Measuring Residual Estrogen Receptor Availability during Fulvestrant Therapy in Patients with Metastatic Breast Cancer

Abstract

It is unknown whether the current dose of fulvestrant, an estrogen receptor (ER) antagonist, is suffi cient for maximal ER downregulation in patients with metastatic breast cancer. We performed a feasibility study to assess ER availability before and during fulvestrant. Sixteen patients with ER-positive metastatic breast cancer underwent positron emission tomography/ computed tomography (PET/CT) at baseline (scan 1), day 28 (scan 2), and day 84 (scan 3) to monitor tumor [ 18 F]fl uoroestradiol (FES) uptake. Incomplete reduction in ER availability was predefi ned as <75% decrease in median tumor FES uptake and a residual standardized uptake value (SUV max ) of ≥1.5.In total, 131 FES-positive lesions were identifi ed (median SUV max of 2.9; range, 1.7-6.5). The median change in patients during fulvestrant treatment was −85% at scan 2, but varied widely (−99% to +60%). Fulvestrant reduced tumor FES uptake incompletely at scan 2 in 6 (38%) of the 16 patients, which was associated with early progression. SIGNIFICANCE:Serial imaging of tumor estrogen uptake by FES-PET can give insight into the dose needed for ER antagonists to completely abolish ER. FES-PET showed signifi cant residual ER availability in tumors during fulvestrant therapy in 38% of patients, which was associated with early progression. Cancer Discov; 5(1);[72][73][74][75][76][77][78][79][80][81]

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

“…In the metastatic setting, fulvestrant has been shown to be effective as a single agent and a recent study demonstrated that the increased dose of 500 mg fulvestrant is superior to the historical 250 mg dose in terms of overall survival (8,12,13). However, there is evidence to suggest that even at the 500 mg dose, suboptimal occupancy of the estrogen receptor can occur in some patients, which may correlate with an earlier progression of disease (14). These data, combined with fulvestrant's intramuscular route of administration underscore the need for a novel orally bioavailable SERD for the treatment of ER þ breast cancer.…”

Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies

“…Furthermore, the degree of ER degradation achieved with fulvestrant appears suboptimal: paired biopsy data indicate that therapy at the initially approved 250 mg dose results in reduction of ERα levels to 50% of baseline, rather than to undetectable levels (Robertson et al 2001). Even at the higher dose of 500 mg, serial [(18)F] fluoroestradiol PET scans reveal incomplete suppression of estrogen uptake in 38% of patients (van Kruchten et al 2015). Taken together, these factors indicate a need to develop next-generation SERDs that would not only be orally bioavailable for patient convenience but also exhibit more efficient receptor degradation.…”

“…There may be advantages to more limited isoform selectivity in some tumors, as this may facilitate an increase in the therapeutic drug exposure without increasing off-target side effects. Tumors with activating mutations in the PIK3CA gene would be expected to be sensitive to a drug selectively inhibiting the p110α isoform, whereas PI3K signaling in PTEN-deficient tumors appears more dependent on the p110β isoform and may benefit from pan-class 1 inhibition (Wee et al 2008, Jiang et al 2010, Vanhaesebroeck et al 2010, Schwartz et al 2015. More selective compounds are entering clinical trials.…”

Diagnostic imaging using positron emission tomography for gynecological malignancy

“…62 This tracer has been reported as useful for imaging estrogen-dependent endometrial cancer and breast cancer. 63 F-FES ratio may offer an accurate index for differentiating endometrial diseases, based on the fact that endometrial carcinoma has reduced estrogen dependency and accelerated glucose metabolism following progression to higher stages or grades. This ratio offers great accuracy in predicting high-and low-risk carcinoma or diagnosing endometrial carcinoma and hyperplasia.…”