摘要:来曲唑联合PR激动剂醋酸甲地孕酮与来曲唑单独治疗绝经后er阳性乳腺癌患者的术前窗口研究

S. Kumar, J. Benson, S. McIntosh, P. King, G. Dougall, A. Kateb, A. Vallier, L. Jones, W. Qian, E. Provenzano, C. Caldas, P. Pantziarka, J. Carroll, R. Baird
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There is also good evidence for the effectiveness of MA as a supportive therapy to ameliorate endocrine therapy-related hot flushes. Trial design: PIONEER is a three-arm, open label, multi-centre randomized phase II pre-surgical window trial evaluating effects of 15 days of preoperative therapy with Letrozole (LET), or LET plus MA 40mg, or LET plus MA 160mg in postmenopausal women with ER+ HER2- invasive primary BC. Eligibility criteria: Inclusion Criteria Postmenopausal women with histologically confirmed invasive BC, ≥T1c, clinical NX or N0-N3, ER+ (Allred≥3), and HER2- 2 groups of patients are potentially eligible: Cohort A: Patients whose cancers have been deemed to be operable by the Multi-Disciplinary Team (MDT) with surgery planned for the next 2-6 weeks Cohort B: Patients with early or locoregionally advanced BC planned for primary endocrine therapy either in lieu of surgery or as neoadjuvant therapy before surgery\n ECOG performance status of 0-2 Adequate Liver, Renal, Bone marrow function Exclusion Criteria Hormone replacement therapy in the last 6 months Treatment with tamoxifen or an aromatase inhibitor (AI) in the last 6 months A progestogen-containing intrauterine system in situ, unless removed prior to randomisation Metastatic disease on presentation Recurrent BC (patients with a new primary invasive BC are eligible) S p ecific aims: The primary endpoint is % change in proliferation between baseline and day 15 tumor biopsies, measured by Ki67 IHC assessment. Secondary endpoints include: expression of Aurora Kinase A, Caspase 3 and AR/PR/EMT markers by IHC; and safety endpoints. Exploratory endpoints: transcription factor mapping (ChIP-seq) and identification of differential ERa-associated proteins (RIME) on paired fresh-frozen tumor samples. PIONEER will help determine whether there is value in conducting a Phase III adjuvant study to investigate the longer term benefit of combining an AI with MA, and if so, at what dose (40mg vs. 160mg). Statistical methods: Patients are randomized in a 1:1.5:1.5 ratio into arms A:B:C. Based on results from previous clinical trials, a mean 66% reduction in Ki67 is anticipated for LET alone (arm A), and a 77.5% reduction for the combination arms B and C, based on preclinical data. Present and target accrual: Patients are being recruited in Cambridge, Cornwall, Belfast & London with 6 other UK sites due to open q3/4 2018. At the time of submission, 29 patients had been recruited. A recruitment total of 189 patients is required. Citation Format: Kumar SS, Benson J, McIntosh S, King P, Dougall G, Kateb A, Vallier A-L, Jones L, Qian W, Provenzano E, Caldas C, Pantziarka P, Carroll J, Baird RD. PIONEER- Pre-operative wIndOw study of letrozole plus PR agonist megestrol acetate versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. 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引用次数: 0

