Bone metastases occur in ~70% of metastatic breast cancer patients often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3) which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n=42). Mechanistic investigations revealed that TGF-β signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ~12.5nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared to equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared to free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site.
Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor-positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI. Two cases have genomic evidence of two independent tumours, most obviously an ER− ‘collision tumour', which was only detected after NAI treatment of baseline ER+ disease. Many mutations are newly detected or enriched post treatment, including two ligand-binding domain mutations in ESR1. The observed clonal complexity of the ER+ breast cancer genome suggests that precision medicine approaches based on genomic analysis of a single specimen are likely insufficient to capture all clinically significant information.
Radial access and closure devices are associated with improved quality of life (QOL) after cardiac catheterization. Whether this is related to the access site or time to ambulation is unknown. Seventy-five patients undergoing cardiac catheterization were randomized to femoral 6 Fr with AngioSeal closure (F+C), femoral 4 Fr without closure, and radial (R) access. All patients were ambulated at 1 hr. QOL was measured utilizing visual analogue scales and Short Form-36 at baseline, 1 day, and 1 week. Time to ambulation and discharge were equivalent, as was postprocedure QOL. However, angiographic quality was lower in the 4 Fr group (P < 0.0001) and catheterization costs were higher in the F+C group (P < 0.0001). Ambulation 1 hr after catheterization can be accomplished utilizing radial, femoral 6 Fr with closure device, or femoral 4 Fr access with equivalent outcomes and QOL. However, this is achieved at a higher cost with a closure device, or lesser angiographic quality with 4 Fr catheters.
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