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The Oncologist, Vol. 8, No. 1, 5–17, February 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
BREAST CANCER

Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention

Rita Nahtaa, Gabriel N. Hortobágyia, Francisco J. Estevaa,b

a Departments of Breast Medical Oncology and b Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Francisco J. Esteva, M.D., Ph.D., Departments of Breast Medical Oncology and Cellular and Molecular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 424, Houston, Texas 77030, USA. Telephone: 713-792-2817; Fax: 713-745-5768; e-mail: festeva{at}mdanderson.org


   ABSTRACT
Top
 Abstract
Introduction
 Epidermal-Growth-Factor-Receptor...
 HER2-Targeted Therapy
 Insulin-Like Growth Factor-I...
 Conclusion
 References
 
Increased expression and activation of receptor tyrosine kinases occurs frequently in human breast carcinomas. Several therapies targeting these receptors are currently in clinical trials. Therapeutic strategies include blockade of individual receptors with monoclonal antibodies and inhibition of tyrosine kinase function. Trastuzumab is the first of these biologic therapies to be approved for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. Novel trastuzumab-based combinations are being investigated in patients with advanced breast cancer. Large clinical trials have also been launched in the adjuvant setting. Small molecules that inhibit specific tyrosine kinases (e.g., epidermal growth factor receptor, HER2) are in phase I and phase II clinical trials. Other growth-factor-targeted drugs that have reached clinical development include STI571 and antibodies directed at the insulin-like growth factor pathway. Biologic therapies directed against these important receptors are promising. In this review we discuss challenges and opportunities for the development of growth-factor-targeted approaches for the treatment of breast cancer.

Key Words. Breast neoplasm • Biologic therapy • Prognostic markers • IGF-IR • EGFR • HER2 • Monoclonal antibodies • Tyrosine kinase inhibitors


   INTRODUCTION
Top
 Abstract
 Introduction
Epidermal-Growth-Factor-Receptor...
 HER2-Targeted Therapy
 Insulin-Like Growth Factor-I...
 Conclusion
 References
 
Traditional cancer therapeutics have relied heavily upon the ability to inhibit DNA replication or cell division [1]. While this approach has proven effective in some patients, lack of tumor-cell selectivity has limited response rates and complicated treatment with numerous adverse effects. Thus, the current goal of anticancer drug design is to directly target specific molecular lesions found in tumor cells in the hope of improving cancer cure rates and reducing cytotoxicity in normal cells. The efficacy of this "targeted" approach is best illustrated by therapies that inhibit estrogen receptor (ER) function or synthesis of estrogen. The ability of the selective ER modulator tamoxifen to inhibit growth of and prevent ER-positive breast cancers demonstrates that specific components of individual growth factor pathways can be directly targeted to successfully treat breast cancer [2].

Breast cancer cells require activated growth factor receptors to proliferate, invade, and metastasize in experimental models. Overexpression of growth factor receptors has been associated with a poor clinical outcome in breast cancer patients. Biological therapy directed against growth factor receptor pathways is being pursued on a variety of fronts. This review focuses on the available preclinical data and on clinical research efforts to develop growth factor receptor inhibitors into novel therapeutics for breast cancer.


   EPIDERMAL-GROWTH-FACTOR-RECEPTOR-TARGETED THERAPY
Top
 Abstract
 Introduction
 Epidermal-Growth-Factor-Receptor...
HER2-Targeted Therapy
 Insulin-Like Growth Factor-I...
 Conclusion
 References
 
Dr. Stanley Cohen first identified the epidermal growth factor (EGF) peptide and its 170-kD receptor (EGFR), both of which were later found to contribute to the unregulated proliferation of cancer cells through an autocrine growth-promoting mechanism [3-5]. The EGFR was first linked to human cancer when homology was identified with the viral oncogene v-erbB, and its tyrosine kinase function was found to be similar to that of the Src oncogene [6-10]. Overexpression of wild-type EGFR or expression of a truncated form of EGFR (EGFR vIII) is found in some breast cancers (Table 1Go). Therapies targeting the EGFR are likely to be beneficial in this subset of tumors. Strategies including antireceptor antibodies, tyrosine kinase inhibitors, ligand-toxin conjugates, and receptor antisense molecules have been explored, as outlined in Figure 1Go. As antireceptor antibodies and tyrosine kinase inhibitors are currently in clinical trials, we focus on experiences related to these strategies.


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  		Table 1. Expression of growth factor receptors in breast cancer
 


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  		Figure 1. Areas of potential therapeutic intervention.

 
Anti-EGFR Antibodies
Several murine monoclonal antibodies (mAbs) targeted toward the EGFR extracellular region have been produced. These antibodies compete with ligands for receptor binding, blocking autocrine and paracrine growth factor loops, and induce receptor dimerization and downregulation [11, 12]. Furthermore, receptor blockade by antibodies inhibits downstream signaling, producing various molecular and biological effects that may inhibit the growth of EGFR- and human epidermal growth factor receptor 2 (HER2)-expressing breast cancer cells. However, the use of these murine mAbs has been limited by their ability to produce immune responses characterized by production of human anti-mouse antibodies. Thus, to reduce immunogenicity, human-mouse chimeric and fully humanized antibodies have been generated [13].

IMC-C225
IMC-C225 (cetuximab; ImClone Systems; New York, NY) is a chimeric mAb directed against an extracellular epitope of the EGFR. IMC-C225 competitively inhibits binding of the EGFR ligands EGF and transforming growth factor-{alpha} due to a 10-fold higher affinity for the receptor. Preclinical evidence of anticancer activity is summarized in Table 2Go. While in vitro data suggest that IMC-C225 is cytostatic [13, 14], MDA468 breast cancer xenografts regressed when treated with IMC-C225, suggesting that additional antitumor mechanisms function in vivo [13, 15]. These mechanisms may include reduced angiogenesis, decreased metastasis, or immunocytotoxicity [11]. Phase I/II studies of IMC-C225 in EGFR-overexpressing cancers achieved stable disease when administered as a single agent and some partial remissions when combined with cisplatin or irinotecan in head and neck, colorectal, and non-small cell lung cancers. No major organ toxicities were documented, but acneiform rash and folliculitis were commonly observed. Across all clinical trials, immunogenic responses against the murine portion of the chimeric mAb were reported in only 4% of patients [16]. IMC-C225 has also demonstrated increased response to radiation therapy in head and neck tumors [17]. Several phase II/III trials of IMC-C225 are currently in progress for various solid tumors (Table 3Go).


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  		Table 2. Preclinical activities of growth-factor-receptor-targeting agents in breast cancer
 

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  		Table 3. Growth-factor-receptor-targeting agents in clinical development
 

ABX-EGF
Fully humanized antibodies eliminate the immunogenic effect of mouse and chimeric mouse-human antibodies and can be produced through XenoMouse® technology (Abgenix; Fremont, CA). Through this method, mouse antibody genes are inactivated and replaced with genes encoding human antibodies. Hence, mice immunized with EGFR will produce fully humanized antireceptor antibodies [18, 19]. ABX-EGF was produced by XenoMouse® technology and possesses high affinity and specificity for the EGFR. Complete eradication of A431 tumor xenografts occurred upon treatment with ABX-EGF in the absence of chemotherapy [20, 21]. Furthermore, ABX-EGF suppressed growth of MDA468 xenografts, demonstrating its potential efficacy against breast tumors [20, 21]. Cooperation of ABX-EGF with chemotherapeutic agents such as doxorubicin has also been demonstrated. Interestingly, ABX-EGF prevented solid tumor formation in nude mice injected with cancer cells, suggesting development of this antibody as a preventive agent [21]. Phase I clinical trials are currently examining ABX-EGF in solid tumors.

