The bone-targetedagents (BTAs), bisphosphonates (BPs) and denosumab, have several roles in breastcancer management in both the advanced metastatic setting and the early curative set- ting. In the advanced setting, both BPs and denosumab reduce the skeletal complications associated with bone metastases. In the early setting, BPs and denosumab prevent the bone loss associated with curative systemic cancer therapies, with oral BPs and denosumab reducing bone loss and fracture rates in postmenopausal women, and zoledronic acid (ZA) being the most effective BP at reducing the high level of treatment- induced bone loss in premenopausal women. More recently, the efficacy of BTAs to prevent breastcancer recurrence and improve survival, when given in early breastcancer, has been evaluated in large adjuvant breastcancer trials with evidence that BPs are effective at preventing recurrence in postmeno- pausal women only, but denosumab does not appear to have a role in metastases prevention in either menopausal group. Despite decades of research with BTAs in breastcancer, several questions remain unanswered, including why there is a lack of benefit in disease recurrence prevention in premenopausal women with early breastcancer and how to optimally schedule BTAs in the metastatic setting. Some of these questions will be answered by ongoing clinical trials, but others will require a return to the preclinical setting.
Results: Five relevant studies (n ¼1287 patients) were identiﬁed. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targetedagents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de- escalated treatment may provide similar beneﬁts compared to 3–4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective.
adjuvant setting, in early breastcancer patients, a Cochrane systematic review concludes that BPs probably lowered the risk of cancer spreading to the bone, but the survival benefit was low and related to the menopausal status (benefit to postmenopausal women). Further studies on this point and the data on survival rate (and other important outcomes) from denosumab trials are awaited. 28 In advanced breast
also identified among others EphA2 and Src as targets of dasatinib in triple negative breastcancer (95) (33) (30) (105). However, all triple negative cell lines tested were resistant to PP2, a laboratory grade selective Src inhibitor. These results suggest that targeting EphA receptors contributes to sensitivity to dasatinib in triple negative breastcancer cells. Consistent with this hypothesis, protein expression analysis in the panel of cell lines showed that dasatinib- sensitive cell lines had higher levels of expression of EphA2 compared to dasatinib-resistant cell lines. EphA2 receptor overexpression has been detected in a variety of cancers, including the majority of breast cancers (106) (107). In addition, higher levels of EphA2 protein have been detected in triple negative breastcancer cell lines as opposed to nontransformed epithelial cells. Upregulation of Eph receptor signalling has been implicated in tumour growth, invasion, resistance to anoikis and neovascularisation (108). In addition,we found elevated caveolin-1 and -2 levels in the dasatinib-sensitive cells. Caveolins interact closely with the Src family kinase and have been identified as markers of basal breastcancer (109) (110).
Heat shock protein 90 (HSP90) is a molecular chaperone important for the proper folding and conformational stability of a variety of client proteins, including HER2 and p95- HER2, that are important in the oncogenic process of cancer cells. In preclinical models, inhibition of HSP90 leads to degradation of HER2 and p95-HER2, tumor cell apoptosis, and growth inhibition. 52 In a phase I trial of trastuzumab in combination with the HSP90 inhibitor alvespimycin (17- DMAG), one con ﬁrmed partial response was observed, and seven cases of stable disease (lasting 4, 5, 6, 7, 8, 9, and 10 months), in 21 patients with heavily pretreated metastatic HER2 þ breastcancer. 53 A phase II trial of the HSP90 inhibitor tanespimycin (17-AAG) in combination with trastuzumab was conducted in patients with HER2 þ meta- static breastcancer after progression on trastuzumab. This trial enrolled 31 patients, with a primary endpoint of response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The ORR was 22%, and the median PFS was 6 months (95% CI Z 4 to 9 months), 54 demonstrating a proof of concept that HSP90 inhibitors are effective agents for HER2 þ breastcancer. Unfortunately, tanespimycin was suspended for further clinical develop- ment. Other novel heat shock protein inhibitors are in clinical development, and results are eagerly awaited. 55
Anti-angiogenic therapy has achieved successful results in several cancer types, including colorectal, hepatocellu- lar, and kidney cancer; however, despite tremendous effort in the past decade, many trials demonstrated only mar- ginal effectiveness over existing treatments. An AVA- GAST trial recently released results, indicating negative OS data  similar to study results from sorafenib and sunitinib. The primary reason for the disappointing results of anti-angiogenesis treatment is the lack of predictive biomarkers for the investigated drugs. Although biomar- kers such as serum VEGFA and microvessel density have repeatedly been cited as potentially useful predictive mar- kers for the effectiveness of anti-angiogenic therapy, they remain unconfirmed by any phase III trial. This makes it difficult to determine which agents are potentially most beneficial to certain patients. Based on the results of the investigations in lung cancer and breastcancer, further clinical analysis of biomarkers may lead to a better under- standing of GC outcomes and appropriate treatment selec- tion. Not limited to anti-angiogenic therapy, “Personalizing cancer care” is the goal for all targeting agents, in order to achieve both improved and optimal results based on ef- fective biomarker selection .
