Bone metastasis, the leading cause of breast cancer-related deaths, is characterized by bone degradation due to increased osteoclastic activity. In contrast, mechanical stimulation in healthy individuals upregulates osteoblastic activity, leading to new bone formation. However, the effect of mechanical loading on the development and progression of metastatic breast cancer in bone remains unclear. Here, we developed a new in vivo model to investigate the role of skeletal mechanical stimuli on the development and osteolytic capability of secondary breast tumors. Specifically, we applied compressive loading to the tibia following intratibial injection of metastatic breast cancer cells (MDA-MB231) into the proximal compartment of female immunocompromised (SCID) mice. In the absence of loading, tibiae developed histologically-detectable tumors with associated osteolysis and excessive degradation of the proximal bone tissue. In contrast, mechanical loading dramatically reduced osteolysis and tumor formation and increased tibial cancellous mass due to trabecular thickening. These loading effects were similar to the baseline response we observed in non-injected SCID mice. In vitro mechanical loading of MDA-MB231 in a pathologically relevant 3D culture model suggested that the observed effects were not due to loading-induced tumor cell death, but rather mediated via decreased expression of genes interfering with bone homeostasis. Collectively, our results suggest that mechanical loading inhibits the growth and osteolytic capability of secondary breast tumors after their homing to the bone, which may inform future treatment of breast cancer patients with advanced disease.

Purpose Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer that has been associated with poor clinical outcomes, as has triple-negative breast (TNBC) cancer. Limited studies compare the clinical characteristics and prognosis of MBC to TNBC. This study uses a large, contemporary US cancer database to compare clinical characteristics and survival outcomes for patients with MBC to those with TNBC. Methods The National Cancer Database was queried for women with cT1-4N1-3M0 MBC or TNBC diagnosed between 2004 and 2013 and treated with definitive surgery. Chi-squared analysis was performed to determine differences between the cohorts. Kaplan-Meier curves compared overall survival (OS), and Cox regression determined patient factors associated with OS. Results Altogether, 55,847 patients met the inclusion criteria; 50,705 (90.8%) had TNBC and 5,142 (9.2%) had MBC. Most patients had no comorbid conditions (82%), N0 disease (71%), poorly differentiated histology (77%), received chemotherapy (87%), and received radiation therapy (60%). Amongst all patients, patients with TNBC disease were observed to have greater OS than those with MBC (5-year OS 72.0% vs 55.8%, p < 0.001). The greater observed OS for patients with TNBC persisted when controlling for stage and when comparing propensity score matched cohorts. On Cox regression, lower age, T1 status, N0 status, chemotherapy, TNBC disease, and radiation therapy (RT) were associated with improved OS. Conclusions MBC had an association with poorer OS compared to TNBC, while RT and chemotherapy receipt were associated with improved OS for patients regardless of stage. Further studies are needed to corroborate the conclusions herein.

Dynamic mechanical loading is a strong anabolic signal in the skeleton, increasing osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) and increasing the bone-forming activity of osteoblasts, but its role in bone metastatic cancer is relatively unknown. In this study, we integrated a hydroxyapatite-containing three-dimensional (3D) scaffold platform with controlled mechanical stimulation to investigate the effects of cyclic compression on the interplay between breast cancer cells and BM-MSCs as it pertains to bone metastasis. BM-MSCs cultured within mineral-containing 3D poly(lactide-co-glycolide) (PLG) scaffolds differentiated into mature osteoblasts, and exposure to tumor-derived soluble factors promoted this process. When BM-MSCs undergoing osteogenic differentiation were exposed to conditioned media collected from mechanically loaded breast cancer cells, their gene expression of osteopontin was increased. This was further enhanced when mechanical compression was simultaneously applied to BM-MSCs, leading to more uniformly deposited osteopontin within scaffold pores. These results suggest that mechanical loading of 3D scaffold-based culture models may be utilized to evaluate the role of physiologically relevant physical cues on bone metastatic breast cancer. Furthermore, our data imply that cyclic mechanical stimuli within the bone microenvironment modulate interactions between tumor cells and BM-MSCs that are relevant to bone metastasis.

No abstract

Introduction: Pelvic reirradiation (re-RT) presents challenges due to concerns for late toxicity to tissuesat-risk including pelvic bone marrow (PBM). We routinely utilize a hyperfractionated, accelerated re-RT for recurrent rectal or anal cancer in the setting of prior radiation. We hypothesized that proton beam radiation (PBR) is uniquely suited to limit doses to pelvic non-target tissues better than photon-based approaches. Materials and methods: All patients who received hyperfractionated, accelerated PBR re-RT to the pelvis from 2007 to 2017 were identified. Re-RT was delivered twice daily with a 6 h minimum interfraction interval at 1.5 Gray Relative Biological Effectiveness (Gy(RBE)) per fraction to a total dose of 39-45 Gy (RBE). Concurrent chemotherapy was given to all patients. Comparison photon plans were generated for dosimetric analysis. Dosimetric parameters compared using a matched-pair analysis and the Wilcoxon signed-rank test. Survival analysis was performed Kaplan Meier curves. Results: Fifteen patients were identified, with a median prior pelvic RT dose of 50.4 Gy (range 25-80 Gy). Median time between the initial RT and PBRT re-RT was 4.7 years (range 1.0-36.1 years). In comparison to corresponding photon re-RT plans, PBR re-RT plans had lower mean PBM dose, and lower volume of PBM getting 5 Gy, 10 Gy, 20 Gy, and 30 Gy (p < 0.001, p < 0.001, p < 0.001, and p = 0.033, respectively). With median 13.9 months follow-up after PBR re-RT, five patients had developed local recurrences, and four patients had developed distant metastases. One-year overall survival following PBR re-RT was 67.5% and one-year progression free survival was 58.7%. No patients developed acute or late Grade 4 toxicity. Conclusion: PBR re-RT affords improved sparing of PBM compared with photon-based re-RT. Clinically, PBR re-RT is well-tolerated. However, given modest control rates with definitive re-RT without subsequent surgical resection, a multidisciplinary approach should be favored in this setting when feasible.