Department of Medical Oncology, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
Breast Cancer Res. 2020 Nov 2;22(1):120. doi: 10.1186/s13058-020-01354-y.
BACKGROUND: Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer. METHODS: This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies. RESULTS: Fifty patients were enrolled. Median number of cycles was 2 (range 1-10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6-2.3). Median OS was 11.2 months (95% CI 6.2-25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease. CONCLUSIONS: Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer. TRIAL REGISTRATION: NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.
背景：三阴性乳腺癌的治疗选择仍然有限。PI3K 通路的激活通过缺失 PTEN 和/或 INPP4B 是常见的。Buparlisib 是一种口服生物利用的、泛 I 类 PI3K 抑制剂。我们评估了 buparlisib 对转移性三阴性乳腺癌患者的安全性和疗效。
方法：这是一项单臂 2 期研究，纳入了三阴性转移性乳腺癌患者。患者以 100mg 每日的起始剂量接受 buparlisib 治疗。主要终点是临床获益，定义为根据 RECIST 1.1 确认完全缓解（CR）、部分缓解（PR）或稳定疾病（SD）≥4 个月。次要终点包括无进展生存期（PFS）、总生存期（OS）和毒性。一部分患者在治疗前和治疗期间进行肿瘤组织活检，进行相关研究。
结果：共纳入 50 例患者。中位数治疗周期数为 2 个（范围 1-10）。临床获益率为 12%（6 例患者，均为 SD 持续≥4 个月）。中位 PFS 为 1.8 个月（95%置信区间[CI]1.6-2.3）。中位 OS 为 11.2 个月（95%CI6.2-25）。最常见的不良反应是疲劳（58%所有级别，8%3 级）、恶心（34%所有级别，无 3 级）、高血糖（34%所有级别，4%3 级）和厌食（30%所有级别，2%3 级）。18%的患者出现抑郁（12%1 级，6%2 级）和焦虑（10%1 级，8%2 级）。在 27 例可进行靶向 DNA 测序（MSK-IMPACT）的患者中，有 6 例存在 PIK3CA/AKT1/PTEN 改变，其中 3 例作为最佳总体反应达到 SD，但均未达到 4 个月以上的临床获益。在 5 例具有基线和治疗期间配对活检的患者中，反转录蛋白阵列（RPPA）分析显示，在 3 例达到 SD 的患者中，有 2 例 S6 磷酸化减少，而在进展性疾病患者中均未观察到。
结论：Buparlisib 与三阴性乳腺癌患者中非常小的一部分患者的 SD 延长相关；然而，没有观察到确认的客观缓解。在达到 SD 的患者中观察到 PI3K 通路关键节点的下调。PI3K 通路抑制可能不足以作为三阴性乳腺癌的治疗策略。
试验注册：NCT01790932. 2013 年 2 月 13 日注册；NCT01629615. 2012 年 6 月 27 日注册。
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