Combined anti-EGF receptor and anti-HER2 receptor therapy in breast cancer: a promising strategy ready for clinical testing.
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Animals↗
Biomedical subjects
J Baselga
Publications and source records attributed to J Baselga.
Unraveling resistance to trastuzumab (Herceptin): insulin-like growth factor-I receptor, a new suspect.
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Antibodies, Monoclonal↗
Metalloprotease-dependent protransforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme.
Zinc-dependent metalloproteases can mediate the shedding of the extracellular domain of many unrelated transmembrane proteins from the cell surface. In most instances, this process, also known as ectodomain shedding, is regulated via protein kinase C (PKC). The tumor necrosis factor alpha-converting enzyme (TACE) was the first protease involved in regulated protein ectodomain shedding identified. Although TACE belongs to the family of metalloprotease-disintegrins, few members of this family have been shown to participate in regulated ectodomain shedding. In fact, the phenotype of tace-/- cells and that of Chinese hamster ovary cell mutants defective in ectodomain shedding points to the existence of a common PKC-activated ectodomain shedding system, whose proteolytic component is TACE, that acts on a variety of transmembrane proteins. Examples of these proteins include the Alzheimer's disease-related protein beta-amyloid precursor protein (betaAPP) and the transmembrane growth factors protransforming growth factor-alpha (pro-TGF-alpha) and, as shown in this report, proheparin-binding epidermal growth factor-like growth factor (pro-HB-EGF). Here we show that the mercurial compound 4-aminophenylmercuric acetate (APMA), frequently used to activate in vitro recombinant matrix metalloproteases, is an activator of the shedding of betaAPP, pro-HB-EGF, and pro-TGF-alpha. Treatment of tace-/- cells or Chinese hamster ovary shedding-defective mutants with APMA activates the cleavage of pro-TGF-alpha but not that of pro-HB-EGF or betaAPP, indicating that APMA activates TACE and also a previously unacknowledged proteolytic activity specific for pro-TGF-alpha. Characterization of this proteolytic activity indicates that it acts on pro-TGF-alpha located at the cell surface and that it is a metalloprotease active in cells defective in furin activity. In summary, treatment of shedding-defective cell lines with APMA unveils the existence of a metalloprotease activity alternative to TACE with the ability to specifically shed the ectodomain of pro-TGF-alpha.
ADAM Proteins↗
Targeting the epidermal growth factor receptor: a clinical reality.
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Antibodies, Monoclonal↗
Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments.
The expression of the activated mitogen-activated kinases/extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 was characterized in 101 humanhead and neck squamous carcinoma specimens. Activated ERK1/2were detected at different levels in the majority of these tumors, as assayed by immunostaining with an antibody specific for the dually phosphorylated and activated ERK1 and ERK2. ERK1/2 activation levels were higher in tumors with advanced regional lymph node metastasis (P = 0.048) and in relapsed tumors (P = 0.021). The expression of epidermal growth factor (EGF) receptor (P = 0.037), transforming growth factor alpha (TGF-alpha; P < 0.001), and HER2 (P = 0.066; positive trend) correlated with activation of ERK1/2. In a multivariate analysis, both TGF-alpha (P < 0.0001) and HER2 (P = 0.045) were independently correlated with ERK1/2 activation. In turn, activation of ERK1/2 was associated with a higher Ki-67 proliferative index (P = 0.002). In EGF receptor-dependent model cells (A431 and DiFi), a specific EGF receptor tyrosine kinase inhibitor ("Iressa"; ZD1839) and a chimeric anti-EGF receptor antibody ("Cetuximab"; C225) inhibited ERK 1/2 activation at concentrations that inhibited autocrine cell proliferation. In patients on treatment with C225, the activation of ERK1/2 in skin, an EGF receptor-dependent tissue, was lower compared with control skin. Parallel changes were seen in keratinocyte Ki67 proliferation indexes in skin from C225-treated patients. Taken together, these studies provide support for a role of activation of ERK1/2 in head and neck squamous carcinoma and a correlation with EGF receptor/TGF-alpha expression. The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies.
Adult↗
Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells.