EGFR Tyrosine Kinase Inhibitors
As tyrosine kinase activity is required for EGFR-mediated tumorigenicity, therapies that ablate this function are currently being tested in clinical trials. Mutations in the EGFR ATP-binding site were shown to eliminate receptor kinase activity and prevent cellular transformation. Thus, small molecule tyrosine kinase inhibitors (TKIs) that competitively block ATP binding were designed as potential anticancer agents. Importantly, since these agents target an intracellular region of the EGFR, they could potentially inhibit the highly tumorigenic EGFR mutant vIII, which is a truncated receptor frequently found in breast cancer and may be inaccessible to mAbs [22]. Quinazoline compounds represent a class of competitive inhibitors of the ATP-binding site that are orally active, potent, and selective tyrosine kinase inhibitors [23]. Among the most widely examined thus far are the EGFR-specific ZD1839 and OSI-774 and an inhibitor of all four Her family receptors (called a pan-Her inhibitor), CI-1033.

ZD1839
ZD1839 (IressaTM; AstraZeneca; Macclesfield, UK) reversibly inhibits the EGFR and its downstream signaling with high specificity, requiring 100 times higher concentrations to inhibit other kinases. Preclinical studies, the results of which are described in Table 2Go, reported a 50% bioavailability of orally administered ZD1839 without drug-related toxicity despite EGFR being a widely expressed protein [24, 25]. Phase I studies of ZD1839 in solid tumors revealed peak plasma levels of drug 3-7 hours after a single oral dose, with a half-life ranging from 12-51 hours [24, 26]. Continuous, daily, oral administration with an intermittent schedule of 14 of 28 days revealed a longer median half-life of 46-49 hours [25, 27]. The dose-limiting toxicity was diarrhea with adverse effects including an acneiform rash, nausea, and vomiting. Phase I/II trials demonstrated partial responses to ZD1839 in non-small cell lung cancer and prostate cancer, with several patients claiming improved quality of life [25, 27, 28]. Phase I/II trials of single-agent oral ZD1839 have included breast cancer patients, but have not yet revealed any change in disease status [25, 27]. Furthermore, ZD1839 did not reduce tumor exposure to chemotherapy when administered as part of a combination regimen [25]. A phase II trial is currently being conducted by the Eastern Cooperative Oncology Group in which HER2-overexpressing, trastuzumab-naïve metastatic breast cancer patients are treated with combined ZD1839 and trastuzumab [29]. Blockade of the EGFR may prevent transactivation of HER2, improving response rates to the HER2 mAb trastuzumab. Such a combination may also be considered for trastuzumab-resistant tumors, which may no longer be responding to trastuzumab due to compensatory signaling by the EGFR.

OSI-774
OSI-774 (TarcevaTM, formerly CP-358, 774; OSI Pharmaceuticals; Tarrytown, NY) is another orally active quinazoline that reversibly inhibits EGFR tyrosine kinase function. Preclinical studies reported an 80% bioavailability of orally administered OSI-774 with negligible drug-related toxicity at doses up to 15 mg/kg/day and emesis and gastrointestinal toxicity at higher doses. Phase I/II studies revealed that continuous administration of 150 mg/day of OSI-774 was well tolerated in patients with solid tumors including five breast cancer patients. The dose-limiting toxicity was diarrhea, occurring at 200 mg/day when administered on a continuous, daily schedule for 21 out of 28 consecutive days [30]. No dose-limiting toxicities were apparent when OSI-774 was given on a weekly schedule for 3-4 weeks at up to 1,600 mg/day. Adverse events included fatigue, headache, nausea, and an acneiform rash, which was similar to that produced by ZD1839 and occurred in 78% of patients [25]. Partial responses for renal and colon cancers and stable disease in prostate, non-small cell lung cancer, cervical, and head and neck cancers have been documented [30]. However, data regarding efficacy of OSI-774 against breast cancer have not yet been reported.

CI-1033
CI-1033 (PD183805; Pfizer; New York, NY) is another orally available quinazoline currently in clinical trials for solid tumors. In contrast to ZD1839 and OSI-774, CI-1033 irreversibly inhibits a region of the catalytic site conserved among all erbB receptors and is, therefore, called a pan-Her inhibitor [31]. CI-1033 is likely to be effective in a larger subset of breast cancer patients than EGFR-specific TKIs. Additionally, due to its irreversible binding to the kinase catalytic site, CI-1033 offers prolonged suppression of enzymatic activity, which may improve tumor response and require less frequent dosing.

Preclinical data are summarized in Table 2Go. Phase I trials have revealed an acceptable safety profile for CI-1033, with dose-limiting toxicities including diarrhea, acneiform rash, nausea, vomiting, and thrombocytopenia [22]. Pre- and post-treatment tumor biopsies were studied for biomarkers and showed 40%-50% reduced EGFR and HER2 phosphorylation, which correlated with decreased proliferation. Although partial remissions and stable disease occurred primarily in squamous cell skin cancer and advanced-stage non-small cell lung cancer, respectively, one heavily pre-treated breast cancer patient remained in a CI-1033 phase I trial for more than 6 months without disease progression [22]. Current clinical trials include testing CI-1033 in metastatic breast cancer patients who have failed trastuzumab therapy. As trastuzumab resistance is a considerable clinical problem that could potentially be due to compensatory signaling by other Her receptors, pan-Her inhibitors like CI-1033 may offer a new therapeutic strategy to these breast cancer patients.


   HER2-TARGETED THERAPY
Top
 Abstract
 Introduction
 Epidermal-Growth-Factor-Receptor...
 HER2-Targeted Therapy
Insulin-Like Growth Factor-I...
 Conclusion
 References
 
The neu gene was discovered in tumors in nitrosourea-treated rats, where it was isolated as a dominant-acting oncogene with a mutation in the transmembrane region [32-35]. The human homolog, known as c-erbB2 or HER2 was identified in human tumors using hybridization with v-erbB and EGF receptor probes and found to be amplified to 4-20 copies per cell [36, 37]. This gene is located at chromosome 17 q11-q12 and encodes a 185-kD transmembrane glycoprotein (p185HER2) having intracellular tyrosine kinase activity and an extracellular domain that is very similar to the EGF-binding domain of the EGF receptor [38]. Amplification of the HER2 gene results in the overexpression of mRNA and protein having a normal sequence. No mutations have been identified in human breast cancer cells. Although the mechanism of gene amplification is not known, experimental data show that HER2 acts as a potent oncogene in vitro [39] and in vivo [40, 41]. The HER2 gene is amplified in approximately 20%-25% of invasive breast cancers (Table 1Go) [42, 43]. A correlation has been noted between HER2 gene amplification and/or protein overexpression and poor disease-free survival [42, 44-49]. HER2 overexpression has also been associated with resistance to chemotherapy [50, 51] and hormone therapy [52]. However, the clinical implications of those associations remain controversial [53].

