Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report

Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC.     

Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II and pharmacokinetic study in Japan

Tolerability and response rate to weekly combination chemotherapy with trastuzumab and vinorelbine in Japanese women with HER2-overexpressing breast cancer not previously receiving either therapy were assessed. Tumor response was evaluated every 4 weeks and adverse events were graded. A total of 23 patients from six participating centers in Japan were enrolled. Median dose intensity of vinorelbine was 16.9 mg/m2/week and response rate was 73% (complete response+partial response); complete response=9%, partial response=64%, and progressive disease=5%. Time to progression was 361 days, with 75.0% of liver metastases and 60% of lung metastases responding to this treatment. The most common adverse events were leukocytopenia and neutropenia (96%); however, hematologic toxicity associated with vinorelbine was manageable by adjusting the dose. No pharmacokinetic differences for vinorelbine were found between single administration and combination with trastuzumab. This combination therapy produced high response rates and good tolerability, indicating a promising role in first-line chemotherapy for HER2-overexpressing metastatic breast cancer in Japan.     

Cardiac dysfunction associated with trastuzumab

The HER2/neu gene is amplified in ～ 25% of breast cancers, leading to HER2 protein overexpression and shortened overall survival and time to relapse. Trastuzumab is a humanised, monoclonal antibody against HER2, which improves survival for women with metastatic HER2-overexpressing breast cancer and reduces the risk of recurrence in women with early stage HER2-overexpressing breast cancer. Cardiac toxicity was an unexpected finding in the pivotal Phase III trial leading to the approval of trastuzumab, and prospective cardiac monitoring has, therefore, been incorporated into more recent clinical trials of trastuzumab. This article reviews the cardiac toxicity findings in key trastuzumab clinical trials and clinical characteristics of trastuzumab-associated cardiac toxicity.     

Induction of remission in a patient with metastatic breast cancer refractory to trastuzumab and chemotherapy following treatment with gefitinib ('Iressa', ZD1839)

Despite new therapies and several treatment options, metastatic breast cancer (MBC) remains incurable. One reason for the low median survival rate may be intense cross-talk between growth factor receptors such as the epidermal growth factor receptor (EGFR/HER1) and the HER2 growth factor receptor. This report describes the case history of a patient with MBC whose disease had progressed despite surgery, radiotherapy and four different chemotherapy regimens, including trastuzumab (a monoclonal antibody that specifically blocks HER2) combined with docetaxel. However, treatment with 500 mg/day gefitinib ('Iressa', ZD1839), an EGFR tyrosine kinase inhibitor, and trastuzumab (2 mg/kg/week) caused a rapid and sustained regression of breast cancer metastases in skin and lymph nodes. Thus, for patients with MBC whose tumors co-express EGFR and HER2, gefitinib in combination with trastuzumab may prevent receptor cross-talk, improving the outcome of MBC.     

Cardiac dysfunction associated with trastuzumab

The HER2/neu gene is amplified in approximately 25% of breast cancers, leading to HER2 protein overexpression and shortened overall survival and time to relapse. Trastuzumab is a humanised, monoclonal antibody against HER2, which improves survival for women with metastatic HER2-overexpressing breast cancer and reduces the risk of recurrence in women with early stage HER2-overexpressing breast cancer. Cardiac toxicity was an unexpected finding in the pivotal Phase III trial leading to the approval of trastuzumab, and prospective cardiac monitoring has, therefore, been incorporated into more recent clinical trials of trastuzumab. This article reviews the cardiac toxicity findings in key trastuzumab clinical trials and clinical characteristics of trastuzumab-associated cardiac toxicity.     

Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance

Approximately 20-30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti-HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor cross-talk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer.     

Additive effects of trastuzumab and genistein on human breast cancer cells

Soy isoflavone genistein, a tyrosine kinase inhibitor and agonist of estrogen receptor-β (ERβ), is known to have antitumoral properties. Given that ERβ often is coexpressed with HER2 in breast cancer, both functions of genistein might be able to enhance the antitumoral action of trastuzumab. In this in-vitro study, we tested whether combined treatment with genistein and trastuzumab exerts additive effects on breast cancer cells. HER2-overexpressing breast cancer cell lines were treated with genistein alone and in combination with trastuzumab. The effects of this treatment on proliferation and gene expression were analyzed. Treatment with high-dose genistein (10 μmol/l) significantly increased the growth-inhibitory effect of trastuzumab on HER2-overexpressing, ERα/β-positive BT-474 breast cancer cells. Combinatory treatment using lower doses of trastuzumab exerted similar effects as a single treatment with standard doses of this drug. In contrast, this effect was absent in ERα-negative SK-BR-3 cells. Similar results were obtained after cotreatment with the ERβ agonist, 2,3-bis(4-hydroxyphenyl)propionitrile. The growth-inhibitory effect of both drugs was accompanied by an increased expression of the putative tumor suppressor ERβ variant, cx, and their combination further elevated mRNA levels of this receptor. In conclusion, genistein significantly enhanced the antitumoral effect of trastuzumab on BT-474 breast cancer cells in vitro. The relevance of these data particularly for women with HER2-overexpressing and ERα/β-positive breast cancer has to be verified in animal or clinical studies.     

Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2.

Trastuzumab is a humanised monoclonal antibody developed to target the HER2 receptor which is overexpressed by some cancer cells, including 25 to 30% of breast cancers. Binding with high affinity to the extracellular domain of HER2, trastuzumab inhibits the proliferation of tumour cells that overexpress HER2. A large well designed multicentre study found that the addition of trastuzumab to either an anthracycline plus cyclophosphamide or to paclitaxel, as first-line therapy for metastatic breast cancer overexpressing the HER2 receptor, significantly increased time to disease progression, rate of objective response, duration of response and survival compared with chemotherapy alone. Single-agent trastuzumab was associated with an objective response in 15% of extensively pretreated patients with metastatic breast cancer overexpressing HER2, and 26% of previously untreated patients. Patients with a HER2 overexpression level of 3+ using immunohistochemical (IHC) assay or a positive HER2 result using fluorescence in situ hybridisation (FISH), benefit more from trastuzumab therapy than those with tumours overexpressing at a level of 2+. Trastuzumab has demonstrated synergistic action with several chemotherapy agents preclinically but the optimal combination clinically is yet to be determined. Trastuzumab is generally well tolerated by most patients; the most significant adverse effects being acute fever and/or chills and the potential to cause cardiac dysfunction. Serious adverse events, including anaphylaxis and death, have occurred in 0.25% of patients. Symptomatic or asymptomatic cardiac dysfunction occurred in 27% of patients receiving an anthracycline and cyclophosphamide combined with trastuzumab. Thus, combination therapy with anthracyclines is not recommended. Symptomatic or asymptomatic cardiac dysfunction occurred in 13% of patients receiving trastuzumab plus paclitaxel and in 4.7% of patients receiving trastuzumab alone. CONCLUSION: Intravenous trastuzumab is effective as a single-agent, and in combination with chemotherapy it significantly improves the median time to disease progression and survival time in patients with metastatic breast cancer overexpressing the HER2 receptor compared with chemotherapy alone. Cardiotoxicity is the main concern with therapy; particularly in patients with pre-existing cardiac dysfunction, the elderly and in combination with, or following, anthracyclines. Trastuzumab is indicated for use with paclitaxel as first-line therapy or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2. Investigation is ongoing to ascertain the optimal combination regimen containing trastuzumab and antineoplastic agents. In addition, current research is focusing on the optimal timing, sequencing and duration of therapy as well as administration in the neoadjuvant and adjuvant setting.     

Trastuzumab and chemotherapy after the treatment failure of lapatinib for HER2-positive metastatic breast cancer

We describe a patient with human epidermal growth factor receptor type 2 (HER2/c-erbB-2)-positive metastatic breast cancer who survived for approximately 6 years after the initiation of combination therapy with trastuzumab and varying types of chemotherapeutic agents. The patient was a 48-year-old postmenopausal female who underwent partial mastectomy with axillary node dissection for cancer of the right breast in March 1994. She developed lung metastases 2 years thereafter, but survived free of relapse for 8 years following chemotherapy and pulmonary lobectomy. The patient failed to respond to lapatinib, a HER1 (EGFR)/HER2 tyrosine kinase inhibitor, received during the course of her treatment but then again responded to subsequently administered trastuzumab. Primary treatment with trastuzumab and paclitaxel was initiated in April 2004 when the patient developed hepatic metastases 8 years after undergoing surgery for lung metastases. Long-term combination therapy with continued trastuzumab and a variety of chemotherapeutic agents was administered for 6 years without any significant adverse events. We discuss the treatment strategies for HER2-positive breast cancer and the role of lapatinib, a recently approved anticancer drug.     

Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer

Trastuzumab (Herceptin) is a humanised monoclonal antibody used in the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), which is associated with clinically aggressive disease and a poor prognosis. The addition of intravenous trastuzumab to first-line chemotherapy improved the time to disease progression, objective response rate, duration of response, and overall survival in randomised, multicentre trials in women with HER2-positive metastatic breast cancer. As such, trastuzumab has become the standard of care in this setting, despite its high acquisition cost and potential for cardiac events, and is licensed for use in combination with paclitaxel (Europe and the US) or docetaxel (Europe). In addition, trastuzumab monotherapy is approved for use in patients with HER2-positive metastatic breast cancer who have previously received chemotherapy for their metastatic disease. Recent data from large phase III trials with trastuzumab in the adjuvant setting revealed significant improvements in disease-free and overall survival. Thus, trastuzumab is also rapidly becoming a standard component of adjuvant therapy for patients with HER2-positive early-stage breast cancer.     

脑膜癌病25例临床分析

目的：探讨脑膜癌病的临床特点和诊断依据。方法对25例确诊为脑膜癌病患者的临床资料及脑脊液细胞学资料进行回顾性分析。结果25例脑膜癌病患者中,临床表现为头痛24例,恶心、呕吐21例,脑膜刺激征阳性20例,视乳头水肿12例,意识障碍6例,四肢无力6例,视力减退5例,癫痫发作5例,精神症状5例,听力障碍3例,头晕3例,发热2例,颈痛1例;20例患者头颅CT/MRI均未见脑膜异常,5例行头颅MRI增强扫描可见2例脑膜强化,1例脑皮质肿胀,1例脑积水,1例小脑蚓部左侧可疑结节;腰椎穿刺脑脊液压力升高12例,蛋白升高16例,糖、氯降低14例,23例患者行脑脊液细胞学检查均发现异型细胞,17例患者行脑脊液免疫组化染色均发现转移癌;17例患者经临床及病理学确定其原发肿瘤,来源于肺癌10例（其中1例肺癌合并前颊黏膜鳞癌）、胃癌3例、贲门癌2、乳腺癌1例、可疑卵巢癌1例,8例来源未明。结论脑膜癌病为恶性肿瘤颅内转移的特殊形式,临床表现复杂,缺乏特异性,早期以颅内压升高为主;头颅MRI增强扫描对脑膜癌病诊断有一定指导意义;脑脊液细胞学检查结合免疫组化染色是脑膜癌病确诊的主要依据。     

Growth differentiation factor 15 (GDF15)-mediated HER2 phosphorylation reduces trastuzumab sensitivity of HER2-overexpressing breast cancer cells

Resistance to the anti-HER2 monoclonal antibody trastuzumab is a major problem in the treatment of HER2-overexpressing metastatic breast cancer. Growth differentiation factor 15 (GDF15), which is structurally similar to TGF beta, has been reported to stimulate phosphorylation of HER2. We tested the hypothesis that GDF15-mediated phosphorylation of HER2 reduces the sensitivity of HER2-overexpressing breast cancer cell lines to trastuzumab. Gene microarray analysis, real-time PCR, and ELISA were used to assess GDF15 expression. Growth inhibition and proliferation assays in response to pharmacologic inhibitors of HER2, TGF beta receptor, or Src were performed on cells stimulated with recombinant human GDF15 or stable GDF15 transfectants. Western blotting was performed to determine effects of GDF15 on HER2 signaling. Cells were infected with lentiviral GDF15 shRNA plasmid to determine effects of GDF15 knockdown on cell survival in response to trastuzumab. Cells with acquired or primary trastuzumab resistance showed increased GDF15 expression. Exposure of trastuzumab-sensitive cells to recombinant human GDF15 or stable transfection of a GDF15 expression plasmid inhibited trastuzumab-mediated growth inhibition. HER2 tyrosine kinase inhibition abrogated GDF15-mediated Akt and Erk1/2 phosphorylation and blocked GDF15-mediated trastuzumab resistance. Pharmacologic inhibition of TGF beta receptor blocked GDF15-mediated phosphorylation of Src. Further, TGF beta receptor inhibition or Src inhibition blocked GDF15-mediated trastuzumab resistance. Finally, lentiviral GDF15 shRNA increased trastuzumab sensitivity in cells with acquired or primary trastuzumab resistance. These results support GDF15-mediated activation of TGF beta receptor-Src-HER2 signaling crosstalk as a novel mechanism of trastuzumab resistance.     

