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Published in final edited form as: J Nucl Med. 2016 Feb;57(Suppl 1):75S–80S. doi: 10.2967/jnumed.115.157933

Imaging Diagnostic and Therapeutic Targets - Steroid Receptors in Breast Cancer

Amy M Fowler 1, Amy S Clark 2, John A Katzenellenbogen 3, Hannah M Linden 4, Farrokh Dehdashti 5
PMCID: PMC4795822  NIHMSID: NIHMS766982  PMID: 26834106

Abstract

Estrogen receptor-alpha (ERα) and progesterone receptor (PR) are important steroid hormone receptor biomarkers used to determine prognosis and predict benefit from endocrine therapies for breast cancer patients. Receptor expression is routinely measured in biopsy specimens using immunohistochemistry, although such testing can be challenging particularly in the setting of metastatic disease. ERα and PR can be quantitatively assayed non-invasively with positron emission tomography (PET). This approach provides the opportunity to assess receptor expression and function in “real-time”, within the entire tumor, and across distant sites of metastatic disease. This article reviews the current evidence of ERα and PR PET imaging as predictive and early response biomarkers for endocrine therapy.

Keywords: Breast cancer, Estrogen receptor (ER), Progesterone receptor (PR), Positron emission tomography (PET), Imaging biomarker

Introduction

Over 230,000 women are predicted to be diagnosed with breast cancer in 2015, making it the most common malignancy among women (1). Most of these patients will be diagnosed with curable breast cancer, though 5 to 9% will have metastatic disease at presentation (1). When breast cancer has spread to distant organs, it is mainly incurable and the goal of therapy is palliative. Treatment of metastatic breast cancer is indefinite and therefore therapies that maximize quality and quantity of life are preferred.

The systemic therapy decision for a specific patient is based on the estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status of the patient’s breast cancer (2). At present, receptor testing from tissue obtained from a metastatic biopsy is the standard method of ascertaining the receptor status. If tissue from a metastatic site is not available, receptor status is inferred from the primary breast tumor. For those with tumors expressing ERα and/or PR (greater than 75% of all breast cancers), endocrine therapy is the preferred treatment for the first several lines of therapy. However, only 50 to 75% of patients with ERα positive (ER+) breast cancer will respond to first line endocrine therapy and the response rate decreases with additional lines of therapy with only 25% responding beyond first line (3).

There are a variety of challenges to determining the hormone receptor status of a metastatic tumor. First, the location of the metastatic disease may not be amenable to biopsy (brain or bone, for example) and the treating clinician will be forced to assume that the receptor status in the metastatic disease is the same as the primary breast tumor. However, this assumption is problematic because the receptor status can differ from 25% to 40% of the time between primary breast tumors and metastatic lesions (3–5). Second, even when a bone biopsy can be performed, issues with sample processing of bone specifically (decalcification) can generate false-negative ERα and/or PR results (6). With a false-negative result, the clinician could be led away from using less toxic endocrine therapy to treat the patient. Finally, there is the issue of both intratumor and intertumor heterogeneity (7). Tumor heterogeneity is of particular relevance, because patients generally have more than one site of metastatic disease. Furthermore, not all cancer cells in a tumor will be the same. Biopsy only samples a small portion of one lesion, and it is not feasible to sample each individual metastatic lesion. Thus, practitioners have to assume that the one biopsy represents all of the cancer. These issues underscore the need to develop standard methods of measuring tumor heterogeneity. One method under development that can better assess tumor heterogeneity is imaging using receptor-targeted radiopharmaceuticals.

Noninvasive imaging is a useful approach for visual assessment and quantitative measurement of steroid hormone receptors in both primary breast cancer and across metastatic sites of disease in a patient. The techniques utilized for steroid receptor imaging have focused predominately on 18F-based radiopharmaceuticals and positron emission tomography (PET) alone or, more recently, in combination with computed tomography (PET/CT) for improved anatomic co-localization. PET imaging has an advantage over other nuclear medicine techniques, such as planar imaging or single-photon emission computed tomography, due to its excellent sensitivity to quantify radioligand binding down to picomolar concentrations (8).