The strong linkage to the pathogenesis of breast cancer and its association with prognosis made HER2 a target for the development of new cancer therapies [54, 55]. There have been a multiplicity of approaches, as outlined in Figure 1Go. The level of HER2 expression found in human cancer cells where gene amplification occurs is much higher than that found in normal adult tissues. A second attractive aspect of the HER2 target is that it is present in a very high proportion of tumor cells [56], and tumors with high expression (score 3+) show uniform intense immunohistochemical staining [45, 57]. This characteristic suggests that, in a given patient, anti-HER2 therapy should be able to attack nearly all cancer cells. Finally, the HER2 overexpression phenotype is apparently shared between the primary tumor and metastatic sites [58]. This is important in that it indicates that therapy for metastatic disease can be selected based on analysis of the primary tumor, and again indicates that an anti-HER2 therapy should be able to treat all sites of disease.

Anti-HER2 Antibodies
A number of studies have shown that mAbs directed against the HER2 protein can reduce the growth rate of human tumor cells [59-64] and sensitize them to chemotherapeutic agents [65, 66]. Although the mechanism of action of passive antibody therapy is not well defined, there is evidence that internalization may be necessary for biological activity [61, 65].

Trastuzumab
Trastuzumab (Herceptin®; Genentech; South San Francisco, CA) is the first HER2-directed therapy to gain approval from the U.S. Food and Drug Administration for the treatment of patients with metastatic breast cancer. Trastuzumab is a humanized mAb directed against the extracellular domain of the HER2 protein. Preclinical data on trastuzumab and its parental murine antibody, known as 4D5 or rhuMabHER2, are outlined in Table 2Go. Phase I trials of trastuzumab showed the antibody was safe, and pharmacokinetics were reliable. Response rates to trastuzumab given as a single agent ranged from 12%-40%, in part depending on the method used to determine HER2 status and the prior treatment received [67-69]. In a pivotal study, Slamon et al. [70] showed that combining trastuzumab with either doxorubicin plus cyclophosphamide (AC) or single-agent paclitaxel produced higher response rates and survival times than chemotherapy alone. However, the administration of AC plus trastuzumab caused severe cardiac dysfunction. This led to the development of trastuzumab-based combinations that do not contain anthracyclines [71, 72]. Regimens evaluated to date with promising results include cisplatin [73], weekly paclitaxel [74], docetaxel [75], vinorelbine [76], and gemcitabine [77]. Combinations of taxanes, platinum salts, and trastuzumab (TCH) are highly synergistic in vitro [78, 79]. Preliminary data from phase II studies of TCH have shown a promising high response rate and time to progression [80]. Slamon and colleagues [81] recently reported a time to progression of 17 months in patients with HER2-amplified metastatic breast cancer treated with docetaxel, carboplatin, and trastuzumab.

One of the lessons learned from the clinical development of trastuzumab is the importance of HER2 overexpression. It is now clear that only patients whose tumors carry HER2 gene amplification or high HER2 protein expression using immunohistochemistry (score 3+) benefit from trastuzumab-based therapy [69, 74, 75, 82]. Another method under investigation for predicting response to trastuzumab is the quantification of the extracellular domain (ECD) of the HER2 protein in the serum. Our group has recently shown that patients with high HER2 ECD levels at baseline had a higher response rate to docetaxel and trastuzumab therapy than patients who had low HER2 ECD levels prior to initiation of therapy [75]. A multicenter, prospective study is ongoing to evaluate the role of the HER2 ECD assay for patients with metastatic breast cancer undergoing trastuzumab-based therapy.

Perhaps the most promising application of trastuzumab mAb therapy will be in the adjuvant setting. Large randomized trials are being conducted by cooperative groups. The National Surgical Adjuvant Breast and Bowel Project (NSABP)-B31 protocol is randomizing node-positive, HER2+ breast cancer patients to either four cycles of AC followed by four cycles of paclitaxel or the same regimen plus trastuzumab (in combination with paclitaxel). The Breast Intergroup protocol N9831 is testing a similar sequential approach using weekly paclitaxel. In addition, trastuzumab is being administered either concomitantly with paclitaxel or after completion of AC and paclitaxel therapy [83]. Both studies allowed HER2 testing at local hospitals initially. However, a significant number of false positives were noted, and a more centralized testing approach was implemented to assure proper patient selection [83, 84]. The Breast Cancer International Research Group (BCIRG protocol 006) is evaluating the role of docetaxel with and without trastuzumab following AC chemotherapy. A third experimental arm incorporates the TCH regimen. This protocol includes node-positive and high-risk node-negative patients. HER2 status must be determined using fluorescence in situ hybridization at a central laboratory.

Novel Approaches to HER2-Antibody-Based Therapy
To increase the potency of antibody-directed therapy, the specificity of an antigen-binding site has been combined with a wide variety of effector agents. Toxins have been targeted to HER2 using chemical conjugation with intact antibodies [85]. Using this approach, trastuzumab has been linked to DM-1 toxin (preclinical studies ongoing). Another approach is to generate recombinant molecules in which an antibody combining site is fused directly to the toxin [85, 86]. These immunotoxin and oncotoxins are extremely potent molecules and show strong selectivity for HER2 binding. Recombinant toxins show promise in that they can be safely delivered to experimental animals at effective doses [87, 88]. Recombinant toxins are also attractive in that they are relatively small proteins and may be able to penetrate tumors more effectively. This is indicated by pharmacokinetic measurements showing that recombinant toxins readily leave the circulation [87, 89]. One potential limitation facing the development of toxin targeting is the potential for an immune response to the protein.

Radionuclides have also been attached to anti-HER2 antibodies. These have shown the ability to image tumors in experimental animals and in humans [90, 91]. The therapeutic application of radiolabelled antibodies to this and other types of cancer may depend on the attachment of isotopes of sufficient specific activity and suitable decay pathlength.

Approaches to immunotherapy have been developed that rely on targeting by anti-HER2 antibodies. Both are designed to deliver immune effector cells to the tumor. In the first approach, a single chimeric protein molecule is designed to have two antibody-binding specificities, one that binds HER2 and the other that binds an immune cell, either via CD16, Fc receptor III [92, 93], or CD3 [94]. Phase I clinical studies have allowed toxicity to be assessed, and there is evidence that a biologically relevant concentration of the experimental therapy can be achieved [95].

Inhibition of HER2 Synthesis
Since a primary event in inducing malignancy is HER2 gene amplification, several investigators have developed strategies to prevent the synthesis of mature HER2 at the cell membrane. The strategy most immediate to the underlying genetic defect derives from the finding that the HER2 gene can be repressed by the introduction of the adenovirus E1A gene [96]. Delivery of E1A expression constructs into human tumor cell lines using liposomes has resulted in inhibition of HER2 expression and loss of tumorigenicity [97]. A phase I clinical trial of E1A therapy showed that intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) is feasible in patients with breast cancer [98]. Antisense approaches to limiting HER2 expression have also been reported [99, 100].

