Small-animal PET of steroid hormone receptors predicts tumor response to endocrine therapy using a preclinical model of breast cancer.
Small-animal PET of steroid hormone receptors predicts tumor response to endocrine therapy using a preclinical model of breast cancer.
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DOI：
10.2967/jnumed.112.103465
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Welch MJ
中科院分区：
文献类型：
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作者：
Fowler AM;Chan SR;Sharp TL;Fettig NM;Zhou D;Dence CS;Carlson KE;Jeyakumar M;Katzenellenbogen JA;Schreiber RD;Welch MJ
雌激素受体-α（ERα）和孕激素受体（PR）在大多数人乳腺癌中表达，是指导治疗的重要预测因素。由于对内分泌治疗的新发和获得性耐药，仍然需要确定哪些ERα阳性（ERα+）/PR阳性（PR+）肿瘤最有可能缓解。本研究的目的是使用基于雌激素和孕激素的放射性药物对基线和激素治疗后小鼠乳腺肿瘤中的ERα和PR进行成像，并确定这些成像生物标志物的变化是否可以作为治疗反应的早期预测指标。使用在信号转导和转录激活因子-1（STAT 1）缺陷的老年雌性小鼠中自发发展的乳腺腺癌。对原发性荷瘤小鼠和植入源自原发性STAT 1缺陷（STAT 1 −/−）肿瘤的乳腺细胞系（SSM 1、SSM 2和SSM 3）的小鼠进行ERα和PR成像。激素治疗包括雌激素受体激动剂雌二醇、芳香酶抑制剂来曲唑和纯雌激素受体拮抗剂氟维司群。小动物PET/CT使用18 F-氟雌二醇（18 F-FES）进行ER，18 F-氟呋喃去甲孕酮（18 F-FFNP）进行PR，18 F-FDG进行葡萄糖摄取。肿瘤中的示踪剂摄取被定量，并与通过切除肿瘤的体外测定确定的受体浓度进行比较。原发性STAT 1 −/−乳腺肿瘤和植入性SSM 2和SSM 3肿瘤显示高18F-FES和18F-FFNP摄取，并被证实为ERα+/PR+。雌二醇处理的SSM 3肿瘤的18F-FFNP摄取增加证明了经典的雌激素诱导的孕酮受体基因调节。氟维司群治疗降低了18F-FFNP、18F-FES和18F-FDG摄取，并抑制了SSM 3肿瘤的生长，但仅降低了SSM 2肿瘤的18F-FES摄取，对生长无影响，尽管两种肿瘤均为ERα+/PR+。SSM 3肿瘤的18F-FFNP摄取减少发生在治疗开始后早期，在可测量的肿瘤生长抑制之前。使用小动物PET，确定了在肿瘤大小变化之前区分氟维司群敏感性和氟维司群耐药ERα+/PR+肿瘤的特征。这项工作表明，成像基线肿瘤18F-FES摄取和18F-FFNP摄取的初始变化，以非侵入性的方式是一个潜在的有用的策略，以确定响应者和无响应者内分泌治疗的早期阶段。
Estrogen receptor-α (ERα) and progesterone receptor (PR) are expressed in most human breast cancers and are important predictive factors for directing therapy. Because of de novo and acquired resistance to endocrine therapy, there remains a need to identify which ERα-positive (ERα+)/PR-positive (PR+) tumors are most likely to respond. The purpose of this study was to use estrogen- and progestin-based radiopharmaceuticals to image ERα and PR in mouse mammary tumors at baseline and after hormonal therapy and to determine whether changes in these imaging biomarkers can serve as an early predictive indicator of therapeutic response. Mammary adenocarcinomas that spontaneously develop in aged female mice deficient in signal transducer and activator of transcription-1 (STAT1) were used. Imaging of ERα and PR in primary tumor–bearing mice and mice implanted with mammary cell lines (SSM1, SSM2, and SSM3) derived from primary STAT1-deficient (STAT1−/−) tumors was performed. Hormonal treatments consisted of estradiol, an ER agonist; letrozole, an aromatase inhibitor; and fulvestrant, a pure ER antagonist. Small-animal PET/CT was performed using 18F-fluoroestradiol (18F-FES) for ER, 18F-fluoro furanyl norprogesterone (18F-FFNP) for PR, and 18F-FDG for glucose uptake. Tracer uptake in the tumor was quantified and compared with receptor concentration determined by in vitro assays of resected tumors. Primary STAT1−/− mammary tumors and implanted SSM2 and SSM3 tumors showed high 18F-FES and 18F-FFNP uptake and were confirmed to be ERα+/PR+. Classic estrogen-induced regulation of the progesterone receptor gene was demonstrated by increased 18F-FFNP uptake of estradiol-treated SSM3 tumors. Treatment with fulvestrant decreased 18F-FFNP, 18F-FES, and 18F-FDG uptake and inhibited growth of SSM3 tumors but decreased only 18F-FES uptake in SSM2 tumors, with no effect on growth, despite both tumors being ERα+/PR+. Decreased 18F-FFNP uptake by SSM3 tumors occurred early after initiation of treatment, before measurable tumor growth inhibition. Using small-animal PET, a profile was identified that distinguished fulvestrant-sensitive from fulvestrant-resistant ERα+/PR+ tumors before changes in tumor size. This work demonstrates that imaging baseline tumoral 18F-FES uptake and initial changes in 18F-FFNP uptake in a non-invasive manner is a potentially useful strategy to identify responders and nonresponders to endocrine therapy at an early stage.