Although steroid receptor PET imaging agents have not yet been approved by the United States Food and Drug Administration (FDA), several factors make them attractive candidates for successful translation, implementation, and acceptance into clinical use for breast cancer patients. Patient preparation for steroid receptor imaging is simpler than for conventional PET/CT imaging with 18F-fluorodeoxyglucose (FDG) since fasting and measurement of blood glucose levels prior to scanning are not necessary. Similar to FDG-PET/CT, patients are injected intravenously with the steroid receptor imaging agent and imaged approximately one hour later using static emission data acquisition. Standardized uptake value (SUV) of the steroid receptor imaging agent in a lesion of interest, calculated as radioactivity in the volume of interest (kBq/mL) divided by the injected dose per kg bodyweight (MBq/kg), has been validated through correlation with in vitro receptor expression assays such as 3H-radioligand binding assays and immunohistochemistry (9–11). While more sophisticated uptake measures using dynamic image acquisition and pharmacokinetic modeling have been reported, they have not been proven superior to simpler SUV measurements (10). Ease of patient preparation, image acquisition and analysis are important factors to keep in mind when evaluating new molecular imaging agents for potential use in clinical practice.

Estrogen Receptor Imaging

16α-[18F]-fluoro-17β-estradiol (FES) is the most studied radiopharmaceutical to quantify ERα and has been reported for nearly 1,000 patients participating in clinical trials as of 2013 (12). This radioligand was developed in the 1980’s (13) with the first-in-human study published in 1988 by Mintun et al. (9). FES displays a favorable tissue biodistribution profile with comparable binding affinity to ERα as 17β-estradiol (14). FES uptake (as measured by SUV with imaging) strongly correlates with ERα expression (as measured by radioligand binding in fresh tissue and immunohistochemistry in fixed tissue) (9, 10) as shown in Figure 1. Sensitivity and specificity of FES imaging for detection of ER+ breast cancer are available in four published studies involving 114 patients (9, 10, 15, 16). The overall sensitivity and specificity was 84% (95% CI: 73–91) and 98% (95% CI: 90–100), respectively (12). Thus, FES-PET is a good surrogate measurement of ERα expression.

Figure 1.

Figure 1

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A Phase II Trial of 18F-Fluoroestradiol (FES) as a Marker of First line Endocrine Sensitivity of Metastatic Breast Cancer

FDG and FES PET coronal slices are shown for two patients in the UW FES trial (22). Both patients have mediastinal nodal metastases from ER+ breast cancer. Both had biopsy of a metastatic site. ER uptake is shown by FES in Patient A but not Patient B.

Patient A has FES uptake at multiple sites, and, in fact, sites are more prominent on FES PET than FDG PET, can be seen with well-differentiated breast cancer. Patient B has mediastinal disease clearly seen by FDG PET, but not seen on FES PET. Biopsy showed ER− breast cancer. (FES values are 1.4 and 1.3)

Use of FES as an investigational PET agent has been reported for nearly 1,000 patients participating in clinical trials as of 2013 (12). The Cancer Imaging Program of the National Cancer Institute sponsors an investigational new drug exemption from the FDA (IND 79,005) for FES and freely provides reference materials to the research community to assist investigators with further FES clinical trials (17). They anticipate that data gained from wider utilization of FES may eventually support an FDA New Drug Application (NDA).

FES as a Predictive Biomarker

Baseline FES SUV value has been studied as a predictive biomarker to endocrine therapy in several small studies in patients receiving various endocrine therapies for metastatic ER+ breast cancer. In all of these studies, response was defined by standard clinical criteria based on symptoms and imaging. In early studies from Washington University, Dehdashti et al. studied 11 patients with FES-PET prior to initiation of tamoxifen therapy (18). Response was assessed by the treating clinician at 2 month intervals. The baseline FES SUV of responders was ≥2.2 and ≤1.7 in nonresponders (18). Later, these investigators studied 40 patients with advanced breast cancer before and after tamoxifen therapy and reported responders had higher baseline tumor FES uptake (SUV, 4.3 ± 6 2.4) than those of nonresponders (SUV, 1.8 ± 6 1.3; p = 0.0007) (19). When the SUV cutoff of 2.0 was used, positive-predictive value (PPV) was calculated to be 79% and negative-predictive value (NPV) 88%, slightly better than the previous study. Subsequently, the same investigators examined 51 patients receiving an aromatase inhibitor (AI) or fulvestrant (20). Baseline FES SUV was again noted to be higher in responders (3.5 ± 2.5) than in nonresponders (2.1 ± 1.8). Logistic regression analysis demonstrated a 40% increase in the odds of response for every unit increase in baseline FES SUV. A prospectively defined cut-off SUV of 2 for FES was considered positive for ER expression, above which patients were more likely to respond to AI or fulvestrant therapy. Based on the SUV cutoff of 2.0, PPV and NPV of FES PET was calculated to be 50% and 81% respectively (20). Finally, in a fourth study at the University of Washington of 47 patients, many of whom had previously received tamoxifen therapy and were planned to initiate a different salvage endocrine therapy, baseline FES SUV and response at 6 months was examined (21). In ROC analysis, FES SUV above 1.5 was associated with response to therapy. None of the 15 patients with SUV below the threshold of 1.5 responded to hormonal therapy. On the other hand, 11 of 32 with SUV>1.5 (above the threshold) responded. This was statistically significant with p<0.01. Of note, patients with HER2 positive disease receiving trastuzumab were permitted in this study, however none of these patients were classified as responders (21).

