In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2 BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM.

HIV-associated sensory neuropathy remains the most common neurological complication of HIV infection and is characterized by dorsal root ganglion (DRG) inflammation and intraepidermal nerve fiber density (IENFD) loss. Chronic peripheral immune cell activation and accumulation may cause damage to the DRG, but has not been fully investigated yet. By using an SIV-infected, CD8-lymphocyte-depleted rhesus macaque model, we defined immune cells surrounding DRG neurons and their role in DRG pathology, measured cell traffic from the bone marrow to the DRGs using 5-bromo-2-deoxyuridine (BrdU) pulse, and serially measured IENFD. We found an increase in CD68(+) and CD163(+) macrophages in DRGs of SIV-infected animals. MAC387(+) recently recruited monocytes/macrophages were increased, along with BrdU(+) cells, in the DRGs of SIV-infected macaques. We demonstrated that 78.1% of all BrdU(+) cells in DRGs were also MAC387(+). The number of BrdU(+) monocytes correlated with severe DRG histopathology, which included neuronophagia, neuronal loss, and Nageotte nodules. These data demonstrate that newly recruited MAC387(+)BrdU(+) macrophages may play a significant role in DRG pathogenesis. IENFD decreased early (day 21), consistent with the development of sensory neuropathy in SIV-infected macaques. Decreased IENFD was associated with elevated BrdU(+) cells in the DRG. These data suggest that increased recruitment of macrophages to DRG is associated with severe DRG histopathology and IENFD loss.

The blood brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers 14C-aminoisobutyric acid (AIB) and Texas Red conjugated dextran (TRD) prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.

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4097 Background: Biliary tract cancers (BTC) are often typically diagnosed at an advanced stage. There is no established second line option for patients with advanced BTC who have failed one prior systemic therapy. The phase II study evaluated safety and efficacy of nivolumab, anti PD-1 antibody in refractory BTC patients. Methods: Pts with histologically proven BTC who progressed on at least one line but no more than three lines of systemic therapy received nivolumab 240mg IV q2weeks for 16 weeks and then 480 mg IV every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study was objective response rate (ORR) by RECIST 1.1 every 8 weeks. The Simon two staged design was used to assess ORR.18 patients were accrued and if one response was seen, the plan was to accrue additional 34 patients. Secondary endpoints were PFS, OS and safety profile. Results: At data cutoff (Jan 14, 2018), 54 patients with BTC (female: 50%, Median age: 65 years) were enrolled. The primary sites of tumor were intrahepatic cholangiocarcinoma (63%) extrahepatic (11%), and gallbladder (26%). 30 pts (56%) failed 1 line of therapy and 24 (44%) failed more than one line of therapy. 45 pts (1 pt withdrew consent, 1pt just enrolled prior to data cutoff and 7 pts came off the study due to clinical progression) were evaluable for response rate. Out of 45 pts, 10 pts (22%) achieved PR (1 unconfirmed PR) and 17 pts (37.8%) achieved SD. DCR was 60%. All patients who responded were microsatellite stable. For evaluable 45 pts with median follow up of 13.34 months, median PFS was 3.98 months (95% CI: 2.33-5.98) and the median OS was 14.22 months (95% CI: 6.64-NA). 6 and 12month OS was 71.4 and 52.3% and 6 and 12 month PFS was 35.2% and 24.1% respectively. Most common treatment related AEs (TRAE) was alkaline phosphatase increased (24.5%). Grade III/IV TRAEs were seen in 11 pts (20.4%); most common were hyponatremia (3 pts) and elevated alkaline phosphatase (2 pts). No treatment related AEs led to discontinuation of the study drug. Tissue samples were collected in all pts with planned correlative studies underway including the PDL 1 status. Conclusions: Nivolumab was well tolerated and has shown promising efficacy in refractory BTC including durable responses lasting 2 years. Further randomized trial is warranted in refractory BTC. Clinical trial information: NCT02829918.