Cancer Metastasis Rev (2007) 26:663–674 DOI 10.1007/s10555-007-9085-8

Evaluating distant metastases in breast cancer: from biology to outcomes Shafaat A. Rabbani & Andrew P. Mazar

Published online: 7 September 2007 # Springer Science + Business Media, LLC 2007

Abstract There is an urgent need to understand distant metastases in breast cancer as they are the most lethal form of recurrence and a major cause of mortality in patients. Some predictors for distant metastases, including nodal status, tumor grade, and hormonal status, are useful in identifying patients at increased risk for distant metastases. Adjuvant endocrine therapy has been the treatment of choice for postmenopausal women with hormone-sensitive breast cancer, and some therapies have shown significant reductions in the risk of distant metastases. Skeletal metastases in breast cancer are treated with bisphosphonates with a certain level of success. With more new agents undergoing clinical trials, a thorough review of the specific and long-term safety of these agents is essential, as is a better understanding of the deterioration in the quality of life and cost concerns of patients who develop distant metastases. Gene-expression profiling is a new entrant in the field of distant metastases diagnosis, which is largely successful in defining gene signatures that predict the development of distant metastases. This review will discuss the biology and the impact of distant metastases on outcomes for patients with breast cancer; it also encompasses the current status, emerging focus, and future perspectives in treatment of skeletal metastases in patients with breast cancer.

S. A. Rabbani (*) Department of Medicine, McGill University Health Centre, Montreal, QC, Canada e-mail: [email protected] A. P. Mazar Attenuon, LLC, San Diego, CA, USA e-mail: [email protected]

Keywords Distant metastases . Breast cancer . Gene expression . Skeletal metastases . Bisphosphonates . Quality of life

1 Introduction There is a risk for recurrence after primary treatment of breast cancer. Local recurrence is when tumor cells in the original site grow back over a period of time. Many clinicians attribute this to failed primary treatment. Regional recurrence marks the spread of the cancer past the breast and the axillary lymph nodes and is considered more serious than local recurrence. Distant recurrence, also known as distant metastases (DM), is the most lethal type of recurrence; DM may occur soon after primary treatment, suggesting the presence of subclinical deposits at the time of locoregional treatment [1]. Metastasis generally occurs when cancer cells dislodge from the primary site of occurrence, travel in the blood stream, and spread to other organs (secondary site) where they interact with other molecules and continue to grow as new tumors [2–4]. DM in breast cancer may spread to almost any region of the body; about 50 to 75% of patients relapse first in a single organ (Fig. 1) [5–7]. Typically metastases to regional lymph nodes are observed in nearly one third of patients with breast, colorectal, uterine, cervical, and oral cavity and pharynx cancers [8]. Breast cancer mortality is often linked with metastasis of cancer cells that remain undetected at the time of diagnosis. Metastases are the primary cause of death in breast cancer, and about 45,000 women succumb to distant metastases each year in United States alone [2, 3, 9]. DM as a potential problem was acknowledged as far back as the 1940s, and the need for developing a therapeutic agent that can combat

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Percentage of 2050 cases

70 60 50 40 30 20 10 Lu n P le g u ra Liv er B on Pe e ri to ne Pa um nc rea Sp s lee n Ga s tr S k in oin tes ti n al Br ain Pe Hea r Ad icard rt re n ium al gla nd Th s yro id K id ne y Ov ar y Ut er u s

0

Organ

Fig. 1 Common metastasis sites of breast cancer at autopsy. Metastases to different sites away from the site of origin are common in patients with breast cancer, although strong preference for lung, bone, and liver is commonly observed. Figure adapted with permission from Macmillan Publishers Ltd. [5]

the disease outside the field of local spread has been emphasized [10].Thus, therapies aimed at preventing the progression of metastases may be a beneficial approach in cancer therapy [4]; and while a cure remains elusive, it appears that therapies that reduce the risk of breast cancer recurrence, especially distant metastatic events, are the likely candidates that will increase the survival rates in patients with breast cancer [11]. The overall poor prognosis associated with DM highlight the critical need to better understand the biology of the disease in order to develop more effective therapies. In this review, we will discuss the biology of DM and its impact on clinical outcomes in breast cancer patients. The current status of and future perspectives for treating skeletal metastases in breast cancer patients will also be discussed.

