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Longitudinal Noninvasive Imaging of Progesterone Receptor As a Predictive Biomarker of Tumor Responsiveness to Estrogen Deprivation Therapy Szeman Ruby Chan1, Amy M

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Longitudinal Noninvasive Imaging of Progesterone Receptor As a Predictive Biomarker of Tumor Responsiveness to Estrogen Deprivation Therapy Szeman Ruby Chan1, Amy M Published OnlineFirst December 17, 2014; DOI: 10.1158/1078-0432.CCR-14-1715 Personalized Medicine and Imaging Clinical Cancer Research Longitudinal Noninvasive Imaging of Progesterone Receptor as a Predictive Biomarker of Tumor Responsiveness to Estrogen Deprivation Therapy Szeman Ruby Chan1, Amy M. Fowler2, Julie A. Allen1, Dong Zhou3, Carmen S. Dence3, Terry L. Sharp3, Nicole M. Fettig3, Farrokh Dehdashti3, and John A. Katzenellenbogen4 Abstract Purpose: To investigate whether longitudinal functional PET gen-deprivation therapy compared with those at pretreatment. In imaging of mammary tumors using the radiopharmaceuticals contrast, estrogen-deprivation therapy led to a reduction in PgR [18F]FDG (to measure glucose uptake), [18F]FES [to measure expression and [18F]FFNP uptake in endocrine-sensitive tumors, estrogen receptor (ER) levels], or [18F]FFNP [to measure proges- but not in endocrine-resistant tumors, as early as 3 days after terone receptor (PgR) levels] is predictive of response to estrogen- treatment; the changes in PgR levels were confirmed by IHC. deprivation therapy. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone Experimental Design: [18F]FDG, [18F]FES, and [18F]FFNP blocked [18F]FFNP tumor uptake, indicating that [18F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors bound specifically to PgR. Therefore, a reduction in FFNP tumor was quantified serially by PET before ovariectomy or estrogen to muscle ratio in mammary tumors predicts sensitivity to estro- withdrawal in mice, and on days 3 and 4 after estrogen-depriva- gen-deprivation therapy. þ tion therapy. Specificity of [18F]FFNP uptake in ERa mammary Conclusions: Monitoring the acute changes in ERa activity by tumors was determined by competition assay using unlabeled measuring [18F]FFNP uptake in mammary tumors predicts tumor ligands for PgR or glucocorticoid receptor (GR). PgR expression response to estrogen-deprivation therapy. Longitudinal noninva- was also assayed by immunohistochemistry (IHC). sive PET imaging using [18F]FFNP is a robust and effective Results: The levels of [18F]FES and [18F]FDG tumor uptake approach to predict tumor responsiveness to endocrine treatment. remained unchanged in endocrine-sensitive tumors after estro- Clin Cancer Res; 21(5); 1063–70. Ó2014 AACR. Introduction assayed using immunohistochemistry (IHC). HER2 amplifica- tion is also frequently detected by fluorescence in situ hybrid- Breast cancer is the second most deadly cancer for women in ization. However, discordance rates ranging from 9% to 39% the United States. About 80% of all newly diagnosed breast þ þ were observed for PgR, depending on the techniques used to cancers are classified as estrogen receptor-a (ERa ; ref. 1). ERa, obtain biopsy specimens (2). This discrepancy can be partly together with progesterone receptor (PgR) and HER2, is part of explained by tumor heterogeneity leading to sampling error the standardized clinicopathologic evaluation of breast cancer. during biopsy (3). Therefore, noninvasive functional imaging Because they provide important information to guide treatment of the whole lesion using positron emission tomography (PET) decisions, accurate and reproducible assessment of the levels of may provide a more complete molecular characterization of the these biomarkers is critical. ERa, PgR, and HER2 are routinely tumor in its native setting. In addition, PET imaging is also an effective approach to monitor advanced metastatic disease dur- ing antitumor therapy when repeated biopsies may not be 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri. 2Department of Radiology, possible. 18 18 18 University of Wisconsin School of Medicine and Public Health, Madi- [ F]Fluoroestradiol ([ F]FES) and [ F]fluoro furanyl norpro- son, Wisconsin. 