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The primary cause of death related to cancers can be traced back to metastases, originated from cancer cells. The presence of metastatic disease, the spread of cancer cells, is the most important prognostic and survival factor in patients with cancer. Although treatment of the primary tumor is well established and usually results in local control, treating metastatic disease is a much more daunting task. At diagnosis, few patients present with clinically detectable metastatic lesions regardless of the clinical prognostic factor.

Clinical trials assessing potential therapeutic agents are important in order to define the best specific treatment for a particular patient, which are the basis for patient-oriented research that eventually lead to personalized medicine. This volume aims to comprehensively present the latest research and information about metastasis. Keywords: Oral cancer, gene expression profiling, lymph node metastasis, microarray, diagnosis and prognosis, biomarker. Abstract: Even though lymph node metastasis accounts for the vast majority of cancer death in patients with oral cancer OC , the molecular mechanisms of lymph node metastasis remain elusive.

Volume 6 , Issue 4 , Journal Home. Close Print this page. Content: Citation Only. Lapatinib appears to be associated with less cardiotoxicity than trastuzumab. An analysis of 3, patients treated with lapatinib in clinical trials reported a 1. A recent analysis from the Lapatinib Expanded Access Program, in which lapatinib was given in combination with capecitabine to 2, patients with advanced breast cancer, reported a 0.

However, as lapatinib development is extended to include the treatment of patients with lower-risk primary breast cancer, it will be increasingly important to monitor cardiotoxic effects. The most common adverse effects associated with lapatinib treatment are gastrointestinal; lapatinib-related diarrhea generally occurs early in the course of treatment, is mild to moderate, and does not require treatment, although monitoring is important to identify patients who may need intervention [ 90 ].

In the U. Gefitinib monotherapy is currently approved in the U. Recent clinical studies have not demonstrated any significant clinical benefit for erlotinib or gefitinib either as single agents or in combination with other agents in MBC [ 93 — 99 ]. Given their lack of activity as monotherapy in MBC, studies continue to investigate the efficacy of erlotinib and gefitinib in combination with other targeted therapies, chemotherapy, or hormonal agents; however, tolerability issues may limit this approach.

Neratinib HKI is an orally administered, irreversible, pan-erbB kinase inhibitor [ ]. The observation that some patients with chronic myelogenous leukemia were developing resistance to the TKI imatinib led to the development of neratinib. In preclinical models, neratinib has been shown to have promising antiproliferative activity in both HER-2—dependent cell lines and tumor xenografts. Clinical development has seen trials conducted in patients with NSCLC and in patients with breast cancer.

A total of 25 patients in that study had MBC. Importantly, all responders were heavily pretreated, having received prior trastuzumab, anthracycline, and taxane therapy [ ]. Phase III trials that are ongoing include a study of single-agent neratinib in trastuzumab-pretreated patients with early breast cancer, a study of neratinib versus lapatinib and capecitabine in trastuzumab-pretreated MBC patients, and a study of neratinib plus paclitaxel versus trastuzumab plus paclitaxel as first-line therapy for patients with MBC [ ].

In summary, experience with agents targeting the HER family shows that agents such as trastuzumab, lapatinib, and neratinib are clinically active in MBC and are generally well tolerated. However, evidence is increasing that agents targeting HER-1 alone are not associated with clinical benefit in the MBC setting. Accurate patient selection based on HER-2 overexpression is essential for trastuzumab-based treatment and is likely to be important for other agents in this class. However, identifying suitable patients may prove more difficult for TKIs, because receptor overexpression alone does not seem to predict response to treatment [ 13 ].

HER-targeted agents may need to be used in combination with chemotherapy to provide clinically relevant activity, according to classical ORR criteria. Targeting HER-2 is associated with cardiac toxicity, which is an especially important consideration in the adjuvant setting and when combining anti—HER-2 agents with cardiotoxic chemotherapeutic drugs.

Targeting HER-1 in combination with HER-2, as with the TKIs lapatinib and neratinib, appears to reduce the risk for cardiotoxicity, although the exact mechanisms underlying this observation remain unclear.

