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Abstract
IntroductionBreast cancer brain metastases (BCBM) are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared pharmacokinetics (PK) and efficacy of PEGylated liposomal doxorubicin (PLD) with non-liposomal doxorubicin (NonL-doxo) in an intracranial model of BC.MethodsAthymic mice were inoculated intracerebrally with MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing mice were administered PLD or NonL-doxo at 6mg/kg IV×1 and were euthanized prior to and 0.083, 1, 3, 6, 24, 72 and 96 h post-treatment. Samples were processed to measure sum total doxorubicin via HPLC. PLD and NonL-doxo were administered IV weekly as single agents (6 mg/kg) or in combination (4.5 mg/kg) with the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival and bioluminescence.ResultsTreatment with PLD resulted in approximately 1,500-fold higher plasma and 20-fold higher intracranial tumor sum total doxorubicin AUC compared with NonL-doxo. PLD was detected at 96 h; NonL-doxo was undetectable after 24 h in plasma and tumor. Median survival of PLD-treated animals was 32 days (d, [CI] 31–38), which was significantly longer than controls (26d [CI 25–28]; p = 0.0012) or NonL-doxo treatment (23.5d [CI 18–28], p = 0.0002). Combination treatment with PLD/ABT-888 yielded improved survival compared to NonL-doxo/ABT-888 (35d [CI 31–38] versus 29.5d [CI 25–34]; p = 0.006).ConclusionsPLD provides both PK and efficacy advantage over NonL-doxo in the treatment of an in vivo model of BCBM. The results provide preclinical rationale to translate findings into early phase trials of PLD, with or without ABT-888, for patients with BCBM.
Highlights
Breast cancer brain metastases (BCBM) are a challenging consequence of advanced BC
Studies illustrate systemic therapy sequenced after cranial radiation improves outcome for many patients with breast cancer brain metastases, the physical properties of the blood brain barrier and the relative paucity of targeted agents to treat intracranial breast cancer remains a significant challenge in the development of systemic therapies capable of controlling both intra- and extracranial advanced breast cancer [7,8,9]
Pharmacologic disposition and drug efficacy studies were conducted in a murine model of intracranial breast cancer
Summary
Breast cancer brain metastases (BCBM) are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. The incidence of brain metastases is highly subtype-dependent [2] such that patients with triple negative and Her2-positive advanced breast cancer are at highest risk for intracranial recurrence [3,4]. Prognosis following the development of brain metastases is associated with breast cancer subtype where survival following central nervous system recurrence is 3 to 4 months for women with triple-negative disease compared to 9 and 15 months for HER2positive and endocrine-sensitive counterparts, respectively [5]. Studies illustrate systemic therapy sequenced after cranial radiation improves outcome for many patients with breast cancer brain metastases, the physical properties of the blood brain barrier and the relative paucity of targeted agents to treat intracranial breast cancer remains a significant challenge in the development of systemic therapies capable of controlling both intra- and extracranial advanced breast cancer [7,8,9]. The benefit of nanoparticle anti-cancer agents, with or without targeted agents capable of crossing the blood brain barrier, has yet to be fully examined in an in vivo model system of intracranial breast cancer
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