3Division of Radiological Sciences, Edward Mallinck- gesterone ([18F]FFNP) are well-validated noninvasive molecular rodt Institute of Radiology,Washington University School of Medicine, 4 imaging radiopharmaceuticals for ERa and PgR, respectively St. Louis, Missouri. Department of Chemistry, University of Illinois at 18 Urbana-Champaign, Urbana, Illinois. (4, 5). [ F]FES is an estradiol analog that binds to ERa with high affinity and selectivity (6). Differences in FES uptake in Corresponding Authors: Szeman Ruby Chan, Department of Pathology and Immunology, Washington University School of Medicine, 425 S. Euclid Avenue, multiple tumor sites within the same patient have demonstrated St. Louis, Missouri 63110. Phone: 314-362-8746; Fax: 314-747-0809; E-mail: heterogeneity of metastases and highlight the value of using [email protected]; and John A. Katzenellenbogen, Department of functional PET imaging to monitor changes in tumor character- Chemistry, University of Illinois, 600 S. Mathews Avenue, 461 RAL, Box 37-5, istics with disease progression (7). In addition, tumor FES uptake Urbana, IL 61801. Phone: 217-333-6310; Fax: 217 333 7325; E-mail: before endocrine treatment is correlated with subsequent clinical [email protected] response to therapy (8–10). Finally, blockade of tumor FES doi: 10.1158/1078-0432.CCR-14-1715 uptake after the initiation of tamoxifen or fulvestrant treatment Ó2014 American Association for Cancer Research. is indicative of the pharmacodynamic effectiveness of the dosing www.aacrjournals.org 1063 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst December 17, 2014; DOI: 10.1158/1078-0432.CCR-14-1715 Chan et al. to assess tumor responsiveness before surgery and to guide Translational Relevance treatment strategies after surgery, our findings that FFNP-PET is Although endocrine therapies are the standard-of-care for more effective than FES-PET and FDG-PET in predicting endo- þ patients with estrogen receptor-alpha-positive (ERa ) breast crine responsiveness provide strong support for noninvasive cancer, about half of the patients do not benefit from these functional imaging as an informative imaging modality. treatments due to intrinsic or acquired resistance. Therefore, biomarkers that predict tumor responsiveness to endocrine Materials and Methods therapies are highly valuable for identifying patients who will require alternative treatments. Noninvasive functional PET Cell cultures þ þ À À imaging offers a unique opportunity to serially follow the The maintenance of the ERa PgR STAT1 / mammary tumor molecular changes in tumors in response to therapies. Using cell lines SSM2 and SSM3 has been described (15). MCF7 breast þ preclinical models of ERa breast cancer, we demonstrated cancer cells from Benita Katzenellenbogen (University of Illinois) þþ that a significant reduction in binding of [18F]FFNP to pro- were maintained in Improved MEM Zinc Option with phenol gesterone receptor predicts a positive tumor response to estro- red supplemented with 5% heat-inactivated bovine calf serum gen-deprivation therapy. In contrast, [18F]FES or [18F]FDG and 5 nmol/L estradiol. uptake by tumors remained unchanged, suggesting that ERa expression and glucose metabolism were not acutely affected Mice by estrogen deprivation. Thus, measurement of ERa function Six to 8-week-old wild-type (WT) 129S6/SvEv mice and athy- by longitudinal FFNP-PET imaging provides a more robust mic nude-Foxn1nu mice were purchased from Taconic Farms and biomarker for response to endocrine deprivation therapies the National Cancer Institute, respectively, and maintained on an than measurement of ERa level by FES-PET. estrogen-free diet (Harlan Teklad). A total of 1.2 Â 106 of SSM2 or SSM3 tumor cells were transplanted into the right thoracic mam- mary fat pads of WT mice. Nude mice were ovariectomized, fed drinking water supplemented with 10 mg/mL 17[b]-estradiol for 7 days, and subsequently transplanted with 5 Â 106 MCF7 cells. schedule (11). Together, these approaches underscore the utilities Tumors were measured with calipers at two perpendicular dia- of functional FES-PET. meters every 3 to 4 days and the average diameters were used for Although pretreatment ERa expression, as measured by IHC or analyses. Tumor-bearing mice were ovariectomized when the FES-PET, is predictive for response to endocrine therapies, about SSM2 or SSM3 tumors measured about 5 mm in diameter. All þ þ 40% to 60% of ERa or FES-PET patients do not derive long- animal experiments were carried out according to the guidelines term benefits from endocrine treatment (8, 12). Because PgR of the American Association for Laboratory Animal Science under expression is directly upregulated by activation of ERa signaling, an approved protocol by the Animal Studies Committees and we hypothesize that monitoring PgR expression before and during performed in AAALAC-accredited specific pathogen-free facilities therapy might provide insights into the functional status of ERa at Washington University School of Medicine in St. Louis. activation and thus the susceptibility of the tumor cells to respond to antiestrogens or estrogen deprivation therapies. [18F]FFNP Radiopharmaceuticals, biodistribution assay, and binds PgR with high affinity, and targets PgR-rich, but not small-animal mPET/CT PgR-poor, organs with high selectivity (13). In clinical studies, [18F]FDG was provided by the Cyclotron Facility at Washington the ratio of FFNP uptake in the primary breast cancer lesion over University School of Medicine in St. Louis. [18F]FES and the contralateral normal breast is closely correlated with results [18F]FFNP
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