The Department of Internal Medicine, University of Kentucky, Lexington, KY, USA,
Breast Cancer Res Treat. 2014 Jan;143(2):325-32. doi: 10.1007/s10549-013-2810-9. Epub 2013 Dec 11.
Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45-85). Prior therapy included tamoxifen (81 %), chemotherapy (71 %), with 26 % of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95 % CI 1.9-12.1) with an objective response rate of 13 % and CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.
氟维司群可降解 ER，在转移性乳腺癌中 AI 治疗失败后使用，但耐药性很快发展。我们假设使用依维莫司抑制 mTOR，这是内分泌耐药的关键信号通路，可能会延迟氟维司群耐药的发生，从而提高其疗效。我们进行了一项 II 期临床试验，评估氟维司群联合依维莫司在 AI 治疗后疾病进展或复发的绝经后妇女中的疗效。主要终点是无进展生存期（TTP），次要终点包括客观缓解率、临床获益率（CBR）、安全性和生物标志物相关性。收集肿瘤块，并对可获得的肿瘤进行活检，以便进行未来的生物标志物分析。共招募了 33 名患者，其中 2 名在入组后被判定为不符合条件，被排除在研究分析之外，共有 31 名可评估的患者。中位年龄为 54 岁（范围 45-85 岁）。既往治疗包括他莫昔芬（81%）、化疗（71%），26%的患者接受了 3 种或更多的内分泌治疗。中位 TTP 为 7.4 个月（95%CI 1.9-12.1），客观缓解率为 13%，临床获益率为 49%。值得注意的是，32%的患者对研究治疗表现出新发耐药性，疾病进展是其最佳反应。最常见的不良事件（AE）是 AST 升高（87%）和 ALT 升高（77%）、贫血（74%）、高血糖（71%）和高胆固醇血症（68%）。突出的临床毒性是粘膜炎（58%）、体重减轻（48%）和皮疹（42%）。大多数 AE 为 1 级或 2 级，且与 everolimus 剂量减少的需要频率低，具有较高的可逆转性。总之，氟维司群联合依维莫司在 AI 治疗失败的转移性 ER 阳性乳腺癌中是有效的，且毒性可管理。在随机研究中，进一步研究该联合方案是合理的。鉴于并非所有患者均受益，且鉴于潜在毒性，生物标志物检查对于帮助选择最有可能从该策略中获益的患者至关重要，这将是未来研究的重点。