HER2 is a ligand-less tyrosine kinase receptor of the ErbB family that is frequently overexpressed in breast cancer. It undergoes proteolytic cleavage that results in the release of the extracellular domain and the production of a truncated membrane-bound fragment, p95. We show that HER2 shedding is activated by 4-aminophenylmercuric acetate (APMA), a well-known matrix metalloprotease activator, in HER2-overexpressing breast cancer cells. The HER2 p95 fragment, which appears after APMA-induced cleavage, is phosphorylated. We analyzed 24 human breast cancer specimens, and a phosphorylated M(r) 95,000 HER2 band could be detected in some of them, which indicated that the truncated receptor is also present in vivo. The activation of HER2 shedding by APMA in cells was blocked with batimastat, a broad-spectrum metalloprotease inhibitor. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody directed at the HER2 ectodomain, which has been shown to be active in patients with HER2-overexpressing breast cancer, inhibited basal and induced HER2 cleavage and, as a consequence, the generation of phosphorylated p95. This inhibitory effect of trastuzumab was not shared by 2C4, an antibody against a different epitope of the HER2 ectodomain. The inhibition of basal and APMA-induced cleavage of HER2 by trastuzumab preceded antibody-induced receptor down-modulation, which indicated that the effect of trastuzumab on cleavage was not attributable to a decrease in cell-surface HER2 induced by trastuzumab. We propose that the inhibition of HER2 cleavage and prevention of the production of an active truncated HER2 fragment represent a novel mechanism of action of trastuzumab.
Adenocarcinoma↗
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
BACKGROUND: The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. METHODS: We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). RESULTS: The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. CONCLUSIONS: Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.
Adult↗
Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells.
The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized by a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcgammaRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2. We tested IL-2-activated NK cells against Her2/neu+ (MCF-7Her2/neu) and Her2/neu- (MDA-468) breast cancer cell lines in a 4-h 51Cr-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (effector : target ratio = 10 : 1). Specific lysis of rhu4D5-coated MCF-7Her2/neu and MDA-468 target cells by IL-2-activated NK cells was 35% and 3%, respectively (p < 0.05). Lysis was less than 5% when targets were treated with either the non-humanized mu4D5 mAb or control huIgG. Lysis of rhu4D5-coated MCF-7Her2/neu cells was inhibited by 80 % when NK cells were pre-treated with an anti-Fc receptor antibody prior to use in the cytotoxicity assay. Enhanced ADCC of MCF-7Her2/neu target cells was seen when the effector cells consisted of mononuclear cells obtained from a patient demonstrating significant expansion of NK cells secondary to therapy with low-dose IL-2. Serum from patients receiving infusions of rhu4D5 mAb could substitute for exogenous antibody in the ADCC assay. NK cells activated by rhu4D5-coated tumor cells in the presence of IL-2 also produced large amounts of IFN-gamma with concomitant up-regulation of cell-surface activation markers CD25 and CD69. These results lend support to the concurrent use of rhu4D5 mAb and IL-2 therapy in patients with cancers that express the Her2/neu oncogene.
Animals↗
Mechanism of action of trastuzumab and scientific update.
The humanized anti-p185(HER2) monoclonal antibody trastuzumab has been shown to effectively inhibit the growth of HER2-overexpressing breast cancer cells in vivo and in vitro. The treatment of cancer cells with trastuzumab results in downregulation of the HER2 receptor. Further downstream cellular events include the accumulation of the cyclin-dependent kinase inhibitor p27 and cell cycle arrest. In vivo, trastuzumab induces antibody-dependent cellular cytotoxicity. Trastuzumab also inhibits constitutive HER2 cleavage/shedding mediated by metalloproteases. The ability of trastuzumab to inhibit HER2 cleavage may correlate with the clinical anticancer activity of the multifunctional HER2-targeting antibody.
Antibodies, Monoclonal↗
Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839.
ZD1839 is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. Based on its promising preclinical antitumor activity and favorable toxicity profile, ZD1839 has recently entered clinical trials. A particular challenge in the clinical development of this exciting compound is to explore its biological (pharmacodynamic) activity against the EGFR and receptor-dependent processes in serial biopsies. Such studies might be of assistance in predicting the subset of tumors that will benefit from therapy. They also may prove whether complete EGFR blockade is achieved in vivo. This latest point is particularly relevant because an optimal biological dose (ie, a dose resulting in complete receptor inhibition) would be preferred to the maximally tolerated dose that is being used with conventional nontargeted chemotherapeutic drugs. A series of preclinical studies have identified potentially useful surrogate markers of EGFR activity (eg, phosphorylation of EGFR and downstream receptor-dependent molecules such as mitogen-activated protein kinase [MAPK], Akt, or p27) that could be used as a surrogate marker of ZD1839 efficacy. In various tumor types, such as head and neck squamous carcinoma and gastric and breast adenocarcinoma, a relationship between EGFR and downstream markers (such as phosphorylated MAPK) has been characterized, further supporting the potential of these molecules for pharmacodynamic studies. Preliminary analysis of serial skin biopsies from patients participating in phase I trials has shown that ZD1839 results in substantial changes in EGFR-dependent molecules, such as phosphorylated MAPK, p27, phosphorylated STAT3, and others. Based on these encouraging results, studies assessing activated EGFR, activated MAPK, and other selected markers in phase II trials in tumors from patients treated with ZD1839 are currently planned or ongoing.
Animals↗
The EGFR as a target for anticancer therapy--focus on cetuximab.
The anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibody cetuximab specifically binds to the EGFR with high affinity, blocking growth-factor binding, receptor activation and subsequent signal-transduction events leading to cell proliferation. Preclinical studies, both in vitro and in vivo, have shown that cetuximab enhances the antitumour effects of chemotherapy as well as radiotherapy by inhibiting cell proliferation, angiogenesis and metastasis and by promoting apoptosis. As of June 2000, 526 patients with advanced solid tumours were treated with cetuximab in phase I/II clinical trials. Analysis of the results of three phase I trials showed that cetuximab has non-linear pharmacokinetics, with saturation of drug-elimination pathways occurring at doses between 200 and 400 mg/m(2). Adverse-event data for 239 patients across most of the completed or ongoing phase I-III trials indicated that the antibody was generally well tolerated. Cetuximab has been evaluated both alone and in combination with radiotherapy and various cytotoxic chemotherapeutic agents in a series of phase I/II studies that primarily treated patients with either head and neck or colorectal cancer. Although not a primary objective of these studies, clinical responses to cetuximab were observed in many patients who had previously failed chemotherapy and/or radiotherapy or were otherwise unlikely to achieve a therapeutic outcome. Based on these promising results, additional phase II and phase III trials are currently underway in head and neck and colorectal cancer.
Antibodies, Monoclonal↗
A feasibility study of carboplatin with fixed dose of gemcitabine in "unfit" patients with advanced bladder cancer.
For the purpose of a subsequent phase II/III European Organization for Research and Treatment of Cancer (EORTC) trial, a gemcitabine/carboplatin feasibility study in "unfit" patients with advanced urothelial cell cancer was conducted. Gemcitabine was given at 1000 mg/m(2) days 1 and 8 with carboplatin (area under the curve (AUC) 4.5 or 5) day 1 every 21 days. 16 patients were treated, median age 68 years (47-75) years, performance status (PS) 0/1/2 in 3/10/3 patients. Creatinine clearance was >1 ml/s in 3 patients, 0.5-1 ml/s in 9 and <0.5 ml/s in 4 patients. Half of the patients had visceral disease. Median number of cycles given was 4 (range 2-6), for a total of 69 cycles. The first 8 patients received 33 cycles using a carboplatin AUC of 5. World Health Organization (WHO) grade 3-4 toxicity was: haemoglobin 5 patients, platelets 6 patients, neutrophils 5 patients and febrile neutropenia 2 patients. In view of this haematological toxicity in subsequent patients, the carboplatin AUC was decreased to 4.5. At this dose level, 8 patients received 36 cycles. WHO grade 3-4 toxicity was: anaemia 1 patient, platelets 4 patients, neutrophils 4 patients with no febrile neutropenia. Thus, this dose level was regarded to be feasible. For the 16 evaluable patients, overall response rate was 44%, (1 complete response (CR), 6 partial response (PR)). In conclusion, the combination of gemcitabine with carboplatin at an AUC of 4.5 appears to be an active and well tolerated regimen with acceptable toxicity in this unfit patient population. Based on these data, a randomised trial in the framework of the EORTC-Genitourinary (GU) group of gemcitabine/carboplatin versus carboplatin/methotrexate/vinblastine (MCAVI) is ongoing.
Aged↗
Mechanism of action of anti-HER2 monoclonal antibodies.
The search for new methods of treating cancer, combined with advances in our understanding of carcinogenesis, molecular biology and technology, has resulted in the development of novel biologic agents with proven clinical efficacy. One such agent is trastuzumab (Herceptin), a humanized monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). HER2 is a member of a family of receptors that interact with each other and various ligands to stimulate various intracellular signal transduction pathways involved in cell growth control. HER2 is overexpressed in 20%-30% of women with breast cancer and is associated with aggressive tumor characteristics and poor prognosis. Trastuzumab is the first humanized monoclonal antibody to be approved for therapeutic use and the first oncogene-targeted treatment with proven survival benefit in women with HER2-positive metastatic breast cancer. However, its mechanism of action has not been fully characterized and appears to be complex. This paper reviews current knowledge of the mechanism of action of trastuzumab, including HER2 protein downregulation, prevention of HER2-containing heterodimer formation, initiation of G1 arrest and induction of p27, prevention of HER2 cleavage, inhibition of angiogenesis, and induction of immune mechanisms. The significance of these mechanisms for selection of concomitant chemotherapy is also considered.
Antibodies, Monoclonal↗
Phase I and II clinical trials of trastuzumab.