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Targeting HER receptors with extracellular monoclonal antibodies and intracellular TKIs has shown promising clinical activity. There is, however, a need for better treatment of MBC patients because many of these current therapies are restricted to a subset of the MBC patient population. Additionally, there is some evidence that targeting heat shock proteins Hsps and the apoptotic pathway may be viable options for future therapeutic strategies in MBC. Recent developments in this field are briefly discussed in the following sections.

The MAPK pathway, also termed the extracellular signal-regulated kinase ERK pathway, contains downstream effectors of the HER family and other tyrosine kinases, and is a central part of the signaling networks that control fundamental cellular processes, including cell proliferation, differentiation, and survival [ ] Fig. The PI3K pathway also plays a central role in numerous cellular signaling pathways, and has been linked to a range of processes involved in tumor development, including cell proliferation, cell growth, cell motility, cell survival, and angiogenesis [ 24 ] Fig. The farnesyl transferase inhibitor tipifarnib R was evaluated in phase III trials for the treatment of breast cancer, although further development has now been terminated [ — ].

Therapies targeting the PI3K pathway include perifosine KRX , which inhibits Akt phosphorylation [ ], and the rapamycin analogs that target mammalian target of rapamycin, such as temsirolimus CCl [ — ] and everolimus RAD [ 46 , 47 , , ]. Although early indications suggest that targeting components of the PI3K pathway may have some activity in the treatment of MBC, additional data, including an understanding of combinations and patient selection, are required.

Apoptosis, the process of programmed cell death, is governed by complex, gene-directed pathways [ — ]. Dysregulation of apoptosis plays a key role in tumorigenesis and can allow tumor cells to become resistant to anticancer treatments [ , ]. Anticancer agents targeting the components of apoptotic pathways are in the early stages of development, and no agent specifically targeting apoptosis has yet been approved for use in cancer treatment.

A range of approaches is being tested, including antisense DNA oligonucleotides and antibody and small molecule inhibitors of the components of apoptotic pathways. Few clinical data are currently available in breast cancer; however, preclinical studies show that such agents do have anticancer activity, suggesting that this may be a promising approach, particularly when used in combination with chemotherapy.

Hsp acts as a regulator of the HER family by functioning as a chaperone protein, binding to and maintaining client molecules in their active conformation [ ]. Hsp is overexpressed two- to tenfold in human tumor cells [ ]. Although Hsp is associated with many cellular pathways and effectors, both HER-1 and HER-2 require chaperoning by Hsp for their stability [ ], and Hsp is able to disrupt the ability of HER-2 to form signaling heterodimers on ligand binding [ ].

A range of Hsp inhibitors has been developed and evaluated in clinical trials for the treatment of breast cancer, including tanespimycin KOS, AAG in Cremophor. Further studies are needed to confirm the effectiveness and safety profile of current Hsp inhibitors. The process of angiogenesis the formation of new blood vessels from a pre-existing vascular bed is complex and dynamic, and it is regulated by a range of pro- and antiangiogenic molecules [ ].

Activation of VEGFRs and PDGFRs initiates signaling that results in numerous cellular responses, including survival, mitogenesis, migration, proliferation, and differentiation [ , ]. Activation of the VEGF pathway also increases vascular permeability and the movement of endothelial progenitor cells from the bone marrow into the peripheral circulation [ ].

Circulating Tumor Cells in the Parallel Invasion Model Supporting Early Metastasis

Primary breast tumors express a variety of different angiogenic factors, with VEGF being the most abundant. High VEGF expression appears to be correlated with poor prognosis and response [ ]. Levels of VEGF in breast cancer tumors are a prognostic factor for relapse-free and overall survival in patients with both lymph node—negative and lymph node—positive disease [ , ], and they predict response to both tamoxifen and chemotherapy in advanced disease [ ].

It is increasingly being accepted that tumor cell proliferation alone is insufficient to result in a substantial tumor mass. Angiogenesis is essential for tumors to develop into detectable localized masses, and for metastasis to occur [ , ]. However, with considerable redundancy in angiogenic signaling pathways, the inhibition of more than one receptor is likely necessary to block angiogenesis.