摘要

背景:已发表的临床前研究结果为乳腺癌(BC)中雌激素受体(ER)和孕激素受体(PR)之间的功能性交叉对话提供了新的见解(Mohammed et al., Nature, 2015)。在抗雌激素中加入PR激动剂可直接改变乳腺癌细胞中的ERa染色质结合和转录反应,并在体外和体内具有抗增殖作用。醋酸甲地孕酮(MA)是一种未获专利的孕酮半合成衍生物,多年来一直被许可用于ER+转移性BC的治疗。也有很好的证据表明,MA作为一种支持治疗的有效性,以改善内分泌治疗相关的潮热。试验设计:PIONEER是一项三组、开放标签、多中心随机II期术前窗口试验,评估绝经后ER+ HER2侵袭性原发性乳腺癌患者术前15天来曲唑(LET)、LET + MA 40mg或LET + MA 160mg治疗的效果。绝经后经组织学证实浸润性BC,≥T1c,临床NX或N0-N3, ER+ (Allred≥3)和HER2- 2组患者可能符合条件:队列A:多学科团队(MDT)认为癌症可手术,计划在未来2-6周进行手术的患者早期或局部进展性BC患者术前计划进行初级内分泌治疗替代手术或作为新辅助治疗ECOG表现0-2肝、肾、骨髓功能正常排除标准最近6个月激素替代治疗最近6个月使用他莫昔芬或芳香化酶抑制剂(AI)原位含孕激素宫内系统除非在随机化之前切除转移性疾病复发性BC(新的原发性浸润性BC患者符合条件)S p特定目的:主要终点是基线和第15天肿瘤活检之间增殖变化的百分比,通过Ki67 IHC评估测量。次要终点包括:IHC中极光激酶A、Caspase 3和AR/PR/EMT标志物的表达;还有安全端点。探索终点:转录因子定位(ChIP-seq)和鉴定配对新鲜冷冻肿瘤样品上的差异era相关蛋白(RIME)。PIONEER将帮助确定进行III期辅助研究是否有价值,以调查AI与MA联合使用的长期益处,如果有,剂量是多少(40mg vs 160mg)。统计学方法:将患者按1:1.5:1.5的比例随机分为a:B:C组。根据先前的临床试验结果,根据临床前数据,预计单独使用LET (a组)的Ki67平均降低66%,联合使用B和C组的Ki67平均降低77.5%。目前和目标收益:在剑桥、康沃尔、贝尔法斯特和伦敦招募患者,其他6个英国站点将于2018年3/4季度开放。在提交时,已经招募了29名患者。总共需要招募189名患者。引文格式:Kumar SS, Benson J, McIntosh S, King P, Dougall G, Kateb A, Vallier A-L, Jones L, Qian W, Provenzano E, Caldas C, Pantziarka P, Carroll J, Baird RD. PIONEER-绝经后雌激素受体阳性乳腺癌患者来曲唑联合PR受体拮抗剂乙酸甲地孕酮的术前窗口研究[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志,2019;79(4增刊):01- 01-07。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract OT1-01-07: PIONEER- Pre-operative wIndOw study of letrozole plus PR agonist megestrol acetate versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer
Background: Published preclinical findings provided new insights into the functional 9cross-talk9 between the oestrogen receptor (ER) and the progesterone receptor (PR) in breast cancer (BC) (Mohammed et al., Nature, 2015). Addition of a PR agonist to anti-oestrogens directly modifies ERa chromatin binding and the transcriptional response in breast cancer cells, and is anti-proliferative in vitro and in vivo . Megestrol Acetate (MA), an off-patent semi-synthetic derivative of progesterone, has been licensed for many years as treatment for ER+ metastatic BC. There is also good evidence for the effectiveness of MA as a supportive therapy to ameliorate endocrine therapy-related hot flushes. Trial design: PIONEER is a three-arm, open label, multi-centre randomized phase II pre-surgical window trial evaluating effects of 15 days of preoperative therapy with Letrozole (LET), or LET plus MA 40mg, or LET plus MA 160mg in postmenopausal women with ER+ HER2- invasive primary BC. Eligibility criteria: Inclusion Criteria Postmenopausal women with histologically confirmed invasive BC, ≥T1c, clinical NX or N0-N3, ER+ (Allred≥3), and HER2- 2 groups of patients are potentially eligible: Cohort A: Patients whose cancers have been deemed to be operable by the Multi-Disciplinary Team (MDT) with surgery planned for the next 2-6 weeks Cohort B: Patients with early or locoregionally advanced BC planned for primary endocrine therapy either in lieu of surgery or as neoadjuvant therapy before surgery ECOG performance status of 0-2 Adequate Liver, Renal, Bone marrow function Exclusion Criteria Hormone replacement therapy in the last 6 months Treatment with tamoxifen or an aromatase inhibitor (AI) in the last 6 months A progestogen-containing intrauterine system in situ, unless removed prior to randomisation Metastatic disease on presentation Recurrent BC (patients with a new primary invasive BC are eligible) S p ecific aims: The primary endpoint is % change in proliferation between baseline and day 15 tumor biopsies, measured by Ki67 IHC assessment. Secondary endpoints include: expression of Aurora Kinase A, Caspase 3 and AR/PR/EMT markers by IHC; and safety endpoints. Exploratory endpoints: transcription factor mapping (ChIP-seq) and identification of differential ERa-associated proteins (RIME) on paired fresh-frozen tumor samples. PIONEER will help determine whether there is value in conducting a Phase III adjuvant study to investigate the longer term benefit of combining an AI with MA, and if so, at what dose (40mg vs. 160mg). Statistical methods: Patients are randomized in a 1:1.5:1.5 ratio into arms A:B:C. Based on results from previous clinical trials, a mean 66% reduction in Ki67 is anticipated for LET alone (arm A), and a 77.5% reduction for the combination arms B and C, based on preclinical data. Present and target accrual: Patients are being recruited in Cambridge, Cornwall, Belfast & London with 6 other UK sites due to open q3/4 2018. At the time of submission, 29 patients had been recruited. A recruitment total of 189 patients is required. Citation Format: Kumar SS, Benson J, McIntosh S, King P, Dougall G, Kateb A, Vallier A-L, Jones L, Qian W, Provenzano E, Caldas C, Pantziarka P, Carroll J, Baird RD. PIONEER- Pre-operative wIndOw study of letrozole plus PR agonist megestrol acetate versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-07.
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