Abstract and Introduction
Activating mutations of PIK3CA are found in 25%-40% of estrogen receptor–positive (ER+), HER2-negative (HER2−) breast cancers (BC), and in 8% of ER-negative (ER−) BC.[1–5] Two recent studies support the benefit of PI3K inhibition in combination with endocrine therapy. SANDPIPER (study of taselisib plus fulvestrant v placebo plus fulvestrant in participants with advanced or metastatic breast cancer who have disease recurrence or progression during or after aromatase inhibitor therapy) demonstrated a small prolongation in progression-free survival with taselisib, and SOLAR-1 (ClinicalTrials.gov identifier: NCT02437318) demonstrated a clinically meaningful improvement in progression-free survival with alpelisib. This led to the approval of alpelisib in combination with fulvestrant in PIK3CA-mutant, hormone receptor–positive (HR+), metastatic BC.
Activation of the PI3K pathway is frequent in BC brain metastases, as evidenced by observation of AKT and S6 phosphorylation and loss of PTEN. Recent data suggest PIK3CA-activating mutations may be associated with an increased risk of CNS metastases in patients with ER+/HER2− disease. In 307 patients with ER+/HER2− metastatic disease, brain metastases were significantly more common in patients with PIK3CA mutations (30.8% v 17.1%; P = .0049). Treatment of brain metastases from ER+ BC remains difficult. A recent retrospective analysis found a clear association of improved survival with continuation of endocrine therapy upon diagnosis of brain metastases. Remarkably, the CDK4/6-inhibitor abemaciclib had a clinical benefit rate of 25%. Preclinical models of BC brain metastases suggest PI3K pathway inhibition may be effective for treatment of brain metastases. Notably, both SANDPIPER and SOLAR-1 excluded patients with untreated or active CNS metastases;[6,7] however, the precursor to alpelisib, buparlisib, did have brain penetration, which was thought to be the cause for the higher incidence of mood disorders. An increase in depression has distinctly not been seen with the α-specific PI3K-inhibitor alpelisib and, in preclinical animal models with intact blood-brain barrier, no significant distribution into the brain was seen (unpublished data). Thus, the activity of alpelisib in brain metastases is unknown.
Herein, we report a case series of 4 patients with ER+/progesterone receptor–positive (PR+)/HER2− metastatic BC with progressive brain metastases (Figure 1) treated with alpelisib. All patients provided consent to publish their information and images.
CNS response measured by magnetic resonance imaging (MRI) of the brain. Pink circles and white arrows represent metastatic disease from breast cancer.
JCO Precis Oncol. 2020;4:572-578. © 2020 American Society of Clinical Oncology