2 The biology of metastases Metastasis of tumor occurs when cancer cells detach from the primary site of origin, invade and travel through blood or lymphatic vessel to a distant site to form new proliferating colonies [12]. Cancer progression is a sequential biological process involving development of premalignant lesions prior to the appearance of lethal invasive tumors. The lesions may be the result of either genetic alterations that induce monoclonal expansion of the tumor, or governed by environmental factors that lead to polyclonal expansion of tumor cells. Repeated alterations in one or more of the premalignant cells result in malignant clonal cells producing a primary tumor. Further accumulation of genetic alterations renders the clone invasive and metastatic [13].

It may be relevant to note that only a limited number of cells in a primary tumor are highly metastatic, and there is a biological heterogeneity both in terms of phenotype and genetic expression in a given tumor differentiating the metastatic from the nonmetastatic cells. The ability of metastatic tumors to invade other tissues is due to its transition from a nonmotile epithelial-like state to an amoeboid or mesenchymal-like migratory state accompanied by loss of cell–cell adhesion [14]. The role of actomyosin cytoskeleton in this process is supported in literature but poorly understood. Preclinical studies show that myosin II isoforms, IIA and IIB, are both actively recruited to the expanding lamellar margin of the spreading breast cancer cells, suggesting their critical roles in mechanism of metastatic cell migration [14]. Metastases can be initiated from the proliferation of a single cell, thus attesting to a clonal origin of the process [15]. Tumor cells may also disseminate from a less progressed state of disease and not just from the most advanced clone within a primary tumor [16]. The presence of metastasizing cells itself is not prognostic; the outcome depends whether or not the tumor develops into a clinically relevant size [17]. The growth of metastasis depends on the interaction of the metastatic cells with various organ environments [15]. It is known that certain tumors have a stronger predilection to metastasize to specific organs, which may be independent of vasculature, blood circulation, or the number of tumor cells delivered to each organ [15]. For example, metastasis of prostate tumor cells to bones may be due to the affinity of their receptors to molecules in the bone tissue [12]. In breast cancer, bone is the preferred site of metastasis; the likelihood of detecting cancer cells is high in the bone marrow [16] (Fig. 1). Bone metastases are also common in a number of other carcinomas such as lung, liver, thyroid, and kidney [18, 19]. The ability of a tumor to metastasize and its tissue tropism depends on the combined action of multiple genes and expression of a different set of genes in each organ to which the tumor spreads [20]. Collective evidence in the literature suggests that cellular microenvironmental factors in the tumor milieu such as hypoxia and vascular insufficiency may critically alter the cellular gene expression both transiently and permanently [21], and proximity to blood and lymph vessels may stimulate directed migration of tumor cells in the early stages of metastases [14]. Table 1 lists a diverse array of genes involved in the process of metastasis [22–44]. Evaluation of the kinetics of DM is critical to deciding when is the optimal time to reduce the risk of DM in patients with breast cancer. One study analyzed the incidence and kinetics of DM in operable breast cancer patients and found that in more than half of patients with DM (51%), the recurrence occurred early within the first 18 months of

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Table 1 Genes promoting tumor invasion and metastasis Molecule Adhesion molecules E-cadherin αvβ3 integrin receptor Integrin-binding protein osteopontin (OPN) Activated leukocyte cell adhesion molecule (ALCAM) ECM remodeling molecules Matrix metalloproteinase 14 (MMP-14) MMP-2,9 Heparanase (Hpa) Tissue inhibitor of metalloproteinases 1 (TIMP 1) Urokinase-type plasminogen activator Transcription factors p53 Smad4 Growth factors and receptors Parathyroid hormone-related peptide (PTHrP) and estradiol Human epidermal growth factor receptor-2 (HER2) HER3 Epidermal growth factor receptor (EGFR) Insulin-like growth factor I receptor (IGF-IR) Transforming growth factor β (TGF-β)

Role

Reference

Promotes tumor cells adhesion at metastatic sites Mediates interaction with bone derived growth factors Induction of tumor metastasis to lymph nodes Marker of inhibition of tumor cell invasion

[22] [23] [24] [25]

Remodeling of the extracellular matrix (ECM) ECM degradation and increased expression in several cancers Induces angiogenesis and ECM degradation Involved in angiogenesis and apoptosis

[26] [27, 28] [29] [30]

ECM degradation, tumor invasion, metastasis and implicated in tumor dormancy

[31]