HER2 Vaccines
As described, the level of expression of HER2 seen in human tumors with gene amplification is unprecedented in normal tissues. Consequently, it has been proposed that peptides derived from the erbB2 sequence could be presented by the human major histocompatibility complex and recognized by the T-cell receptor on lymphocytes [101, 102]. Although the gene amplified in human tumors is apparently normal, tolerance might be broadened by a quantitative increase in epitope display. Consistent with this concept is the finding that T-helper, cytotoxic, and antibody responses have been identified in patients whose tumors overexpress HER2 [103]. As a consequence, several peptide sequences within erbB2 that mediate T-helper or cytotoxic responses have been identified [104, 105]. Such peptides, or potentially a larger expression construct containing more of the erbB2 coding sequence, might be used as a vaccine. No evidence of autoimmune consequences have been observed in these or in tumor-bearing patients [101].

STI571
STI571 (imatinib mesylate; GleevecTM; Novartis; Basel, Switzerland) was the first successful rationally developed receptor-targeted agent for chronic myelogenous leukemia (CML). This phenylaminopyrimidine derivative was selected from a screen of molecules for its ability to competitively target the ATP-binding site of the platelet-derived growth factor receptor (PDGFR) [106]. In vitro analysis revealed that STI571 also selectively inhibits the ABL and KIT (CD117) tyrosine kinase receptors. Initial phase I/II studies of STI571 were performed in CML patients who failed interferon therapy and in acute lymphoblastic leukemia (ALL) patients harboring constitutively active ABL due to bcr-abl chromosomal translocations (i.e., Philadelphia chromosome). CML patients in chronic phase (i.e., less than 15% blasts) demonstrated that the threshold maximum effective dose for STI571 is 300 mg, at which complete hematologic and cytogenetic responses were achieved in 98% and 13% of patients, respectively. Responses were still evident after a median follow-up time of almost 1 year [107, 108]. Kantarjian and colleagues [109] recently reported a phase II study of 532 chronic-phase CML patients previously treated with interferon alpha. In that study, 400 mg oral STI571 daily produced major cytogenetic responses in 60% of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95%. Phase I studies in relapsed Bcr-abl+ ALL patients and CML patients in myeloid or lymphoid blast crisis demonstrated reduced marrow blasts of less than 5% in 21% of myeloid patients and 55% of lymphoid patients [107, 108]. Toxicity was low in all trials, although grade 2-3 myelosuppression was observed in 10%-20% of patients, and may represent the therapeutic effect of reduced lymphocyte counts.

STI571 has also demonstrated activity against conditions in which either KIT or PDGFR is activated. Activating mutations of c-kit (CD117) are common in gastrointestinal stromal tumors [110]. An open-label, randomized trial of 400 mg or 600 mg STI571 in 147 GIST patients demonstrated partial responses in 54% of patients and stable disease in 28%, but did not result in any complete responses [111]. Four patients with chronic myeloproliferative disease harboring an activating translocation of the PDGFR-ß gene treated with STI571 demonstrated normal blood counts and reduced levels of PDGFR within 3 months of treatment initiation [112]. Additionally, a patient with unresectable metastatic dermatofibrosarcoma protuberans achieved 75% tumor shrinkage upon 4 months of STI571 treatment, allowing resection of the mass [113].

PDGFR and KIT are expressed in most breast tumors (Table 1Go). Autocrine stimulation of KIT and PDGFR by stem cell factor and PDGF, respectively, is observed in breast tumors and may enhance mitogenic signaling [108, 114]. Therapeutic inhibition of KIT and PDGFR by STI571 is being examined in a phase II study at the University of Texas M. D. Anderson Cancer Center in metastatic breast cancer patients.


   INSULIN-LIKE GROWTH FACTOR-I-RECEPTOR-TARGETED THERAPY
Top
 Abstract
 Introduction
 Epidermal-Growth-Factor-Receptor...
 HER2-Targeted Therapy
 Insulin-Like Growth Factor-I...
Conclusion
 References
 
The insulin-like growth factor (IGF) mitogenic signaling pathway is an attractive therapeutic target in breast cancer as its ligands and receptors are frequently overexpressed and implicated in cellular proliferation, transformation, and metastasis [115]. The IGF system is composed of ligands IGF-I and IGF-II, receptors IGF-IR and IGF-2R, and at least six IGF binding proteins (IGFBPs). High circulating levels of IGF-I are associated with a greater risk of breast cancer in premenopausal women, with an especially high risk among those younger than 50 years [116]. Elevated expression of IGF-II is linked to poor prognosis in breast cancer [117]. The IGF-IR is highly expressed and activated in breast tumors, and loss of heterozygosity is observed at IGF-2R (also called the mannose-6-phosphate receptor) [118, 119]. Additionally, high levels of IGFs prevent apoptosis in response to chemotherapeutics and radiation, and overactive IGF-IR signaling is linked to resistance to trastuzumab in HER2-overexpressing breast cancer cells [120, 121].

The importance of IGF signaling in breast cells is highlighted by evidence of crosstalk with ER signaling, such that transcription of IGF-I, IGF-II, IGF-IR, and IGFBPs is activated by the ER, which itself activates expression of IGF-I [120]. Treatment of breast cancer patients with the antiestrogens tamoxifen or raloxifene decreased the IGF-I/IGFBP-3 molar ratio such that lower amounts of circulating IGF-I were available for mitogenic signaling [122, 123]. Somatostatin analogues also reduce IGF signaling by reducing IGF-I levels. RC-160 (vapreotide) significantly lowered IGF-I levels in heavily pretreated metastatic breast cancer patients but was unable to achieve objective tumor responses in phase II trials despite preclinical evidence of tumor inhibition [124]. Combination treatment with tamoxifen and the somatostatin analogue octreotide was also unable to achieve antitumor response [125]. However, a meta-analysis indicated that somatostatin analogues given as first-line therapy were associated with at least a partial tumor response with few side effects [126].

Several targeted therapies in preclinical development directly abrogate IGF signaling, including antisense strategies and antibody blockade. Antisense oligonucleotides against IGF-IR mRNA blocked proliferation of murine mammary carcinoma cells and demonstrated antitumor effects in vivo [127]. {alpha}IR3, a mouse anti-IGF-IR antibody, blocked IGF activity and tumor formation and growth in xenograft models of human breast cancer. However, {alpha}IR3 demonstrated some level of agonist activity as well as a cross-reaction with the insulin receptor. Furthermore, targeting IGF-IR alone may not be effective, since multiple receptors mediate IGF signaling [115, 128-131]. Hence, targeting other components of the IGF pathway may be more beneficial.

IGFBPs bind and regulate circulating IGFs. Levels of IGFBP-1 and IGFBP-3 predicted recurrent disease at distant sites in breast cancer patients [132]. Subcutaneous delivery of a recombinant form of IGFBP-1 fused to polyethylene glycol (PEGBP-1) blocked IGF-I- and estrogen-mediated breast tumor growth in vivo [115]. Interestingly, IGFBP-3 restored sensitivity to trastuzumab in HER2+ breast cancer cells and, thus, may be a candidate for development to treat trastuzumab-resistant tumors [121].


