 and 12 weeks after starting SARM therapy. Archival or fresh tumor biopsy specimens underwent central review for AR status (qualitative: positive/negative; quantitative: % positive nuclei). Percent change of FDHT-SUVmax of the hottest lesion was calculated between baseline, week 6 and week 12 scans. Tumor response was assessed every 12 weeks according to RECIST 1.1. Patients were grouped according to their best overall response as having clinical benefit (CB: complete/partial response or stable disease), or progressive disease (PD). Statistical analyses are primarily descriptive due to the pilot nature of study.
Results: 9 patients completed all 3 FDHT-PET/CT scans; 2 came off study prior to week 12. For 9 patients with tumor AR status available, baseline FDHT-SUVmax was higher for AR positive (n=7) versus AR negative (n=2) tumors (Figure 1A). A trend for higher baseline FDHT SUVmax was seen with higher quantitative AR expression levels (Spearman rho=0.57, p=0.12), and when excluding one outlier, Spearman rho=0.81, p=0.02, (Figure 1B). Within 12 weeks after treatment, 7 patients had clinical benefit and 4 had progressive disease. Median baseline FDHT-SUVmax was 2.93 (range 1-4.38) for 7 patients with CB within 12 weeks after therapy and 2.15 (0.96-3.77) for 4 patients with PD (Figure 2A). Those with CB within 12 weeks had decline in FDHT uptake whereas those with PD did not (Figure 2B). Conclusions: This hypothesis-generating data supports the proof-of-principle that FDHT uptake in metastatic breast cancer correlates with tumor AR expression. The data also supports a potential role for FDHT-PET/CT as a whole-body non-invasive imaging biomarker that can be used in larger, well-designed clinical trials to optimize strategies modulating AR signaling to treat metastatic breast cancer and other AR-expressing malignancies.
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