Tumor suppressor gene Contributes to skeletal metastasis via activation of IL-11

[32] [33]

Affects tumor growth, osteolytic metastasis and hypercalcemia of malignancy

[34]

Blood-borne epithelium derived HER2 clustered cells responsible for formation of distant metastases Associated with chemotaxis Chemotaxis and tumor cell growth Transformation of tumor cells into invasive and metastatic phenotype Activates intracellular signaling pathways and epithelial-mesenchymal transition (EMT) Vascular endothelial growth factor (VEGF) Angiogenesis Fibroblast growth factor receptor-1 (FGFR1) Mediator of inflammatory response Cell migration molecules/homing on target organ molecules Oncostatin M (OSM) Member of IL-6 family of cytokines involved in inflammation Chemokine receptors 4 and 7 (CXCR4/CCR7) Acts as chemotactic agent to promote tumor invasion VEGF receptor 1 (VEGFR1/Flt1) Preparation of distant metastatic sites for tumor cell seeding Lysyl oxidase (LOX) Mediator of hypoxia-associated metastasis

follow-up, and even in node-negative patients, the rate for early DM was about 10% [1]. The study also revealed that the timing of the occurrence of DM marginally depends on the tumor stage, i.e., for T3 patients the average time to DM is 1.6 times shorter than that for T2 patients and showed that even in early T stages and node-negative cases, DM significantly contributes to the cause of failure (26 to 46%) [1]. Breast cancer metastases can also occur after a prolonged period of successful treatment of primary tumor, after completion of 5 years’ adjuvant endocrine therapy, and even in node-negative patients [45, 46]. One reason for this tumor dormancy could be that preangiogenic micrometastases exhibit an internal balance between active cell division and apoptosis that arrests the vascularization. Persistence of solitary cells in secondary sites that fail to initiate cell division may also account for long periods of an asymptomatic state [4, 47].

[35, 36] [36] [37] [38] [39] [32] [40] [41] [42] [43] [44]

3 Predictors of distant metastases Many studies have addressed the issue of predictive markers of DM which include tumor size, tumor grade, proliferation factors and hormone receptor status [48]. Human epidermal growth factor receptor 2 (HER2) expression has been correlated with reduced distant recurrence-free survival (DRFS), and higher expression of the Bcl2 (B-cell leukemia/lymphoma 2, involved in antiapoptosis) and tumor protein p53-binding protein 2 (TP53BP2) has been associated with longer DRFS, while upregulation of GRB7, an HER2 adaptor, has been associated with shorter DRFS [49]. Additional valuable predictive factors associated with risk of DM include age (<40 years), premenopausal hormonal status, tumor stage (≥T3), axillary nodes (>2), and/or extracapsular invasion and clinical stages IIIB and IIIC [1, 50]. Margin status,

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lymphovascular invasion, poorly differentiated ductal carcinoma in situ, and nuclear grade are other factors that significantly correlated with DM [51, 52]. One of the most consistent prognostic factors that determine the risk of DM and patients’ survival is the involvement of axillary lymph nodes [53]. Yet, although node-positive patients are at increased risk for DM, nodenegative patients are also at risk for developing DM [53– 55]. The presence of tumor cells in the bone marrow is another strong predictor of DM. Disseminated tumor cells have been found in the marrow of node-positive and nodenegative patients [55] and are indicative of worse prognosis [56, 57]. Patients revealing residual initial local recurrences are at greater risk for DM than patients with de novo, second primary neoplasms [58, 59]. Many studies have consistently shown that the annual risk of developing DM increases over a period of 10 years in patients with locoregional recurrences [60–63]. In fact, a study has shown that local recurrences within a shorter median time increased the risk of DM [64]. Locoregional failure after breast-conserving surgery has also been recognized as a high risk predictor of DM and death [57, 59], as is ipsilateral breast tumor recurrence [51, 64, 65]. Another study estimated that patients developing a local recurrence were at >4.4-fold greater risk of relapsing at distant sites than patients who had none [66]. A meta-analysis has found an increased risk for DM (hazard ratio [HR]=1.91; 95% confidence interval [CI], 1.52 to 2.40) and death (HR=1.6; 95% CI, 1.38 to 1.76) with increased body mass index suggesting the susceptibility of obese women compared with nonobese women [67, 68]. A prospective cohort study has demonstrated a significant association of insulin and obesity with locoregional breast cancer and its direct correlation to the increased risk of DM and death [68]. Gene expression profile by microarray analysis is being viewed as a more attractive tool for predicting outcome in patients with breast cancer [69, 70]. Molecular profiling by clustered analysis can identify risk of recurrence in breast cancer patients that can facilitate therapy tailored to individual patients [71]. For example, Oncotype DX™ (Genomic Health Inc., Redwood City, CA), a commercially available diagnostic assay, is a typical working example that uses gene expression profile for detecting the likelihood of breast cancer recurrence in patients with newly diagnosed, node-negative, estrogen receptor (ER)-positive, early-stage breast cancer. The assay is based on the expression of 21 genes, including HER2 and ER. The assay also assesses the magnitude of drug response resulting from chemotherapy. In a study by Wang et al., a 76-gene signature profile by microarray accurately predicted distant tumor recurrence in