Abstract: Triple-negative breastcancer (TNBC) remains the poorest-prognosis breastcancer (BC) subtype. Gene expression profiling has identified at least six different triple-negative subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN tumors may justify the difficulty in treating this BC subtype. Several targetedagentshave been investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic treatment is an effective option of care. The achievement of a pathological complete response represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitiv- ity. In this review, we provide a brief description of the main predictive biomarkers for tumor response to systemic treatment. Moreover, we review the treatment strategies investigated for TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC patients may be treated on the basis of tumor molecular profile.
Hormone-refractory breastcancer metastatic to bone is a clinically challenging disease associated with high morbid- ity and poor prognosis. Common complications of bone metastasis include skeletal-related events such as patho- logic fractures, spinal cord compression, and nerve root compression, as well as hypercalcemia of malignancy. Moreover, bone pain impairs quality of life in patients with bone metastases. Strategies to target bone metastases have included bisphosphonate therapy (zoledronic acid), recep- tor activator of nuclear factor kappa-B ligand (RANK-L)– directed monoclonal antibody therapy (denosumab), and palliative radiation in addition to systemic therapy [1-4]. A recent major therapeutic advance was the US Food and Drug Administration (FDA) approval of radium-223 (Ra-223) dichloride (Xofigo injection, Bayer HealthCare Pharmaceuticals Inc) alpha particle therapy for the treat- ment of symptomatic bone metastases in patients with castration-resistant prostate cancer and no known visceral metastatic disease [3,5-8]. Ra-223 is an isotope of radium with an 11.4-day half-life, in contrast with the common isotope Ra-226, discovered by the Curies, which has a 1601-year half-life.
Integrins are heterodimeric cell-surface receptors that mediate adhesion to the extracellular matrix and immunoglobulin superfamily molecules. Structurally, integrins are composed of non-covalently bound a and β subunits forming 24 different heterodimers. Each has an extracellular domain, a single trans-membrane region and a short cytoplasmic tail. The extracellular domain shows high affinity for a defined RGD-motif expressed by vitronectin, fibronectin, osteopontin and other extracellular matrix components. Ligand binding propagates outside-in and inside-out intracellular signalling. The unique integrin repertoire of a given cell determines the extent of adhesion and migration of that cell in different matrices. Abnormal integrin overexpression by tumour and/or host cells has been associated with tumour proliferation, survival, angiogenesis, migration and metastasis . Particularly, in osteotropic tumours, overexpression of avβ3 integrin has been linked with increased bone colonization by breast, prostate and lung cancer cells and osteomimetism by multiple myeloma cells. The interaction of cancer cells with stromal cells and immune cells via avβ3 integrin induces the production of cytokines and growth factors that recruit and differentiate osteoclast precursors, thus inducing lytic lesions . Other integrins, such as αvβ5, αvβ6, α5β1, α6β4, α4β1, have also been implicated in the tumour progression of different tumour types . Therefore, integrin-targeting strategies either by the use of RGD-motif peptidomimetics or of monoclonal antibodies has reached preclinical and clinical development. avβ3 integrin is the predominant integrin in osteoclasts and it is involved in osteoclast attachment to the bone matrix .