Van Kruchten et al. combined the results of these four studies and determined that lack of response to endocrine therapy was predicted by FES SUV under 1.5 in this heterogeneous group of patients (12). Using the 1.5 threshold, 96 of 114 patients would have been selected to receive endocrine therapy, and 62 of these would have had a clinical benefit (PPV of 65%). Alternatively, of the 42 patients with FES SUV below 1.5, 37 derived no clinical benefit from endocrine therapy (NPV 88%). They also examined a cutoff of 2.0 and found that 31% of patients who responded to endocrine therapy would have been considered FES negative using this cutoff, and thus potentially would not have received the endocrine therapy to which they responded. Finally, a fifth study of 15 patients showed that two of two patients with low baseline FES uptake had progressive disease at 6 months (22). These would imply that a cutoff of 1.5 is most appropriate if using FES-PET as a tool to predict response to endocrine therapy and further would suggest that patients with disease that has FES SUV values below 1.5 should potentially receive cytotoxic therapy rather than endocrine therapy. Before using it in clinical practice, however, larger studies are needed to further refine and validate the threshold cutoff.

A potential advantage of FES imaging is visualization of multiple lesions, and hence appreciation of the true heterogeneity of uptake across the entire body burden of tumor (23). While FES can be measured at multiple tumor sites, uptake in liver is confounded by clearance of the tracer, and as such FES cannot measure tumor uptake at this common site of breast cancer metastasis. As the standard of care is one biopsy sample, little is known about the significance of heterogeneity in predicting response. Further studies are needed to understand the predictive value of knowledge of ER binding at multiple sites.

FES to Monitor Efficacy of Receptor Blockade and Response to Anti-estrogen Therapy

Serial imaging is a standard method of evaluating response to treatment, and FES PET has been evaluated in such a fashion in a few small trials. In the previously discussed trial of 40 patients receiving first line tamoxifen for metastatic ER+ metastatic breast cancer, FES PET was obtained at baseline and 7 to 10 days after initiation of therapy. FES SUV in lesions of responders decreased at the second time point compared to baseline. The percent decrease in FES SUV following 7 to 10 days of tamoxifen in responders was 54.8% ± 14.2% and 19.4 ± 17.3% in nonresponders, p=0.0003. The mean change in FES SUV was also higher among responders (−2.5 +− 1.8) compared to non-responders (−0.5 +− 0.6) (19). These results suggest that an early evaluation following introduction of tamoxifen can help determine who will respond by monitoring the efficacy of tamoxifen to block FES binding to ERα.

A similar approach for determining the optimal dose of ERα antagonists needed for complete suppression of FES uptake in serial imaging has been also demonstrated. Linden et al. reported a retrospective study of patients with metastatic breast cancer and prior ERα+ primary diagnosis undergoing FES PET/CT imaging before and after initiation of salvage endocrine therapy (24). Complete blockade of tumor FES uptake was observed for all patients treated with tamoxifen (5 of 5) but only 36% (4 of 11) of patients treated with fulvestrant (24). They concluded that the dosing of fulvestrant was insufficient for complete ERα inhibition but did not have data on subsequent patient clinical response to correlate. A subsequent prospective study of 16 patients with ER+ metastatic breast cancer treated with the current standard dose of 500 mg intramuscular fulvestrant was performed to measure ERα availability for FES binding before and during therapy (25). Residual FES uptake was observed in 38% (6 of 16) of patients treated with fulvestrant, which was associated with early clinical disease progression (25). Use of FES PET/CT imaging for determining optimal ERα inhibition could also be applied to new drug development and evaluation as reported in a recent scientific meeting abstract for an investigational oral selective estrogen receptor degrader, ARN-810 (26).

