Abstract
BackgroundTreatment 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.MethodsThis 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.ResultsFifty 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.ConclusionsBuparlisib 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 registrationNCT01790932. Registered on 13 February 2013; NCT01629615. Registered on 27 June 2012.
Highlights
IntroductionTriple-negative breast cancer (estrogen receptor [Estrogen receptor (ER)]negative, progesterone receptor [Progesterone receptor (PgR)]-negative, and human epidermal growth factor receptor 2 [Human epidermal growth factor receptor 2 (HER2)]-negative) accounts for approximately 12–17% of all breast cancers and is associated with poor outcomes, with an increase in the risk of recurrence compared to other breast cancer subtypes and more frequent spread to visceral organs and the central nervous system (CNS) [1,2,3,4]
Triple-negative breast cancer accounts for approximately 12–17% of all breast cancers and is associated with poor outcomes, with an increase in the risk of recurrence compared to other breast cancer subtypes and more frequent spread to visceral organs and the central nervous system (CNS) [1,2,3,4]
Buparlisib was associated with prolonged stable disease (SD) in a very small subset of patients with triple-negative breast cancer; no confirmed objective responses were observed
Summary
Triple-negative breast cancer (estrogen receptor [ER]negative, progesterone receptor [PgR]-negative, and human epidermal growth factor receptor 2 [HER2]-negative) accounts for approximately 12–17% of all breast cancers and is associated with poor outcomes, with an increase in the risk of recurrence compared to other breast cancer subtypes and more frequent spread to visceral organs and the central nervous system (CNS) [1,2,3,4]. The phosphatidylinositol-3-kinase (PI3K) pathway is involved in diverse cellular functions, including cell growth and metabolism, migration, proliferation, and survival [6]. The molecular alterations leading to activation of the PI3K pathway in cancer are varied and include mutations in the genes encoding the PI3K alpha (PIK3CA) and beta (PIK3CB) catalytic subunits, AKT1 mutations, and loss of expression of the phosphatidylinositol-3,4,5 trisphosphate (PIP3) phosphatases PTEN and INPP4B. Mutations in PIK3CA and AKT1 are relatively uncommon in triple-negative breast cancer [7]; loss of PTEN and/or INPP4B has been reported in 30–60% of basal-like tumors [7,8,9]. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer
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