In recent years the description of well-defined molecular subtypes of breastcancer, together with the identification of the driving genetic alterations and signaling pathways, has led to the clinical development of a number of successful molecular targetedagents. This is best exemplified in the subset of HER2-amplified breast cancers, in which an increasing number of active agents are changing the natural history of this aggressive disease. Other targets are under exploration, and the clinical development of these agents will require a change from the current large, randomized trials in unselected patient populations to smaller trials in groups with a molecularly defined tumor type. In addition, combinatorial approaches that act on the secondary mutations and/or compensatory pathways in resistant tumors may
One bone-anabolic agent is currently widely used in the treatment of osteoporosis: once-daily injection of PTH 1-34 (teriparatide). When given to experimental animals, teriparatide increased new bone formation and resulted in suppression of myeloma growth . The authors pro- posed that osteoblasts were stimulated to secrete anti- myeloma factors. Identification of such factors would facilitate development of more selective anti-myeloma treatments that might also be effective against bone me- tastases due to solid tumors, including breastcancer. The authors isolated myelomatous bone from mice treated with PTH or saline for 4 weeks and examined RNA for changes in gene expression by array hybridization. PTH increased many markers of osteoblast activity, such as collagens and osteocalcin, but also altered members of the WNT signaling pathway, including reducing DKK1 mRNA, but not sclerostin. Teriparatide carries a black box warning against its use in patients with cancer, due to an increase in osteosarcomas in rats treated with high doses of PTH, and is unlikely to be approved for use in oncology. Nonetheless, the anti-tumor effects of PTH provide proof-of-principal for the use of bone- anabolic agents against myeloma bone disease and osteo- lytic breast metastases. The anabolic actions of drugs can be tested on bone separately from their effects on tumor growth, as has been done for proteasome inhibitors and MM. However, it is very difficult to evaluate the relative contributions to anti-tumor efficacy of a multi-tasking agent with both direct, anti-tumor and indirect, bone- anabolic actions. A potent bone-anabolic agent without direct actions on breastcancer growth might be useful against bone metastases in the clinic.
Gotte M et al 2006 summarized glycosaminoglycan’s has major constituents of the cancer cell surface and the tumour stroma. The heparan sulfate degrading enzyme heparanase, hyaluronan (HA), and its receptor CD44 are up-regulated in BC, generating a microenvironment that promotes tumour progression and metastasis. Recent experimental and clinical evidence shows that heparanase, hyaluronan, and CD44 regulate cancer cell proliferation, migration, and invasion, as well as tumour-associated angiogenesis and are correlated with patient survival. The findings suggests the coupling of conventional chemotherapeutic drugs with HA allows for selective targeting of CD44-expressing cancers, thus lowering the dosage of anticancer medication administered and reducing unwanted side effects. Estrogen-antagonistic BC therapy using tamoxifen, fulvestrant, or aromatase inhibitors may lead to a down-regulation of heparanase expression. As heparanase, hyaluronan, and CD44 promote tumour cell proliferation, migration, and angiogenesis through different molecular mechanisms, simultaneous targeting of these three molecules may be expected to produce synergistic effects and prevent cancer cells from using alternative salvage pathways during treatment. Future studies will provide further insight into the pathophysiologic roles of these molecules and may offer important tools for BC management and prognostication .
a cohort of adolescent daughters of women with breastcancer had difficulties in resolving the illness experience , and these findings need confirmation. The theory of parent/child attachment is interesting in this context, because it suggests that disruption to this relationship because of separation, illness or death can have an influ- ence on relationships and behaviour in adult life, depend- ing on the security of the original attachment . This could help explain differences in the resolution of early bereavement from cancer and subsequent risk perception, but these ideas are as yet largely unexplored. The theory could also help to explain variations (as yet unquantified) in ability to communicate about risk: feeling free to talk openly about the loss or risk would be associated with secure attachment/realistic risk; whereas being preoccu- pied and communicating negatively would be associated with insecure attachment/overestimating risk. These hypotheses warrant further exploration.