Summary

Thus, through its investigation in clinical trials, FES appears to be both a predictive biomarker to identify patients with ERα+ metastatic breast cancer who will respond to endocrine therapy and also a useful tool to assess the pharmacodynamics of endocrine therapy at early time points. Larger studies are necessary to better determine and validate the FES SUV threshold above which clinicians can report response to therapy, and these will also aid in better determination of the sensitivity and specificity of baseline FES SUV values to predict response (27). Such a study is about to open through the Eastern Cooperative Oncology Group/American College of Radiology Imaging Network (ECOG/ACRIN) consortium (NCT02398773), and will enroll patients receiving first line endocrine-based therapy for ER+ metastatic breast cancer.

Progesterone Receptor Imaging

Similar to ERα, prognostic and predictive information can be gained from knowledge of PR status. As such, PR is routinely assayed along with ERα as part of the standard immunohistochemical analysis of newly diagnosed breast cancers and their recurrences (28). Since ERα and PR expression in breast cancer are strongly associated, ERα-negative PR-positive tumors are uncommon and may be caused by a false-negative ERα immunohistochemical result (29). However, endocrine therapy remains a therapeutic option for patients with ERα-negative PR-positive breast cancers.

PR is a classic estrogen-regulated gene whose expression is dependent upon a functional ERα signaling pathway (30). Thus, PR is a pharmacodynamic or early response biomarker; “a downstream biomarker that can be used as a surrogate measure of response to treatment-induced modulation of the upstream signaling components” (31). For example, an increase in PR protein measured on repeat biopsy shortly after initiating tamoxifen resulting from its partial agonist activity correlates with prolonged time to progression and improved survival (32). Supporting this notion is the observation that patients with metastatic ER+PR+ breast cancer are the most likely to benefit from endocrine therapy (33).

The most promising PET agent for imaging PR is 21-18F-fluoro-16α,17α-[(R)-(1′-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione (FFNP). This radioligand was developed in the 1990’s and fulfills several important criteria for effective steroid receptor imaging (34, 35). It has high relative binding affinity to PR, low nonspecific binding, and thus a high binding selectivity index (34, 35). Recently optimized and automated synthesis methods result in a final product with good yield (up to 77%), high radiochemical purity, and high specific activity (1300–8500 mCi/μmol) (36). Tissue biodistribution studies in estrogen-primed female rats demonstrated high PR-selective uptake in the uterus and ovaries (34). Importantly, FFNP exhibits minimal defluorination evidenced by low bone uptake and is less prone to metabolism by dehydrogenases which was the major factor in the unsuccessful application of an earlier PR imaging agent, 21-18F-fluoro-16 α-ethyl-19-norprogesterone (FENP), in humans (37).

FFNP to Monitor Response to Endocrine Therapy

The hypothesis that imaging changes in PR can be an early response biomarker indicative of treatment-induced changes of upstream ER signaling pathway has been tested in preclinical breast cancer models (38, 39). These studies demonstrate that an early decrease in tumoral FFNP uptake predicts responsiveness to fulvestrant and estrogen-deprivation therapy. Decreases in FFNP uptake occurred prior to changes in tumor growth. Further, monitoring ERα function through imaging PR with longitudinal FFNP-PET was more predictive of response to estrogen-deprivation therapy than FES-PET and FDG-PET imaging (39). These preclinical data provide the proof-of-principle to support further translational studies in breast cancer patients.

The first-in-human study of FFNP was published in 2012 and demonstrated safety and dosimetry data in 20 women with breast cancer (11), see example figure 2. No adverse or pharmacologic effects of the injected mass dose (1.34±1.24 μg) were observed. The whole-body effective dose for FFNP was 0.020 mSv/MBq, which is similar to FES (0.022 mSv/MBq) and FDG (0.024 mSv/Bq) (11, 40, 41). Similar to FES, FFNP is eliminated by hepatobiliary clearance. Thus, evaluation of FFNP uptake in liver lesions is a potential limitation.

Figure 2.

Figure 2

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FFNP detects PgR + tumors

Representative transverse CT (left) and fused FFNP-PET/CT (right) images in a patient with a progesterone-receptor positive (PR+) breast cancer demonstrate focally increased uptake in the known left breast cancer (arrows).