   CONCLUSION
Top
 Abstract
 Introduction
 Epidermal-Growth-Factor-Receptor...
 HER2-Targeted Therapy
 Insulin-Like Growth Factor-I...
 Conclusion
References
 
The relevance of growth factor receptors and their signaling pathways to breast cancer is well established. Several clinical trials testing agents that directly interfere with these pathways are currently in progress. Treatments include mAbs that block receptor activation and tyrosine kinase inhibitors that competitively block ATP binding and prevent kinase signaling. Evidence to date suggests that direct targeting of growth factor receptors is a promising therapeutic strategy for breast cancers with abnormalities in these pathways. The challenge is to identify the patient population most likely to benefit from this biological therapy approach.


   ACKNOWLEDGMENT
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 Abstract
 Introduction
 Epidermal-Growth-Factor-Receptor...
 HER2-Targeted Therapy
 Insulin-Like Growth Factor-I...
 Conclusion
 References
 
Francisco J. Esteva is a recipient of a Career Development Award from the National Cancer Institute (K23 CA82119). We thank Katy Hale for her editorial assistance and Francisco Vergaray for his medical graphics expertise.


   REFERENCES
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 Introduction
 Epidermal-Growth-Factor-Receptor...
 HER2-Targeted Therapy
 Insulin-Like Growth Factor-I...
 Conclusion
 References
 

