Chen Nan, Matossian Margarite, Saha Poornima, Rampurwala Murtuza, Kamaraju Salaija, Hahn Olwen, Howard Frederick M, Fleming Gini F, Freeman Jincong Q, Karrison Theodore, Conzen Suzanne, Nanda Rita, Stringer-Reasor Erica M
Department of Medicine Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
Department of Medicine, NorthShore University Health System, Evanston, IL, USA.
Breast Cancer Res Treat. 2025 May;211(1):111-119. doi: 10.1007/s10549-025-07626-5. Epub 2025 Feb 10.
Glucocorticoid receptor (GR) activity may mediate chemoresistance in advanced triple-negative breast cancer (TNBC). Preclinical studies demonstrate that GR antagonism can augment the effect of taxanes in TNBC models. We hypothesized that pretreatment with mifepristone, a potent GR antagonist, would enhance nab-paclitaxel efficacy in advanced TNBC.
This trial was terminated early due to poor accrual. 29 of 64 planned patients were enrolled. Patients were randomized to receive nab-paclitaxel with or without mifepristone; oral mifepristone 300 mg was administered the day prior and day of each dose of nab-paclitaxel. The primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included response rate and correlation of response with GR expression.
The addition of mifepristone to nab-paclitaxel did not improve PFS (3.0 m vs 3.0 m, p = 0.687) or overall response rate (23% vs 31.5%) compared to nab-paclitaxel alone. There was a trend towards improved overall survival in the combination group, primarily driven by one long-term responder. Increased rates of grade 3 neutropenia (46% vs 7%) and febrile neutropenia were observed in the combination arm, while other toxicities were similar in both groups. Increased GR expression was not correlated with clinical response in the combination arm.
While there were responders to the combination, the study was underpowered to meet the primary endpoint. Higher rates of neutropenia were observed in the combination, but overall it was well tolerated. Preclinical data in TNBC and clinical data in other malignancies support further investigation of GR modulators. Future studies should incorporate biomarkers to select patients who benefit from GR inhibition.
糖皮质激素受体（GR）活性可能介导晚期三阴性乳腺癌（TNBC）的化疗耐药。临床前研究表明，GR拮抗作用可增强紫杉烷类药物在TNBC模型中的疗效。我们假设，用强效GR拮抗剂米非司酮进行预处理会增强纳米白蛋白结合型紫杉醇在晚期TNBC中的疗效。
由于入组情况不佳，该试验提前终止。计划入组的64例患者中有29例入组。患者被随机分为接受纳米白蛋白结合型紫杉醇联合或不联合米非司酮治疗；在每次纳米白蛋白结合型紫杉醇给药前一天及给药当天口服300 mg米非司酮。主要终点是无进展生存期（PFS）；次要/探索性终点包括缓解率以及缓解与GR表达的相关性。
与单独使用纳米白蛋白结合型紫杉醇相比，在纳米白蛋白结合型紫杉醇中添加米非司酮并未改善PFS（3.0个月对3.0个月，p = 0.687）或总缓解率（23%对31.5%）。联合治疗组有总体生存期改善的趋势，主要由一名长期缓解者推动。联合治疗组3级中性粒细胞减少症（46%对7%）和发热性中性粒细胞减少症的发生率增加，而两组的其他毒性反应相似。联合治疗组中GR表达增加与临床缓解无关。
虽然联合治疗有缓解者，但该研究的效能不足以达到主要终点。联合治疗组中中性粒细胞减少症的发生率较高，但总体耐受性良好。TNBC的临床前数据和其他恶性肿瘤的临床数据支持对GR调节剂进行进一步研究。未来的研究应纳入生物标志物，以选择能从GR抑制中获益的患者。