This report summarizes the efficacy of trastuzumab (Herceptin) based on its completed clinical trial program in patients with HER2-positive metastatic breast cancer for phase I and II studies which have been completed to date and were integral in the submission that led to approval of trastuzumab for clinical use in the USA. There were three small-scale, phase I clinical trials conducted, which were primarily designed to determine the safety and pharmacokinetics of trastuzumab (10-500 mg) administered i.v. as single or weekly doses. This was followed by two phase II clinical trials of fixed-dose trastuzumab either as a single-agent or in combination with cisplatin in 46 and 39 patients, which produced overall response rates of 11.6%, and 24.3%, respectively. In a pivotal phase II clinical trial, trastuzumab was administered on a bodyweight-adjusted basis as a single agent to 222 patients with HER2-positive metastatic breast cancer who had relapsed after one or two prior chemotherapy regimens. The overall response rate was 21% when assessed in evaluable patients by the investigators and 15% when analyzed on an intent-to-treat basis by an independent Response Evaluation Committee. The pharmacokinetics of trastuzumab were evaluated in these studies and the results are summarized.
Adult↗
Herceptin alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: pivotal trials.
Large pivotal phase II and III clinical trials investigated the therapeutic efficacy and safety of the humanized anti-HER2 monoclonal antibody, Herceptin, alone and in combination with standard chemotherapy, respectively, in HER2-positive metastatic breast cancer. Eligible patients were HER2 2+ and 3+ overexpressors, as determined by immunohistochemistry (IHC). Herceptin was well tolerated in both trials. Single-agent second/third-line Herceptin produced durable tumor responses. First-line Herceptin in combination with chemotherapy, in particular paclitaxel, significantly improved time to disease progression, duration of response and time to treatment failure. Combination therapy also provided a significant 25% improvement in overall survival. These clinical benefits have led to the approval of Herceptin for clinical use in the USA and elsewhere. Greater efficacy was noted in IHC 3+ patients compared with the overall population in both trials. Retrospective fluorescent in situ hybridization (FISH) testing of patient-tumor HER2 status revealed similar clinical outcomes in IHC 3+ and FISH-positive patients, consistent with the reported high concordance between IHC and FISH. Responses in the single-agent Herceptin trial were seen exclusively in FISH-positive patients. Approximately a quarter of HER2 2+ patients test FISH positive and may therefore benefit from therapy. Numerous studies are underway or planned to evaluate other Herceptin combinations and regimens in the metastatic and adjuvant settings.
Adult↗
Weekly docetaxel in breast cancer: applying clinical data to patient therapy.
The use of weekly 35-40 mg/m2 docetaxel, typically on a schedule of 6 weeks of therapy followed by a 2-week break, has produced response rates ranging from 33%-50% in patients with advanced breast cancer, the majority of whom have already received chemotherapy. These encouraging levels of response are seen across disease sites and in patients with prior anthracycline exposure. Importantly, the weekly administration of docetaxel allows prolonged treatment to a high cumulative dose: the weekly regimen is minimally myelotoxic, and neuropathy and other adverse events are infrequent. Weekly single-agent docetaxel may be a useful therapy in particular groups of patients such as those with reduced bone marrow reserve. It may also be a helpful means of delivering a highly active cytotoxic drug in combination with radiation therapy, other proven chemotherapy agents such as doxorubicin, and new, highly promising biological agents such as HERCEPTIN:
Antineoplastic Agents↗
Clinical trials of Herceptin(trastuzumab).
This report summarises the clinical efficacy and safety findings from clinical trials of the new anti-HER2 monoclonal antibody Herceptin(trastuzumab). Data from pivotal trials indicate that trastuzumab is active when added to chemotherapy in patients with advanced metastatic breast cancer. In particular, the combination significantly prolonged the median time to disease progression, increased the overall response rate, increased the duration of response, and improved median survival time by approximately 25% compared with chemotherapy alone. Furthermore, trastuzumab is active as a single agent in women with HER2-positive metastatic breast cancer, inducing durable objective tumour responses. In total, 15% of patients who had received extensive prior treatment for metastatic disease had an objective response. The median duration of response was 9.1 months following administration of single-agent trastuzumab. Notably, 2% of patients were free of disease progression at 6 months. The safety profile of trastuzumab either given alone or in combination was favourable.
Antibodies, Monoclonal↗
Clinical trials of Herceptin(R) (trastuzumab).
This report summarises the clinical efficacy and safety findings from clinical trials of the new anti-HER2 monoclonal antibody Herceptin(R) (trastuzumab). Data from pivotal trials indicate that trastuzumab is active when added to chemotherapy in patients with advanced metastatic breast cancer. In particular, the combination significantly prolonged the median time to disease progression, increased the overall response rate, increased the duration of response, and improved median survival time by approximately 25% compared with chemotherapy alone. Furthermore, trastuzumab is active as a single agent in women with HER2-positive metastatic breast cancer, inducing durable objective tumour responses. In total, 15% of patients who had received extensive prior treatment for metastatic disease had an objective response. The median duration of response was 9.1 months following administration of single-agent trastuzumab. Notably, 2% of patients were free of disease progression at 6 months. The safety profile of trastuzumab either given alone or in combination was favourable.
Journal Article↗