  1. Atkins JH, Gershell LJ. Selective anticancer drugs. Nat Rev Drug Discov 2002;1:491–492.[CrossRef][Medline]
  2. Buzdar AU, Hortobagyi G. Update on endocrine therapy for breast cancer. Clin Cancer Res 1998;4:527–534.[Abstract]
  3. Cohen S, Taylor JM. Epidermal growth factor: chemical and biological characterization. Recent Prog Horm Res 1974;30:533–550.
  4. Taylor JM, Mitchell WM, Cohen S. Characterization of the binding protein for epidermal growth factor. J Biol Chem 1974;249:2188–2194.[Abstract/Free Full Text]
  5. Taylor JM, Mitchell WM, Cohen S. Characterization of the high molecular weight form of epidermal growth factor. J Biol Chem 1974;249:3198–3203.[Abstract/Free Full Text]
  6. Downward J, Yarden Y, Mayes E et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 1984;307:521–527.[CrossRef][Medline]
  7. Lin CR, Chen WS, Kruiger W et al. Expression cloning of human EGF receptor complementary DNA: gene amplification and three related messenger RNA products in A431 cells. Science 1984;224:843–848.[Abstract/Free Full Text]
  8. Ullrich A, Coussens L, Hayflick JS et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 1984;309:418–425.[CrossRef][Medline]
  9. Cooper JA, Hunter T. Similarities and differences between the effects of epidermal growth factor and Rous sarcoma virus. J Cell Biol 1981;91:878–883.[Abstract/Free Full Text]
  10. Chinkers M, Cohen S. Purified EGF receptor-kinase interacts specifically with antibodies to Rous sarcoma virus transforming protein. Nature 1981;290:516–519.[CrossRef][Medline]
  11. Arteaga CL. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 2001;19(suppl 18):32S–40S.
  12. Fan Z, Lu Y, Wu X et al. Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. J Biol Chem 1994;269:27595–27602.[Abstract/Free Full Text]
  13. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMC-C225). Curr Opin Oncol 2001;13:506–513.[CrossRef][Medline]
  14. Tortora G, Caputo R, Pomatico G et al. Cooperative inhibitory effect of novel mixed backbone oligonucleotide targeting protein kinase A in combination with docetaxel and anti-epidermal growth factor-receptor antibody on human breast cancer cell growth. Clin Cancer Res 1999;5:875–881.[Abstract/Free Full Text]
  15. Masui H, Kawamoto T, Sato JD et al. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1984;44:1002–1007.[Abstract/Free Full Text]
  16. Baselga J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur J Cancer 2001;37(suppl 4):S16–S22.
  17. Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 2002;94:1593–1611.[CrossRef][Medline]
  18. Mendez MJ, Green LL, Corvalan JR et al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet 1997;15:146–156.[CrossRef][Medline]
  19. Lynch DH, Yang XD. Therapeutic potential of ABX-EGF: a fully human anti-epidermal growth factor receptor monoclonal antibody for cancer treatment. Semin Oncol 2002;29(suppl 4):47–50.
  20. Yang XD, Jia XC, Corvalan JR et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999;59:1236–1243.[Abstract/Free Full Text]
  21. Yang XD, Jia XC, Corvalan JR et al. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001;38:17–23.[Medline]
  22. Allen LF, Lenehan PF, Eiseman IA et al. Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol 2002;29(suppl 11):11–21.
  23. Slichenmyer WJ, Fry DW. Anticancer therapy targeting the ErbB family of receptor tyrosine kinases. Semin Oncol 2001;28(suppl 16):67–79.
  24. Arteaga CL, Johnson DH. Tyrosine kinase inhibitors-ZD1839 (Iressa). Curr Opin Oncol 2001;13:491–498.[CrossRef][Medline]
  25. Elsayed YA, Sausville EA. Selected novel anticancer treatments targeting cell signaling proteins. The Oncologist 2001;6:517–537.[Abstract/Free Full Text]
  26. Swaisland H, Laight A, Stafford L et al. Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers. Clin Pharmacokinet 2001;40:297–306.[CrossRef][Medline]
  27. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002;20:2240–2250.[Abstract/Free Full Text]
  28. Baselga J, Yano S, Giaccone G et al. Initial results from a phase II trial of ZD1839 (Iressa) as second- and third-line monotherapy for patients with advanced non-small-cell lung cancer (IDEAL 1). Clin Cancer Res 2001;7:3780.
  29. Arteaga CL, Moulder SL, Yakes FM. HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Semin Oncol 2002;29:4–10.[Medline]
  30. Hidalgo M, Siu LL, Nemunaitis J et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001;19:3267–3279.[Abstract/Free Full Text]
  31. Rusnak DW, Affleck K, Cockerill SG et al. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res 2001;61:7196–7203.[Abstract/Free Full Text]
  32. Padhy LC, Shih C, Cowing D et al. Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas. Cell 1982;28:865–871.[CrossRef][Medline]
  33. Bargmann CI, Hung MC, Weinberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature 1986;319:226–230.[CrossRef][Medline]
  34. Bargmann CI, Hung MC, Weinberg RA. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell 1986;45:649–657.[CrossRef][Medline]
  35. Schechter AL, Stern DF, Vaidyanathan L et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 1984;312:513–516.[CrossRef][Medline]
  36. Coussens L, Yang-Feng TL, Liao YC et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230:1132–1139.[Abstract/Free Full Text]
  37. King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 1985;229:974–976.[Abstract/Free Full Text]
  38. Yamamoto T, Ikawa S, Akiyama T et al. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature 1986;319:230–234.[CrossRef][Medline]
  39. Di Fiore PP, Pierce JH, Kraus MH et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 1987;237:178–182.[Abstract/Free Full Text]
  40. Guy CT, Webster MA, Schaller M et al. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 1992;89:10578–10582.[Abstract/Free Full Text]
  41. Guy CT, Cardiff RD, Muller WJ. Activated neu induces rapid tumor progression. J Biol Chem 1996;271:7673–7678.[Abstract/Free Full Text]
  42. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the HER2/neu oncogene. Science 1987;235:177–182.[Abstract/Free Full Text]
  43. Esteva-Lorenzo FJ, Sastry L, King CR. The erbB-2 gene: from research to application. In: Dickson RB, Salomon DS, eds. Hormones and Growth Factors in Development and Neoplasia. New York: John Wiley & Sons, 1998:421-444.
  44. Tsuda H, Hirohashi S, Shimosato Y et al. Immunohistochemical study on overexpression of c-erbB-2 protein in human breast cancer: its correlation with gene amplification and long-term survival of patients. Jpn J Cancer Res 1990;81:327–332.[CrossRef][Medline]
  45. Paik S, Hazan R, Fisher ER et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 1990;8:103–112.[Abstract/Free Full Text]
  46. Lovekin C, Ellis IO, Locker A et al. C-erbB-2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer 1991;63:439–443.[Medline]
  47. McCann AH, Dervan PA, O’Regan M et al. Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer. Cancer Res 1991;51:3296–3303.[Abstract/Free Full Text]
  48. Isola JJ, Holli K, Oksa H et al. Elevated erbB-2 oncoprotein levels in preoperative and follow-up serum samples define an aggressive disease course in patients with breast cancer. Cancer 1994;73:652–658.[CrossRef][Medline]
  49. Horiguchi J, Iino Y, Takei H et al. Immunohistochemical study on the expression of c-erbB-2 oncoprotein in breast cancer. Oncology 1994;51:47–51.[Medline]
  50. Thor AD, Berry DA, Budman DR et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998;90:1346–1360.[Abstract/Free Full Text]
  51. Paik S, Bryant J, Park C et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998;90:1361–1370.[Abstract/Free Full Text]
  52. Bianco AR, De Laurentiis M, Carlomagno C et al. HER2 overexpression predicts adjuvant tamoxifen (TAM) failure for early breast cancer (EBC): complete data at 20 yr of the Naples GUN randomized trial. Proc Am Soc Clin Oncol 2000;19:289a.
  53. Bacus SS, Gudkov AV, Esteva FJ et al. Expression of erb-B receptors and their ligands in breast cancer: implications to biological behavior and therapeutic response. Breast Dis 2000;11:63–75.
  54. Esteva FJ, Pusztai L, Symmans WF et al. Clinical relevance of HER-2 amplification and overexpression in human cancers. Ref Gynecol Obst 2000;7:267–276.
  55. Pusztai L, Esteva FJ, Cristofanilli M et al. Chemo-signal therapy, an emerging new approach to modify drug resistance in breast cancer. Cancer Treat Rev 1999;25:271–277.[CrossRef][Medline]
  56. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene 1990;5:953–962.[Medline]
  57. Esteva FJ, Seidman AD, Fornier M et al. Analysis of response to weekly 1 h Taxol (T) plus Herceptin (H) by immunophenotypic analysis in HER2 overexpressing (H2+) and non-overexpressing (H2-) metastatic breast cancer. Breast Cancer Res Treat 1999;57:17a.
