This is a clinical trial with a molecularly stratified parallel cohort, single arm design to explore the efficacy and safety of BKM120 in combination with tamoxifen in patients with ER/PR-positive, HER2-negative breast cancer with prior exposure to antihormonal therapy, and different biomarker profiles, two of them potentially indicative of constitutive PI3K pathway activation.

This is a clinical trial with a molecularly stratified parallel cohort, single arm design to explore the efficacy and safety of BKM120 in combination with tamoxifen in patients with ER/PR-positive, HER2-negative breast cancer with prior exposure to antihormonal therapy, and different biomarker profiles, two of them potentially indicative of constitutive PI3K pathway activation:

• PIK3CA mutation/preserved PTEN expression
• PIK3CA wildtype or mutation/ loss of PTEN expression
• PIK3CA wildtype/preserved PTEN expression. This trial will explore, if the combination of BKM120 and tamoxifen can overcome resistance to antihormonal therapies. BKM120 is selective for class I PI3K enzymes with no mTOR inhibitory activity that has entered Phase II and III clinical trials. The tumor suppressor PTEN is the most important negative regulator of the PI3K signaling pathway. Therefore, in addition the trial will prospectively evaluate PIK3CA mutations and/or loss of PTEN expression as predictive biomarkers for clinical benefit from combined treatment with BKM120 and tamoxifen.

Inclusion Criteria:

• Patient has histologically and/or cytologically confirmed diagnosis of breast cancer
• Patient has radiologic or objective evidence of inoperable locally advanced, or metastatic breast cancer
• Patient has a known hormone receptor status HR-positive (ER and/or PR positive) and HER2-negative status
• Patient has a representative archival formalin-fixed tumor biopsy (metastasis or primary tumor)
• Patient has prior exposure to antihormonal therapy
• Patient has received ≤ 2 prior antihormonal treatments in the metastatic setting
• Prior treatment with tamoxifen in the (neo-)adjuvant setting is allowed but has to be discontinued for at least 1 year.
• Patient may have received up to one prior chemotherapy in the metastatic setting
• Measurable or non-measurable lesions according to RECIST v1.1 criteria
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2

Exclusion Criteria:

• Patient has received previous treatment with a PI3K- or AKT-inhibitor or mTOR-inhibitors
• Prior treatment with Tamoxifen in the metastatic setting. Treatment with tamoxifen in the (neo-)adjuvant setting is allowed, but has to be discontinued for at least 1 year
• Patient has symptomatic CNS metastases
• Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM-IV).
• Patient has a known history of HIV infection (testing not mandatory) infection