1Osteoarthritis (OA) is a debilitating and prevalent chronic disease, but there are no 2 approved disease modifying OA drugs (DMOADs), only pharmaceuticals for pain management. 3 OA progression, particularly for post-traumatic osteoarthritis (PTOA), is associated with 4 inflammation and enzymatic degradation of the extracellular matrix. In particular, Matrix 5Metalloproteinase 13 (MMP13) breaks down collagen type 2 (CII), a key structural component of 6 cartilage extracellular matrix, and consequently, matrix degradation fragments perpetuate 7 inflammation and a degenerative cycle that leads to progressive joint pathology. Here, we tested 8 targeted delivery of endosome-escaping, MMP13 RNA interference (RNAi) nanoparticles (NPs) 9 as a DMOAD. The new targeting approach pursued here deviates from the convention of targeting 10 specific cell types (e.g., through cell surface receptors) and instead leverages a monoclonal 11 antibody (mAbCII) that targets extracellular CII that becomes uniquely accessible at early OA 12 focal defects. Targeted mAbCII-siNPs create an in situ NP depot for retention and potent activity 13 within OA joints. The mAbCII-siNPs loaded with MMP13 siRNA (mAbCII-siNP/siMMP13) 14 potently suppressed MMP13 expression (95% silencing) in TNFa-stimulated chondrocytes in 15 vitro, and the targeted mAbCII-siNPs had higher binding to trypsin-damaged porcine cartilage 16 than untargeted control NPs. In an acute mechanical injury mouse model of PTOA, mAbCII-17 siNP/siMMP13 achieved 80% reduction in MMP13 expression (p = 0.00231), whereas a non-18 targeted control achieved only 55% silencing. In a more severe, PTOA model, weekly mAbCII-19 siNP/siMMP13 long-term treatment provided significant protection of cartilage integrity (0.45+/-20 .3 vs 1.6+/-.5 on the OARSI scale; p=0.0166), and overall joint structure (1.3+/-.6 vs 2.8+/-.2 on 21 the Degenerative Joint Disease scale; p<0.05). Intra-articular mAbCII-siNPs better protected 22 articular cartilage (OARSI score) relative to either single or weekly treatment with the clinical gold 23 Abstract Figure: PTOA targeted delivery of MMP13 siRNA to block disease progression.

Background: Very little is known about the survival of patients with inflammatory breast cancer (IBC) and distant metastasis. Furthermore, the American Joint Committee on Cancer classification of breast cancer does not recognize metastatic IBC as a distinct entity within stage IV. We hypothesized that the survival of patients with IBC and distant metastasis is worse than the survival of patients with stage-matched non-IBC. Patients and Methods: We retrospectively reviewed 5314 consecutive patients with stage III or IV breast cancer (IBC or non-IBC) who were treated at our institution between 1986 and 2012. A total of 1079 patients presented with IBC (stage III: 861; stage IV: 218) and 4235 non-IBC (stage III: 2781; stage IV: 1454). We compared the time to distant metastasis from initial diagnosis, distant metastasis–free survival (DMFS), and overall survival (OS) in stage-matched patients with IBC or non-IBC. Results: The median follow-up periods were 3.3 years for patients with stage III disease (range, 0-32.2 years) and 1.8 years for patients with stage IV disease (range, 0-19.9 years). The total number of recorded events (metastasis/death) was 1657 for stage III, while the numbers of deaths for stage III and IV were 1337 and 973, respectively. In patients with stage III, the time to distant metastasis was shorter in IBC than in non-IBC (median 1.3 vs. 1.7 years, P &lt; .001). DMFS and OS were shorter in patients with stage III IBC than in those with stage III non-IBC (2.5 vs. 6.9 years, P &lt; .001; and 4.7 vs. 8.9 years, P &lt; .001; respectively). However, there was no significant difference in OS after development of distant metastasis between stage III IBC and non-IBC (median for both 1.3 years, P = .83). In multivariate analysis, the diagnosis of IBC remained significantly associated with mortality after adjusting for potential confounders. De novo stage IV IBC presented more frequently with multiple sites of metastasis than de novo stage IV non-IBC (P = .02). In patients with de novo stage IV disease, OS was shorter in IBC than in non-IBC (2.3 vs. 3.4 years, P = .004). In the multicovariate Cox model, while ethnicity, tumor grade, hormone receptor status and HER2 status, site of metastasis, number of sites of metastasis, and definitive breast surgery by 1 year were all significant factors in OS for stage IV breast cancer, the diagnosis of IBC conferred a hazard ratio of 1.33 (95% confidence interval: 1.05 - 1.69) in multivariate analysis. Conclusion: Our findings suggest that IBC patients with metastasis at diagnosis have worse outcomes than stage-matched non-IBC patients. IBC patients presenting with de novo stage IV disease should be considered as a separate subcategory of stage IV in the tumor-node-metastasis classification because their clinical course and prognosis are different from those of patients with stage IV non-IBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-02.