  58. Niehans GA, Singleton TP, Dykoski D et al. Stability of HER-2/neu expression over time and at multiple metastatic sites. J Natl Cancer Inst 1993;85:1230–1235.[Abstract/Free Full Text]
  59. Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci USA 1987;84:7159–7163.[Abstract/Free Full Text]
  60. Park JW, Stagg R, Lewis GD et al. Anti-p185HER2 monoclonal antibodies: biological properties and potential for immunotherapy. Cancer Treat Res 1992;61:193–211.[Medline]
  61. Hurwitz E, Stancovski I, Sela M et al. Suppression and promotion of tumor growth by monoclonal antibodies to erbB-2 differentially correlate with cellular uptake. Proc Natl Acad Sci USA 1995;92:3353–3357.[Abstract/Free Full Text]
  62. Kasprzyk PG, Song SU, Di Fiore PP et al. Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. Cancer Res 1992;52:2771–2776.[Abstract/Free Full Text]
  63. Harwerth IM, Wels W, Schlegel J et al. Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth. Br J Cancer 1993;68:1140–1145.[Medline]
  64. Xu F, Lupu R, Rodriguez GC et al. Antibody-induced growth inhibition is mediated through immunochemically and functionally distinct epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185. Int J Cancer 1993;53:401–408.[Medline]
  65. Pietras RJ, Fendly BM, Chazin VR et al. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 1994;9:1829–1838.[Medline]
  66. Pegram MD, Finn RS, Arzoo K et al. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 1997;15:537–547.[CrossRef][Medline]
  67. Baselga J, Tripathy D, Mendelsohn J et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996;14:737–744.[Abstract/Free Full Text]
  68. Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639–2648.[Abstract/Free Full Text]
  69. Vogel CL, Cobleigh MA, Tripathy D et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719–726.[Abstract/Free Full Text]
  70. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
  71. Livingston RB, Esteva FJ. Chemotherapy and herceptin for HER2(+) metastatic breast cancer: the best drug? The Oncologist 2001;6:315–316.[Free Full Text]
  72. Fornier M, Esteva FJ, Seidman A. Trastuzumab in combination with chemotherapy for the treatment of metastatic breast cancer. Semin Oncol 2000;27(suppl 11):38-45; discussion 92-100.[Medline]
  73. Pegram MD, Lipton A, Hayes DF et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998;16:2659–2671.[Abstract]
  74. Seidman AD, Fornier M, Esteva FJ et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001;19:2587–2595.[Abstract/Free Full Text]
  75. Esteva FJ, Valero V, Booser D et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:1800–1808.[Abstract/Free Full Text]
  76. Burstein HJ, Kuter I, Campos SM et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2001;19:2722–2730.[Abstract/Free Full Text]
  77. O’Shaughnessy JA, Vukelja S, Marsland T et al. Gemcitabine and trastuzumab for HER-2 positive metastatic breast cancer: preliminary results of a phase II study. Breast Cancer Res Treat 2001;69:302a.
  78. Pegram MD, Lopez A, Konecny G et al. Trastuzumab and chemotherapeutics: drug interactions and synergies. Semin Oncol 2000;27(suppl 11):21-25;92-100.[Medline]
  79. Konecny G, Untch M, Slamon D et al. Drug interactions and cytotoxic effects of paclitaxel in combination with carboplatin, epirubicin, gemcitabine or vinorelbine in breast cancer cell lines and tumor samples. Breast Cancer Res Treat 2001;67:223–233.[CrossRef][Medline]
  80. Nabholtz JM. Preliminary results of two open-label multicenter pilot phase II trials with Herceptin in combination with docetaxel and platinum salts (cis- or carboplatin) (TCH) as therapy for advanced breast cancer in women with overexpressing HER2/neu. Breast Cancer Res Treat 2000;58:327a.
  81. Slamon DJ, Patel R, Northfelt R et al. Phase II pilot study of Herceptin combined with Taxotere and carboplatin in metastatic breast cancer patients overexpressing the HER2-neu proto-oncogene: a pilot study of the UCLA Network. Proc Am Soc Clin Oncol 2001;20:193a.
  82. Mass RD, Press M, Anderson S et al. Improved survival benefit from Herceptin (trastuzumab) in patients selected by fluorescence in situ hybridization (FISH). Proc Am Soc Clin Oncol 2001;20:85a.
  83. Roche PC, Suman VJ, Jenkins RB et al. Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst 2002;94:855–857.[Abstract/Free Full Text]
  84. Paik S, Bryant J, Tan-Chiu E et al. Real-world performance of HER2 testing—National Surgical Adjuvant Breast and Bowel Project experience. J Natl Cancer Inst 2002;94:852–854.[Abstract/Free Full Text]
  85. Batra JK, Kasprzyk PG, Bird RE et al. Recombinant anti-erbB-2 immunotoxins containing Pseudomonas exotoxin. Proc Natl Acad Sci USA 1992;89:5867–5871.[Abstract/Free Full Text]
  86. Wels W, Harwerth IM, Mueller M et al. Selective inhibition of tumor cell growth by a recombinant single-chain antibody-toxin specific for the erbB-2 receptor. Cancer Res 1992;52:6310–6317.[Abstract/Free Full Text]
  87. King CR, Fischer PH, Rando RF et al. The performance of e23(Fv)PEs, recombinant toxins targeting the erbB-2 protein. Semin Cancer Biol 1996;7:79–86.[CrossRef][Medline]
  88. King CR, Kasprzyk PG, Fischer PH et al. Preclinical testing of an anti-erbB-2 recombinant toxin. Breast Cancer Res Treat 1996;38:19–25.[CrossRef][Medline]
  89. Reiter Y, Pai LH, Brinkmann U et al. Antitumor activity and pharmacokinetics in mice of a recombinant immunotoxin containing a disulfide-stabilized Fv fragment. Cancer Res 1994;54:2714–2718.[Abstract/Free Full Text]
  90. Smellie WJ, Dean CJ, Sacks NP et al. Radioimmunotherapy of breast cancer xenografts with monoclonal antibody ICR12 against c-erbB2 p185: comparison of iodogen and N-succinimidyl 4-methyl-3-(tri-n-butylstannyl) benzoate radioiodination methods. Cancer Res 1995;55(suppl 23):5842s–5846s.[Abstract/Free Full Text]
  91. Allan SM, Dean C, Fernando I et al. Radioimmunolocalisation in breast cancer using the gene product of c-erbB2 as the target antigen. Br J Cancer 1993;67:706–712.[Medline]
  92. Weiner LM, Holmes M, Adams GP et al. A human tumor xenograft model of therapy with a bispecific monoclonal antibody targeting c-erbB-2 and CD16. Cancer Res 1993;53:94–100.[Abstract/Free Full Text]
  93. Weiner LM, Holmes M, Richeson A et al. Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1. J Immunol 1993;151:2877–2886.[Abstract]
  94. Shalaby MR, Carter P, Maneval D et al. Bispecific HER2 x CD3 antibodies enhance T-cell cytotoxicity in vitro and localize to HER2-overexpressing xenografts in nude mice. Clin Immunol Immunopathol 1995;74:185–192.[CrossRef][Medline]
  95. Weiner LM, Clark JI, Davey M et al. Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. Cancer Res 1995;55:4586–4593.[Abstract/Free Full Text]
  96. Yu D, Shi D, Scanlon M et al. Reexpression of neu-encoded oncoprotein counteracts the tumor-suppressing but not the metastasis-suppressing function of E1A. Cancer Res 1993;53:5784–5790.[Abstract/Free Full Text]
  97. Yu D, Matin A, Xia W et al. Liposome-mediated in vivo E1A gene transfer suppressed dissemination of ovarian cancer cells that overexpress HER2/neu. Oncogene 1995;11:1383–1388.[Medline]
  98. Hortobagyi GN, Ueno NT, Xia WY et al. Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. J Clin Oncol 2001;19:3422–3433.[Abstract/Free Full Text]
  99. Bertram J, Killian M, Brysch W et al. Reduction of erbB2 gene product in mammary carcinoma cell lines by erbB2 mRNA-specific and tyrosine kinase consensus phosphorothioate antisense oligonucleotides. Biochem Biophys Res Commun 1994;200:661–667.[CrossRef][Medline]
  100. Colomer R, Lupu R, Bacus SS et al. ErbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification. Br J Cancer 1994;70:819–825.[Medline]
  101. Disis ML, Bernhard H, Gralow JR et al. Immunity to the HER-2/neu oncogenic protein. Ciba Found Symp 1994;187:198-207; discussion 207-211.[Medline]
  102. Disis ML, Smith JW, Murphy AE et al. In vitro generation of human cytolytic T-cells specific for peptides derived from the HER-2/neu protooncogene protein. Cancer Res 1994;54:1071–1076.[Abstract/Free Full Text]
  103. Disis ML, Calenoff E, McLaughlin G et al. Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 1994;54:16–20.[Abstract/Free Full Text]
  104. Yoshino I, Goedegebuure PS, Peoples GE et al. HER2/neu-derived peptides are shared antigens among human non-small cell lung cancer and ovarian cancer. Cancer Res 1994;54:3387–3390.[Abstract/Free Full Text]
  105. Peoples GE, Smith RC, Linehan DC et al. Shared T cell epitopes in epithelial tumors. Cell Immunol 1995;164:279–286.[CrossRef][Medline]
  106. Druker BJ. STI571 (GleevecTM) as a paradigm for cancer therapy. Trends Mol Med 2002;8:S14–S18.[CrossRef][Medline]