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lymph node-negative patients with a sensitivity of 93% and specificity of 48% [72]. These results were recently validated in a TRANSBIG multicenter, independent population in which the 76-gene signature panel accurately predicted the development of DM and overall survival (OS) in a low-risk prognosis group [73]. A more recent study has deduced metastatic probabilities based on prognostic gene signature in breast cancer. Such metastatic scores, as a measure of DM risk, could serve as a guiding tool for choosing therapeutic options [74]. Such options allow for the identification of patients who may be susceptible to early relapse and thus be better treated with compounds such as letrozole, an aromatase inhibitor that has demonstrated significant 27% reduction in the risk of DM in hormone receptor-positive patients in the initial adjuvant setting [75]. Other studies attempt to understand metastatic progression and site-specific metastases in primary breast cancer. In one study, site-specific distant relapse in breast cancer was assessed by gene expression profile, which resulted in developing a classifier of 31 genes that could predict bone relapse with a specificity of 50% [76]. In another study, Minn and colleagues have identified a gene signature that predicts a propensity for lung metastasis [77]. Finally, the European project MetaBre is a European-funded effort that investigates molecular mechanisms of breast cancer organspecific metastases. The effort has yielded specific gene signatures for lung, liver, bone, and brain metastases that are capable of distinguishing tumors metastasizing to different organs [78]. It is clear that gene profiling may be an exciting new advance in breast cancer because it may allow for the selection of patients for whom organ-specific treatment options can be used to their full advantage, as well as to identify patients unlikely to benefit from treatment, thus sparing unwanted expense and exposure to toxic therapeutic agents. Overall, the current evidence supports the clinical utility of gene expression signatures in predicting the susceptibility of patients to develop early distant metastatic disease and the secondary sites, but further validation is needed.

4 The impact of metastases 4.1 Patient outcomes Breast cancer recurrences, regardless of type, are associated with increased mortality in patients with early breast cancer, but the effect on mortality is substantially more pronounced in patients with DM [11]. Between local recurrence and DM, it is clear that women suffering from

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the former are more likely to survive longer than those suffering from the latter [79]. One study showed that the 10-year survival rate was 56% for local recurrence versus 9% following DM, with the median survival rate for women with a local recurrence of 12.9 years in comparison with 2.2 years for women with DM [80]. Similarly, a recent prospective study conducted by the Strathfield Breast Cancer Centre indicated that 58% of all recurrences occurred within the first 3 years after surgery and that the most common site of first relapse was to the bone [18]. Five-year disease-free survival was better in patients with local recurrence (41%) compared with patients with regional (20%) and DM (13%; p<0.0001) (Fig. 2) [18]. Of note, outcomes also varied by the site of metastatic spread; the 5-year OS rate was 16% for bone metastases, 12% for lung metastases, and zero for metastases in liver [18]. These latter findings support the conclusions by an earlier study, which showed that the prognosis of breast cancer is better in patients with first bone metastases than in those with first visceral metastases [19]. The presence of bone marrow micrometastases is also associated with poor OS. At a median follow-up of 12.5 years, 10-year relapse-free survival and OS were significantly better in patients without micrometastases at presentation (62.7 and 65.7%, respectively) than in patients with micrometastases (43.9 and 44.9%, respectively; p< 0.001) [81]. One hundred, fifty-one of 350 women with primary breast cancer had bone marrow micrometastatic disease, and 136 patients had died from breast cancer [81]. Furthermore, results from a study with a median follow-up of 20 years, showed that all micrometastatic patients relapsed and died of disease progression within 6 years with evident osseous metastases [82]. Another study has also shown that the presence of disseminated tumor cells in the marrow is associated with poor outcome of OS, cancerspecific survival, and DSF, and the presence of micro1