It has been hypothesized that anti-VEGF agents may prevent the development of new tumor vasculature and induce normalization of existing, inefficient tumor vasculature resulting from overexpression of VEGF [ ]. These agents, then, may allow better delivery of cytotoxic therapies to the tumor, suggesting a potential role for anti-VEGF therapy in conjunction with chemotherapy [ , ]. Several therapies targeting angiogenesis are in development for breast cancer. Bevacizumab is an anti-VEGF humanized monoclonal antibody administered as an i.

Bevacizumab is currently approved for use in combination with paclitaxel as first-line treatment for patients with MBC [ ]. A number of single-agent TKIs with multiple molecular targets have been developed as an alternative to combining multiple agents. These were developed based on previous studies showing that combining agents that target different pathways may have synergistic activity and delay or reverse resistance [ 59 , — ].

It has antiangiogenic and antitumor activities and is approved multinationally for the treatment of advanced renal cell carcinoma RCC and for gastrointestinal stromal tumors after disease progression on or intolerance to imatinib mesylate therapy [ ]. In both the U. Phase III studies have investigated bevacizumab combined with chemotherapy Table 4 [ — ].

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In , the U. Food and Drug Administration FDA approved bevacizumab in combination with paclitaxel for the first-line treatment of locally recurrent breast cancer or MBC [ ].

Tumor growth

This approval was controversial after the FDA's Oncologic Drugs Advisory Committee recommended that the phase III data E were insufficient to establish a favorable risk—benefit profile, with the efficacy data based on PFS rather than overall survival. Based on the results from the AVADO trial, the existing EU label permitting the use of bevacizumab in combination with docetaxel was extended to allow bevacizumab to be combined with docetaxel, thus allowing additional patients access to bevacizumab treatment.

Further analyses of the AVADO trial have revealed that treatment continuation with single-agent bevacizumab after discontinuation of docetaxel appears to delay disease progression [ ], that there is no apparent correlation between the efficacy of bevacizumab plus docetaxel and hypertension or G-CSF use [ ], and that the combination does not appear to be associated with a higher incidence of grade 3—5 bleeding events [ ]. In summary, although bevacizumab has shown little activity as a single agent in MBC patients, combination therapy with chemotherapeutic agents has been associated with clinical activity in this patient population.

This suggests that VEGF inhibition combined with chemotherapy is a promising treatment strategy in this setting.

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Further studies are under way to explore the use of bevacizumab with different chemotherapeutic regimens, hormonal treatments, and other targeted therapies including lapatinib and trastuzumab in patients with MBC. Additionally, trials of bevacizumab are ongoing in the adjuvant and neoadjuvant settings, and preliminary reports suggest that this approach may be feasible; however, there are concerns about hypertension and bleeding [ ].

Indeed, hypertension, bleeding, and thrombosis remain potential safety concerns with a number of anti-VEGF therapies, and this area requires further study. Future trials should focus on identifying those patients who will derive the most benefit from bevacizumab-based regimens and how best to combine bevacizumab with other cancer therapies which therapies should be combined and whether sequential or concurrent administration is most effective.

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  5. Overall, growing clinical experience with agents targeting angiogenic processes, such as bevacizumab, has provided proof of concept for the use of these treatments in MBC patients. Sunitinib has been shown to have antitumor activity in breast cancer preclinical studies, both as a single agent and in combination with chemotherapy [ , , ]. Studies and case series evaluating sunitinib given in combination with taxane therapy for MBC have reported antitumor activity and a manageable and tolerable safety profile [ — ].

    Of 18 evaluable patients in an exploratory study, Phase III trials of sunitinib in combination with a variety of cytotoxic agents are under way in first- and second-line MBC therapy [ ]. Although two phase III studies of sunitinib in the advanced disease setting single-agent sunitinib in the first, second, and third lines of therapy and first-line sunitinib plus paclitaxel versus bevacizumab plus paclitaxel have been stopped after preplanned interim analyses indicated that the primary endpoint would not be reached, other combination phase III studies are ongoing.

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    7. These include SUN second- and third-line sunitinib plus capecitabine and SUN first-line sunitinib plus docetaxel.