Hereditary breast cancer (BC) accounts for about 5-10% of cases. BRCA-associated tumors have been identified as a separate group of malignant neoplasms with distinctive clinical manifestations and specific treatment features. Understanding of biological mechanisms leading to cancer in BRCA1/2 mutation carriers and discovery of potential molecular targets, such as poly (ADP-ribose) polymerase (PARP), involved in base excision repair mechanisms, led to the development of a new class of targeted drugs belonging to the PARP inhibitors group. PARP inhibition leads to the preservation of single-stranded DNA breaks, the arrest of the replication fork, and the realization of the “synthetic lethality” phenomenon due to the inability to repair double-stranded DNA breaks by homologous recombination in cells with mutations in the BRCA1/2 genes. Two randomized trials OlympiAD and EMBRACA evaluated and proved the effectiveness of PARP inhibitors in patients with metastatic BRCA-mutated HER2-negative breast cancer in comparison with standard chemotherapy. At the same time, data on the potential use of PARP inhibitors for the treatment of BRCA-mutated HER2-positive breast cancer patients are extremely limited. This article presents a clinical example of the use of olaparib in a patient with BRCA-mutated HER2-positive metastatic breast cancer.
Brain metastases (BM) are associated with poor prognosis, short overall survival, and severely compromised quality of life in patients with advanced breast cancer (BC). BM create therapeutic challenges in BC due to the difficulty for the majority of drugs to cross the blood-brain barrier. Hormone-positive HER2-negative breast cancer usually progresses slowly compared to other subtypes and it is the most common subtype among patients with BC. The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have rapidly transformed breast cancer treatment landscape within past few years. Integrating CDK4/6 inhibitors in clinical practice significantly improved both progression-free and overall survival in all patient population, including patients with BM. In this article we summarize the results of phase III randomized controlled trials (MONALEESA-2, MONALEESA-3, MONALEESA-7, and Completion-1), suggesting the efficacy of the combination of ribociclib with various endocrine therapies, and present a clinical case discussion of a patient with advanced hormone-positive HER2-negative BC with brain, hepatic and bone metastases treated with combined targeted and endocrine therapy.
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