Local

Percentage surviving

0.9

Regional

0.8

Distant

0.7 0.6 0.5 0.4 0.3

metastases in the first years of follow-up were associated with significant reduction in OS (HR=1.81; p<0.001) [57]. 4.2 Costs of distant metastases A few studies that have investigated the economic impact on breast cancer recurrence indicate that the costs are significantly higher in patients treated for metastatic relapse than those with metastasis at diagnosis. This is further supported by a retrospective cohort study of 1616 patients with early breast cancer, which showed that the mean total care charges were higher by $43,803 in contralateral recurrences, $66,927 in locoregional recurrences, and $102,504 in DM compared with patients who had no recurrence [83]. With such startling economic differences by site of breast cancer recurrence, it may be prudent for therapies to focus on reducing the risk of recurrence, especially DM, in order to reduce the cost of care for patients with early breast cancer. 4.3 Quality of life and distant metastases The emotional well-being of women suffering from breast cancer recurrence is probably the most difficult aspect of the disease to deal with or treat, and yet very little empirical analysis exists in this domain of disease management. A study undertaken to assess quality of life (QoL) in patients with recurrent breast cancer indicated serious dampening effects on the physical, functional, and emotional wellbeing of patients and their immediate family members caring for them [84]. It is also increasingly evident that patients with DM in breast cancer suffer from acutely compromised QoL [85], which may include a worsening of physical health, functional status, and psychological distress compared with those who remain free of recurrence [86]. Another study illustrates that patients with DM experience substantially poor health states compared with patients with locoregional recurrences [87] and that women with metastatic recurrences reported significant decline in social support compared with disease-free survivors, probably resulting from the physical limitations imposed by the disease on their social lives [85]. Yet, it should be noted that over half (65%) of breast cancer patients readily accept treatment-related decline in QoL in exchange for a small to modest reduction (5%) in the risk of recurrence [88].

0.2 0.1

5 Current issues

0 0

1

2

3

4

5

Years since relapse

Fig. 2 Disease-specific survival by site of recurrence (p<0.0001 local versus nodal or distant). Figure reprinted with permission from Elsevier Ltd. [18]

5.1 Advances in the detection of metastases Physical attributes of tumors, microscopy and histopathology, have traditionally been the indicators of metastasis

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and, thus, the focus of detection methods [48, 52, 89]. The presence of micrometastatic lesions, which exhibit a limited disease burden at the time of diagnosis, is consistently cited as the cause for failure in the treatment of cancer. Micrometastases cannot be detected by the routine clinical or histopathological techniques [90]. Immunohistochemistry assessing expression of specific prognostic marker (for example, E-cadherin) has met with limited success [22]. Given the critical need for early detection of micrometastases that lead to high risk of relapse, sensitive diagnostic tools that may aid in the timely management of patients with distant metastatic disease have been under scrutiny. Recent advances in the form of ultrasensitive immunocytochemical and molecular assays enable the detection of a single metastatic cell. Disseminated tumor cells as a measure of metastatic disease are being investigated, and the presence of circulating tumor cells in patients with metastatic disease was marked by disease progression and increased levels of the tumor marker [91]. Interestingly, one study found that about 20 to 40% of patients with epithelial tumors have metastatic cells in the marrow but do not demonstrate apparent lymph node metastasis or clinical symptoms of DM [92]. 18Ffluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans have been used to provide more information on lymph node involvement and distant lesions related to metastases [93]. Reverse transcription polymerase chain reaction (RT-PCR) provides a valuable detection tool to search for tumorassociated mRNA transcripts in breast cancer, especially in the absence of specific DNA markers. However, the low transcript level of tumor-associated genes is a serious limitation for detection of single tumor cells by this method [92]. These advances in detection, however, need further validation and international consensus on defining quality control issues. 5.2 Breast cancer treatment and distant metastases The ultimate success in treating DM is dependent on the integration of effective systemic treatment with localized treatments (surgery and/or radiotherapy) [94]. Postmastectomy radiotherapy has been shown to effectively alter the disease recurrence pattern in breast cancer patients, reducing both locoregional recurrence and overall DM [95]. A 20-year follow-up study comparing the efficacy of radical mastectomy with breast-conserving surgery found a similar reduction in DM in both arms (83 events versus 82 events, p=0.8), and the long-term survival rates among the two arms are also similar [96]. Several clinical trials have shown the efficacy of adjuvant chemotherapy and endocrine therapy in improving distant disease-free survival and, with longer follow-up, OS in breast cancer patients [97].

