ABSTRACT
BACKGROUND: Resistance to HER2-targeted therapy is a critical issue in breast cancer that must be addressed immediately. PIK3R1 mutations are more common in Chinese breast cancer patients (17%, 25/147, Fudan University Shanghai Cancer Center FUSCC vs. 1.8%, 87/4602, TCGA all breast cancer studies). However, very limited information is available on the relationship between PIK3R1 mutation status and resistance to HER2-targeted therapies in patients with HER2-positive breast cancer. CASE REPORT: We present a case of a HER2-positive advanced breast cancer patient with the PIK3R1EY451delinsD mutation who developed resistance to HER2-targeted therapy and had a better response to everolimus combined with trastuzumab and carboplatin. CONCLUSIONS: To the best of our knowledge, this is the first study to show that the PIK3R1EY451delinsD mutation confers resistance to anti-HER2 therapy in breast cancer and that combining with everolimus treatment may overcome this resistance mechanism. We hypothesize that the PIK3R1EY451delinsD mutation is associated with the resistance to anti-HER2 therapy, and that this mutation merits further investigation as a clinical biomarker and therapeutic target.
Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , China , Class Ia Phosphatidylinositol 3-Kinase/therapeutic use , Drug Resistance, Neoplasm/genetics , Everolimus/therapeutic use , Female , Humans , Receptor, ErbB-2/genetics , Trastuzumab/therapeutic useABSTRACT
Idelalisib is a novel, highly selective, small-molecule, tyrosine kinase inhibitor with potent activity against phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PI3Kδ). Given the highly selective inhibition of this compound, studies have shown that idelalisib is able to achieve significantly increased apoptotic activity in B-cell acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia (CLL) cell lines, without significant increase in apoptosis among normal T and natural killer cells. Recent studies have suggested potential clinical benefit with idelalisib as either a single agent or in combination with established chemotherapeutic compounds including bendamustine and rituximab in relapsed/refractory CLL. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of idelalisib in the treatment of various indolent forms of non-Hodgkin's lymphoma.