In addition to investigating safety and dosimetry, correlation of FFNP uptake with in vitro PR measurement via immunohistochemistry was performed by Dehdashti et al (11). In their patient population with 16 PR+ and 6 PR− primary breast cancers, tumor-to-normal breast tissue uptake ratios (T/N) of FFNP were greater in PR+ cancers (2.6±0.9) compared to PR− cancers (1.5±0.3; p=0.001) (11). Dynamic imaging demonstrated rapid FFNP uptake within the PR+ tumor and no significant washout over the 60 minute imaging interval (11). Thus, FFNP-PET can be safely used in patients to assess the PR status of breast cancer.

Investigations into the utility of FFNP-PET as an early response biomarker for endocrine therapy are currently in progress. The clinical trial, NCT02455453, aims to measure FFNP uptake before and after administration of estradiol for one day (“estradiol challenge”) for postmenopausal patients with ERα+ breast cancer to determine if the change in FFNP uptake is predictive of response to endocrine therapy. Furthermore, preclinical studies have demonstrated that FFNP uptake of hormone-sensitive mouse mammary tumors increases in response to estradiol treatment (38).

Summary

Clinical studies of PR PET imaging significantly lag behind those of ERα and considerable work is still required before FFNP is ready for translation into clinical practice. Larger scale investigations into the sensitivity and specificity of FFNP PET for detection of PR and its utility as an early response biomarker for endocrine therapy are needed with subsequent validation through multi-institutional studies. Comparison of the performance of FFNP with 18F- and 11C-radiolabeled Tanaproget, a non-steroidal progestin analog with in vitro and preclinical data demonstrating high binding affinity for PR and less cross reactivity with glucocorticoid and androgen receptors, could also be considered (42–44).

Future Directions

Combined ERα and PR imaging

Information gained from imaging with both FES and FFNP could result in the highest predictive power for endocrine therapy response. A baseline FES-PET would determine if the therapeutic target (ERα) is present in some, most or all of a patient’s metastatic lesions; thus, it can provide important information regarding tumor heterogeneity. The strength of ERα imaging with FES is its high NPV (88%); i.e., if FES SUV is less than 1.5, patients are very unlikely to have clinical benefit from endocrine therapy (12). However, the PPV of FES-PET is only 65% (12). Thus, the presence of ERα capable of binding to FES does not guarantee its function. Baseline and short follow-up FFNP-PET imaging after endocrine therapy initiation or estradiol challenge may be helpful as a probe of PR expression to confirm a functional ERα-driven pathway. However, a drawback of using 18F-radioligands for this approach is the inability to perform multiplex molecular imaging thus requiring repeat, longitudinal PET-CT studies which raises potential concerns regarding radiation exposure. Fortuitously, simultaneous PET-magnetic resonance imaging (MRI) scanners have recently been developed for clinical use which can reduce radiation exposure by eliminating the CT component of the examination and thus be a more suitable modality for serial imaging for therapy response assessment.

Steroid receptor imaging in the era of personalized cancer medicine

Evidence is increasing regarding the complementary role of targeted therapy of growth factor activation and cell-cycle control pathways with endocrine therapy for patients with recurrent or metastatic breast cancer and indications for this approach have been recently incorporated into clinical practice guidelines (2, 45). These include everolimus, an inhibitor of the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, in combination with exemestane, a steroidal aromatase enzyme inactivator, and palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in combination with fulvestrant or letrozole, a non-steroidal aromatase inhibitor. The ability of steroid receptor imaging to predict response to these types of combined endocrine and molecular pathway-targeted therapies will need to be investigated.

In this emerging era of precision medicine and “big data”, how information gained from molecular imaging is best integrated with “omics”-level tissue data will also need to be considered. For breast cancer, these assays include measuring the overall gene expression pattern for molecular subtyping (46), measuring a subset of 21 genes to quantify the likelihood of distant recurrence in tamoxifen-treated patients with axillary lymph node-negative, ERα+ primary breast cancer (47), and whole genome sequencing of metastatic tumor samples to identify “druggable” gene mutations (48). An approach that incorporates molecular imaging with genomics tissue data may improve the overall clinical utility of the individual tests. A multidisciplinary approach, such as a molecular genomics/imaging tumor board, would be the ideal setting for guiding clinical decision-making particularly for patients with progressive metastatic breast cancer.

Footnotes

Financial support: N/A

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