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Adjuvant endocrine therapy with tamoxifen had been the mainstay therapy for postmenopausal women with hormone-sensitive breast cancer for more than 20 years, yet studies suggest that it was more beneficial in reducing locoregional recurrences than distant metastatic recurrences [98, 99]. In fact, a recent gene expression profiling study found that patients at increased risk of DM benefited least from tamoxifen [100], which is in agreement with another study wherein the gene expression profile revealed that about one third of patients (29%) treated with tamoxifen developed early DM [101]. Fortunately, the development of aromatase inhibitors led to the displacement of tamoxifen as the gold standard, because the superior benefits of aromatase inhibitors over tamoxifen in reducing relapse risk have been consistently demonstrated in several large clinical trials [75, 102, 103]. As distant metastatic events account for the majority of early relapse events, it seems that initiating treatment with an aromatase inhibitor would be the most prudent course of action [104]. Moreover, as surgery has been hypothesized to induce angiogenesis and the proliferation of distant dormant micrometastases [105], the use of initial adjuvant aromatase inhibitor therapy to minimize the incidence of metastatic spread may be optimal. Between the two approved aromatase inhibitors in the initial adjuvant indication, letrozole has demonstrated a more pronounced effect in reducing the risk of DM early in the course of therapy at 2 years than anastrozole [106, 107]. 5.3 Skeletal metastases in breast cancer: unmet needs Imaging techniques are predominantly used for the diagnosis of bone metastases in cancer patients, however, these techniques have limited potential in providing early diagnosis and also in predicting disease outcome [108]. Bone metastases are associated with increased skeletal complications and increased activity of osteoclasts. Use of bisphosphonates against increased bone resorption has gained support because of their potential to inhibit the activity of osteoclasts. Both preclinical and preliminary clinical data are indicative of their therapeutic potential in preventing the onset of malignant bone disease in patients with early-stage cancer [109]. Bisphosphonate therapy has also been shown to reduce the incidence and number of new bony and visceral metastases in women with breast cancer who were at risk for DM [110]. Among the bisphosphonates available, intravenous zoledronic acid is widely used for the treatment of skeletal metastases in many countries [109]. Zoledronic acid has proven beneficial effects against skeletal complications and is approved for the treatment of bone metastases occurring from any solid tumor [111]. Emerging evidence points to the antiangiogenic activity of zoledronic acid, which further

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extends its utility as a therapeutic agent in advanced breast cancer patients [112]. A variety of studies have identified potential biomarkers associated with increased risk of skeletal metastases as well as those predictive of drug response to bisphosphonates; these may not only help to better identify appropriate candidates for bisphosphonate therapy but also aid in monitoring drug response in patients [113–116]. In nonskeletal metastases the benefit of bisphosphonates is still inconclusive due to conflicting data [117]. It is, however, important to note that bisphosphonates do not have direct cytotoxic effects on the tumor cells but bind to bone surfaces, block signal transduction of osteoclasts, and effectively inhibit osteolysis [118]. It has also become increasingly necessary to evaluate the long-term use of bisphosphonates especially in breast cancer patients who have prolonged survival, particularly in the context of skeletal-related events [119]. Despite the success of bisphosphonates in treating bone metastases, some skeletal events and cancer progression may still occur, which emphasizes the need for improvement in skeletal metastases therapy. Trastuzumab, a monoclonal antibody directed against HER2/neu oncogene, has been shown to inhibit skeletal metastases in breast cancer [120], but trastuzumab has also been associated with cardiac dysfunction, congestive heart failure, and pulmonary toxicity [121]. New agents are being developed to treat skeletal metastases (Table 2) [122–131], but they also have some safety and specificity drawbacks. Receptor activator of nuclear factor-κB ligand (RANKL) mediates osteoclast