Background Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer. HMG-CoA reductase inhibitors (statins) are cholesterol reducing agents with pleiotropic effects, including antitumorigenic and anti-inflammatory properties. We hypothesized that statins reduce the metastatic potential in primary IBC. Methods We retrospectively reviewed 724 patients diagnosed with and treated for primary IBC at The University of Texas MD Anderson Cancer Center between Jan. 12, 1995 and Jan. 27, 2011. Patients with records indicating statin use at the time of IBC diagnosis on the electronic medical record were compared with those without. We further compared outcomes stratified by statin type (hydrophilic [H] versus lipophilic [L]). We used the Kaplan-Meier method to estimate the median disease-free survival (DFS) after surgery, overall survival (OS), and disease specific survival (DSS), followed by Cox proportional hazards regression model to test statistical significance of several potential prognostic factors. Results For primary IBC patients who had information on their statin use status at IBC diagnosis, the median DFS time were 4.88 years, 2.47 years and 1.76 years (P= 0.04); the median OS time 5.05 years, 3.79 years and 4.32 years (P= 0.35); and the median DSS time 5.10 years, 3.79 years and 4.52 years (P= 0.37), for patients who took “ H”, “L” and no statin, respectively. In multivariable Cox model stratified by radiation therapy, ER/PR status and HER2 status, statin “H” use was associated with significantly improved DFS compared to no statin use (HR=0.49; 95% CI: 0.28–0.84; p&lt;0.01), adjusted for lymphatic/vascular invasion. Although there is a trend that patients who used statin “H” had a longer time to death compared to patients who did not take statin, it did not reach statistical significance for OS (HR=0.80; 95% CI: 0.43–1.49; p=0.49) and DSS (HR=0.85; 95% CI: 0.46–1.57, p=0.59) after adjustment for lymphatic/vascular invasion, nuclear grade and surgery status within one year. Conclusions Hydrophilic statin use was associated with improved DFS. There was a trend for reduced HR in OS and DSS among primary IBC patient who used hydrophilic statins. A prospective randomized study to evaluate the potential survival benefits of statins in primary IBC population is warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-08.

Background Radium-223 dichloride (Ra-223) is a therapeutic alpha particle-emitting radiopharmaceutical compound which have antitumor effect targeted on bone metastases. Alpha particles induces double strand DNA breaks and localized cytotoxic effect to cancer cells with limiting harm on normal tissues. We are conducting a phase II clinical trial of combination of Ra-223, hormonal therapy, and denosumab treatment in patients with hormone receptor (HR)-positive bone-dominant metastatic breast cancer (NCT02366130). In this preliminary analysis of the study, we aimed to evaluate the feasibility and safety of this combination therapy. Methods This single-center phase II study seeks to determine the efficacy and safety of Ra-223 in combination with hormonal therapy and denosumab. Major eligibility criteria include HR-positive breast cancer with bone and/or marrow predominant metastases. Patients with two or more visceral metastases were not eligible. There was no limit in the number of prior hormonal therapies in the metastatic setting. Patients received Ra-223 injection (55 kBq/kg intravenously) on day 1 of the study and then every 4 weeks thereafter for 6 cycles. Patients were also administered a single hormonal agent (i.e., tamoxifen, aromatase inhibitor, or fulvestrant at standard doses) daily and denosumab (120 mg subcutaneously) every 4 weeks. For this analysis, adverse events (AEs) were summarized using descriptive statistics. Results A total of 25 patients were enrolled and 22 were evaluable between March 2015 and December 2016. Median age was 58.5 years (range 31-79), and 59% of patients were postmenopausal. ECOG performance status was 0 in 16 patients (73%), and 1 in six patients (27%). HER2/neu was positive in only one patient. Four patients (18%) were de novo metastasis, no patients had visceral metastasis, and multiple bone metastases in 20 patients (91%) vs. focal metastasis in 2 (9%). Median time from diagnosis of bone metastasis was 4.8 months (range 0.5-96.6). Prior therapy for metastatic disease consisted of hormonal therapy in 50% of the patients (eight patients with one line and three patients with two lines), chemotherapy (9%), palbociclib (14%), radiation to bone metastasis (50%), and bone-supportive therapy (27% with zoledronic acid, 27% with denosumab). The median number of cycles of Ra-223 administered was 6 (range 4-6). The median follow-up time was 4 months (range 2-8). There were no grade 3 or 4 AEs. Major non-hematological grade 1 and 2 AEs were bone pain (77%), fatigue (45%), nausea (36%), diarrhea (32%), AST/ALT elevation (23%), hot flashes (23%), and headache (18%). The most common hematological AEs were grade 1 or 2 neutropenia (23%), anemia (14%), and thrombocytopenia (18%). There was no treatment delay or discontinuation due to AEs. Conclusion Our results suggest that the addition of Ra-223 to hormonal therapy and denosumab is a feasible and safe combination therapy in patients with HR-positive breast cancer with bone-dominant metastasis. We continue to enroll patients in the phase II trial to evaluate the efficacy of the treatment. Citation Format: Tahara RK, Fujii T, Saigal B, Ibrahim NK, Damodaran S, Barcenas CH, Murray JL, Chasen BA, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Ueno NT. Phase II study of the feasibility and safety of radium-223 dichloride in combination with hormonal therapy and denosumab for the treatment of patients with hormone receptor-positive breast cancer with bone-dominant metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-02.