Business process outsourcing, specifically HRM BPO, is a special case of HRO in which the provider delivers the end results of an HRM business process with responsibility for quality, timeliness and cost. Although we should have evalu- ated the HRM BPO provider's people, processes and technology as part of our evaluation and selection of the provider, and we should certainly, as part of ven- dor management, conduct ongoing checks to ensure that the provider continues to perform as expected, our day-to-day use of the provider isn't burdened with the specifics of how they deliver the results but rather focuses on those results. Classic examples of HRM BPO can be found in background checking or tax filing, in single benefit plan administration to much more comprehensive benefits ad- ministration (assuming that this isn’t just about systems but includes respond- ing to employee/manager questions, either online or via a contact center, and providing related analytics), payroll (but not on a service bureau basis, which is much more of a managed IT service, but rather as if the provider were our payroll department), and job board delivery of vetted applicants, search firm delivery of qualified candidates, and RPO (recruitment process outsourcing, a much broader use of BPO that encompasses much beyond sourcing). What's important in BPO that distinguishes it from the rest of HRO is that we judge the BPO provider on the results of a business process rather than on the basis of tasks, products, utility services, etc.
2. While in the community, all Hidden Springs’ staff are required to wear medical or cloth face masks that are sterilized in house laundry overnight. Wehave implemented targeted testing and personal contact tracing. If there is any chance that staff
People begin to demand answers. Did the Japanese go to the reception centers voluntarily, or under duress? What is their ultimate destination? … Are they innocent? Are they guilty? Are they even really gone? Be- cause isn’t it odd that no one we know actually saw them leave? … Perhaps, says a local air-raid warden, the Japanese are still with us, and watching us from the shadows, scrutinizing our faces for signs of grief and remorse. Or maybe they’ve gone into hiding beneath the streets of our town and are plotting our eventual demise. Their letters, he points out, could easily have been faked. Their disappearance is a ruse. Our day of reckoning, he warns, is yet to come. (Otsuka, Buddha 123) As we can see in the quotation, the initial concern for their fellow citizens soon turns into apprehensive questions that echo the common stereotypes of the Japanese as treacherous, sly and violent. They are not seen as vic- tims of injustice, but instead their disappearance is construed as suspicious. Furthermore, these reactions demonstrate a disinclination to find out what really happened to the Japanese Americans.
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Ascitic fluid is the carrier of ovarian malignant cells and allows these cells to circulate within the abdominal cavity and subsequently increase the chance of cancer cell metastases. Patients with ascitic fluid always display the spread of cancer into various internal organs, suggesting ascitic fluid plays an important role in the contribution to the secondary growth of ovarian cancer. Current ovarian cancer research is mainly focused on the studies of tumors at the primary and metastatic sites, but is largely ignore the importance of ascitic fluids being a valuable biological clinical sample which is routinely obtained from patients and discarded during the clinical procedure. Ascitic fluids are comprised an heterogeneity of growth factors, cytokines, chemokines, bioactive fatty acids, immune cells, mesenchymal stem cells, and ovarian cancer cells . The levels of these mixture components are varied among ovarian cancer patients suggesting the biological activity of the tumor microenvironment may be unique in individual patients . Little is known about the mechanisms underlying ovarian cancer progression from the primary to the peritoneal seeding. Furthermore, the biological profiles of cancer cells during the exposure to the ascitic fluid are not discernible to target cancer cells with novel intervention chemotherapy. More importantly, wedo not yet understand the effects of ascitic fluids during chemotherapy, via intravenous (IV) and intraperitoneal (IP), in ovarian cancer patients. It is very tempting to speculate that ovarian cancer cells in women in the advanced stage have acquired resistance to commonly used cytotoxic agents, carboplatin and taxol due to the presence of ascitic fluids.