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differentiation and is found to be elevated in breast cancer cells causing excessive bone resorption. A recently developed anti-RANKL antibody, denosumab, binds to RANKL, inhibiting its action. A phase II safety and efficacy trial of denosumab revealed a modest 1.9% incidence of neoplasm and 1% incidence of unspecified infection in the antibody arm versus the placebo arm, both of which were not significant [132]. Monoclonal antibodies, however, run the risk of immunogenicity, and antibodies against denosumab were detected in two patients in the phase II trial but did not have an effect on the overall response [122]. Myelosuppression, although mild, was a safety concern with α-emitter radium 223Ra when evaluated for treatment of skeletal metastases in breast and prostate cancer patients [123]. The disease mechanism and prognosis of skeletal metastases may demand more selective molecular targets such as therapeutics that target the bone cells and the bone microenvironment or agents that prevent the paracrine or autocrine activities of tumor cells. This is of particular relevance as it is plausible that the selective affinity of breast cancer cells to grow in the skeleton is associated with its osteoblast-like phenotype [133], and the advent of newer studies that point to the specificity of osteolytic bone destruction are of great interest. Bendre et al. [134] presented data that supported the view that tumor-derived interleukin-8 (IL-8) stimulates osteolysis independent of RANK pathway and that different IL-8-derived peptides may have distinct proosteoclastogenic activity. Another study established the involvement of connective tissue growth factor (CTGF/CCN2) and parathyroid hormone-

Table 2 Investigative agents for the treatment of skeletal metastases associated with breast cancer Agent

Description

Development Status

Reference

Denosumab

Monoclonal antibody to receptor activator of nuclear factor-κB ligand (RANKL) Radiopharmaceutical; α-emitter Fusion gene encoding the extracellular and transmembrane domains of the human nerve growth factor receptor and the cytoplasmic portion of the yeast CD gene (NGFR-CD(y)) Natural compound present in vegetables of the genus Brassica; can inhibit NF-κB in breast cancer cells An antibody against the extracellular bone matrix protein bone sialoprotein (BSP), considered being involved in the pathogenesis of lytic skeletal lesions, which are associated with severe morbidity in breast cancer patients Non-RGD-based integrin binding peptide TGF-β type I receptor kinase inhibitor An antibody against parathyroid hormone-related protein (PTHrP), which is implicated in bone metastasis αvβ3 integrin selective inhibitor Vitamin D analogue

Phase III clinical

[122]

Phase II clinical Preclinical

[123] [124]

Preclinical

[125]

Preclinical

[126]

Preclinical Preclinical Preclinical

[127] [128] [129]

Preclinical Preclinical

[130] [131]

Radium-223 (Ra223) Cytosine deaminase (CD) gene therapy plus radiation treatment Indole-3-carbinol Antibody against bone sialoprotein

ATN-161 TβRI-I Humanized antiparathyroid hormone-related protein mAb S247 EB 1089 (seocalcitol)

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related peptide in osteolytic metastasis and effective targeted therapy with anti-CCN2 [135]. There is also evidence that human platelet-derived growth factor BB isoform (PDGF-BB) may play a critical role in the development of osteosclerotic bone metastases [136]. While delineating the mechanism of bone metastasis, Park et al. demonstrated the specific role of NF-κB in osteolysis, which is mediated by granulocyte-macrophage colonystimulating factor (GM-CSF) induction [137]. This could unravel a plethora of opportunities in terms of therapy for skeletal metastases, because NF-κB is one of the wellunderstood molecular targets. Furthermore, bone matrix protein such as osteopontin, osteonectin, and bone sialoprotein are also being investigated as drug targets, because elevated expression of these proteins has been observed in breast cancer [138, 139].

6 Conclusions For breast cancer patients even after successful management of the primary tumor, the risk of developing DM remains. Distant metastatic recurrences are the most lethal form of breast cancer relapses and are associated with a high rate of mortality, a highly compromised QoL, and increased costs for care. Offering better treatment options that effectively reduce DM risk early will likely translate into improved survival for patients. It is important for the practitioner to be honest with patients in discussing the recurrence risk and the various therapeutic options that may substantially reduce DM risks, especially early on. For instance, tamoxifen may have a less pronounced effect in reducing DM early in the course of therapy when compared with aromatase inhibitors such as letrozole. With exciting new advances in the detection, diagnosis, and treatment of DM, a better and positive future is at hand for breast cancer patients. Acknowledgments This work was supported by grants MOP 10630 and 12609 to SAR from Canadian Institutes for Health Research (CIHR).

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