  107. Druker B. Signal transduction inhibition: results from phase I clinical trials in chronic myeloid leukemia. Semin Hematol 2001;38(suppl 8):9–14.[Medline]
  108. Mauro MJ, O’Dwyer M, Heinrich MC et al. STI571: a paradigm of new agents for cancer therapeutics. J Clin Oncol 2002;20:325–334.[Abstract/Free Full Text]
  109. Kantarjian H, Sawyers C, Hochhaus A et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–652.[Abstract/Free Full Text]
  110. Hirota S, Isozaki K, Moriyama Y et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577–580.[Abstract/Free Full Text]
  111. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–480.[Abstract/Free Full Text]
  112. Apperley JF, Gardembas M, Melo JV et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002;347:481–487.[Abstract/Free Full Text]
  113. Rubin BP, Schuetze SM, Eary JF et al. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 2002;20:3586–3591.[Abstract/Free Full Text]
  114. DiPaola RS, Kuczynski WI, Onodera K et al. Evidence for a functional kit receptor in melanoma, breast, and lung carcinoma cells. Cancer Gene Therapy 1997;4:176–182.[Medline]
  115. Yee D. The insulin-like growth factor system as a treatment target in breast cancer. Semin Oncol 2002;29(suppl 11):86–95.[Medline]
  116. Hankinson SE, Willett WC, Colditz GA et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998;351:1393–1396.[CrossRef][Medline]
  117. Yu H, Levesque MA, Khosravi MJ et al. Associations between insulin-like growth factors and their binding proteins and other prognostic indicators in breast cancer. Br J Cancer 1996;74:1242–1247.[Medline]
  118. Hankins GR, De Souza AT, Bentley RC et al. M6P/IGF2 receptor: a candidate breast tumor suppressor gene. Oncogene 1996;12:2003–2009.[Medline]
  119. Byrd JC, Devi GR, De Souza AT et al. Disruption of ligand binding to the insulin-like growth factor II/mannose 6-phosphate receptor by cancer-associated missense mutations. J Biol Chem 1999;274:24408–24416.[Abstract/Free Full Text]
  120. Sachdev D, Yee D. The IGF system and breast cancer. Endocr Relat Cancer 2001;8:197–209.[Abstract]
  121. Lu YH, Zi XL, Zhao YH et al. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001;93:1852–1857.[Abstract/Free Full Text]
  122. Campbell MJ, Woodside JV, Secker-Walker J et al. IGF status is altered by tamoxifen in patients with breast cancer. Mol Pathol 2001;54:307–310.[Abstract/Free Full Text]
  123. Torrisi R, Baglietto L, Johansson H et al. Effect of raloxifene on IGF-I and IGFBP-3 in postmenopausal women with breast cancer. Br J Cancer 2001;85:1838–1841.[CrossRef][Medline]
  124. O’Byrne KJ, Dobbs N, Propper DJ et al. Phase II study of RC-160 (vapreotide), an octapeptide analogue of somatostatin, in the treatment of metastatic breast cancer. Br J Cancer 1999;79:1413–1418.[CrossRef][Medline]
  125. Ingle JN, Suman VJ, Kardinal CG et al. A randomized trial of tamoxifen alone or combined with octreotide in the treatment of women with metastatic breast carcinoma. Cancer 1999;85:1284–1292.[CrossRef][Medline]
  126. Dolan JT, Miltenburg DM, Granchi TS et al. Treatment of metastatic breast cancer with somatostatin analogues—a meta-analysis. Ann Surg Oncol 2001;8:227–233.[Medline]
  127. Chernicky CL, Tan H, Yi L et al. Treatment of murine breast cancer cells with antisense RNA to the type I insulin-like growth factor receptor decreases the level of plasminogen activator transcripts, inhibits cell growth in vitro, and reduces tumorigenesis in vivo. Mol Pathol 2002;55:102–109.[Abstract/Free Full Text]
  128. Kull Jr FC, Jacobs S, Su YF et al. Monoclonal antibodies to receptors for insulin and somatomedin-C. J Biol Chem 1983;258:6561–6566.[Abstract/Free Full Text]
  129. Arteaga CL, Kitten LJ, Coronado EB et al. Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 1989;84:1418–1423.
  130. Arteaga CL, Osborne CK. Growth inhibition of human breast cancer cells in vitro with an antibody against the type I somatomedin receptor. Cancer Res 1989;49:6237–6241.[Abstract/Free Full Text]
  131. Kato H, Faria TN, Stannard B et al. Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3). J Biol Chem 1993;268:2655–2661.[Abstract/Free Full Text]
  132. Goodwin PJ, Ennis M, Pritchard KI et al. Insulin-like growth factor binding proteins 1 and 3 and breast cancer outcomes. Breast Cancer Res Treat 2002;74:65–76.[CrossRef][Medline]
  133. Palmu S, Soderstrom KO, Quazi K et al. Expression of C-KIT and HER-2 tyrosine kinase receptors in poor-prognosis breast cancer. Anticancer Res 2002;22:411–414.[Medline]
  134. Hines SJ, Litz JS, Krystal GW. Coexpression of c-kit and stem cell factor in breast cancer results in enhanced sensitivity to members of the EGF family of growth factors. Breast Cancer Res Treat 1999;58:1–10.[CrossRef][Medline]
  135. Feakins RM, Wells CA, Young KA et al. Platelet-derived growth factor expression in phyllodes tumors and fibroadenomas of the breast. Hum Pathol 2000;31:1214–1222.[CrossRef][Medline]
  136. Peres R, Betsholtz C, Westermark B et al. Frequent expression of growth factors for mesenchymal cells in human mammary carcinoma cell lines. Cancer Res 1987;47:3425–3429.[Abstract/Free Full Text]
  137. Yi B, Williams PJ, Niewolna M et al. Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Res 2002;62:917–923.[Abstract/Free Full Text]
  138. Klijn JG, Berns PM, Schmitz PI et al. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr Rev 1992;13:3–17.[Abstract/Free Full Text]
  139. Knowlden JM, Gee JM, Seery LT et al. c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer. Oncogene 1998;17:1949–1957.[CrossRef][Medline]
  140. Tang CK, Concepcion XZ, Milan M et al. Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor-positive breast cancer cells inhibits proliferation both in vitro and in vivo. Cancer Res 1999;59:5315–5322.[Abstract/Free Full Text]
  141. Srinivasan R, Gillett CE, Barnes DM et al. Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers. Cancer Res 2000;60:1483–1487.[Abstract/Free Full Text]
  142. Kew TY, Bell JA, Pinder SE et al. c-erbB-4 protein expression in human breast cancer. Br J Cancer 2000;82:1163–1170.[CrossRef][Medline]
  143. Yee D, Lee AV. Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mammary Gland Biol Neoplasia 2000;5:107–115.[CrossRef][Medline]
  144. Chou JL, Fan Z, DeBlasio T et al. Constitutive overexpression of cyclin D1 in human breast epithelial cells does not prevent G1 arrest induced by deprivation of epidermal growth factor. Breast Cancer Res Treat 1999;55:267–283.[CrossRef][Medline]
  145. Baselga J, Norton L, Masui H et al. Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst 1993;85:1327–1333.[Abstract/Free Full Text]
  146. McClelland RA, Barrow D, Madden TA et al. Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). Endocrinology 2001;142:2776–2788.[Abstract/Free Full Text]
  147. Moulder SL, Yakes FM, Muthuswamy SK et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001;61:8887–8895.[Abstract/Free Full Text]
  148. Ciardiello F, Caputo R, Borriello G et al. ZD1839 (IRESSA), an EGFR-selective tyrosine kinase inhibitor, enhances taxane activity in bcl-2 overexpressing, multidrug-resistant MCF-7 ADR human breast cancer cells. Int J Cancer 2002;98:463–469.[CrossRef][Medline]
  149. Hirata A, Ogawa S, Kometani T et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 2002;62:2554–2560.[Abstract/Free Full Text]
  150. Normanno N, Campiglio M, De Luca A et al. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol 2002;13:65–72.[Abstract/Free Full Text]
  151. Chan KC, Knox WF, Gee JM et al. Effect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast. Cancer Res 2002;62:122–128.[Abstract/Free Full Text]
  152. Pollack VA, Savage DM, Baker DA et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 1999;291:739–748.[Abstract/Free Full Text]
  153. Citri A, Alroy I, Lavi S et al. Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. EMBO J 2002;21:2407–2417.[CrossRef][Medline]
  154. Nelson JM, Fry DW. Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. J Biol Chem 2001;276:14842–14847.[Abstract/Free Full Text]
  155. Rao GS, Murray S, Ethier SP. Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor. Int J Radiat Oncol Biol Phys 2000;48:1519–1528.[CrossRef][Medline]
  156. Nahta R, Iglehart JD, Kempkes B et al. Rate-limiting effects of Cyclin D1 in transformation by ErbB2 predicts synergy between herceptin and flavopiridol. Cancer Res 2002;62:2267–2271.[Abstract/Free Full Text]
  157. Agus DB, Akita RW, Fox WD et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002;2:127–137.[CrossRef][Medline]
Received October 18, 2002; accepted for publication December 11, 2002.




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