New target therapies for brain metastases from breast cancer

Central nervous system (CNS) metastases from breast cancer (BC) represent an important cause of disease-related morbidity and mortality. For BC patients who develop CNS metastases, local control measures (both surgery and radiation) are essentially palliative and usually poorly effective, with systemic therapies often failing to achieve optimal control mainly due to the presence of the blood-brain barrier which hampers adequate penetration of therapeutic agents into the brain. However, recent evidence suggests that the status of the human epidermal growth factor receptor-2 (HER2) strongly influences the incidence of CNS metastases and the survival of BC patients from the time of development of CNS metastases, with HER2-positive (HER2+) patients generally experiencing higher rates of CNS metastases and prolonged overall survival compared to patients with HER2-negative disease. This phenomenon likely reflects the difficult CNS drug-penetration and improved control of extra-CNS disease following the clinical use of the anti-HER2 monoclonal antibody trastuzumab. Importantly, this HER2-based survival difference has important implications when planning the optimal treatment of BC patients with CNS metastases. To date, although no systemic therapy has been specifically approved for the treatment of CNS metastases from BC, several targeted agents are being clinically developed for this purpose. In the present review we will discuss the targeted therapies that are under investigation for the treatment of CNS metastases from BC, highlighting the different implications based on whether a given agent is being developed to target CNS metastases from HER2+ or HER2-negative breast cancer.     

血清HER2检测在乳腺肿块中的应用

目的 建立血清HER2水平检测方法,研究乳腺肿瘤患者血清HER2的水平、影响因素及临床意义,为乳腺癌治疗及预后判断提供参考.方法 采用酶联免疫吸附(ELISA)方法检测10例正常人、20例乳腺良性病变、50例早期手术及13例晚期转移性乳腺癌患者血清HER2的水平,并对乳癌手术组患者用免疫组化检测组织HER2/neu的表达情况.结果 健康对照组、乳腺良性病变组及乳癌手术组之间的血清HER2水平及阳性率无明显差异(P＞0.05),晚期转移性乳腺癌组的血清HER2水平及阳性率与前三者之间有显著性差异(P＜0.05);乳癌手术组血清HER2水平与肿瘤大小有相关性(P＜0.05),与组织HER2/neu表达、淋巴结转移无关(P＞0.05).结论 血清HER2的水平与乳腺肿块的肿瘤负荷密切有关,可作为免疫组化的补充,用于监测复发转移性乳腺癌并指导其治疗.     

Role of trastuzumab in adjuvant therapy for locally invasive breast cancer.

PURPOSE: The role of trastuzumab in adjuvant therapy for locally invasive breast cancer is discussed. SUMMARY: Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor-2 (HER2). Currently, trastuzumab is indicated for use in HER2-positive patients with metastatic breast cancer. Because trastuzumab specifically targets a receptor that is overexpressed in tumor cells, it is less likely to cause the cytotoxic adverse effects of traditional chemotherapy. Cardiotoxicity has been a major concern, however. Several trials were started to evaluate trastuzumab in the adjuvant setting in patients diagnosed with early-stage breast cancer. The interim results of these trials have shown a promising effect of adjuvant therapy with trastuzumab in improving overall survival, disease-free survival, relapse-free survival, and distant-disease-free survival. CONCLUSION: The use of trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer can lead to increased survival. The appropriateness of trastuzumab therapy should be considered based on HER2 status, cost, and risk of toxicity.     

Evaluation of Serum Levels of HER2, MMP-9, Nitric Oxide,and Total Antioxidant Capacity in Egyptian Breast Cancer Patients: Correlation with Clinico-Pathological Parameters

Breast cancer is by far the most common cancer in women worldwide and the main cause of cancer-related mortality. Breast cancer accounts for 38% of all malignancies among Egyptian women. The aim of our study was to evaluate the serum levels of human epidermal growth factor receptor-2 (HER2), matrix metalloproteinase-9 (MMP-9), nitric oxide (NO), and total antioxidant capacity (TAC) in breast cancer patients and to correlate these markers with clinico-pathological parameters. Serum HER2, MMP-9, and carcinoma antigen 15-3 (CA 15-3) were assessed in 80 breast cancer patients and ten healthy subjects as a control group by the enzyme-linked immunosorbent assay (ELISA) technique while NO and TAC were assessed by a colorimetric method. Serum HER2 was ≥15 ng/mL in nine patients (11.3%). High HER2 ECD levels were significantly associated with tissue HER2 (P<0.0001), metastasis (P= 0.0024), and negativity of both estrogen (P=0.0075) and progesterone (P=0.0239) receptors. Serum MMP-9 (P=0.0013), NO (P<0.0001), and CA 15-3 (P<0.0001) were significantly increased while serum TAC was significantly (P=0.01) decreased in breast cancer patients as compared to the control group. Serum MMP-9 was increased significantly (P=0.028) in metastatic patients as compared to non-metastatic patients. We found a positive correlation between serum HER2 and CA 15-3 (r=36, p=0.005). In conclusion, serum HER2 reflects the tissue HER2 status of breast cancer, so the determination of serum HER2 is helpful in assessing HER2 status, but in addition, a high level may reflect metastatic disease. Also, serum MMP-9 can be useful for denoting the development of metastasis in breast cancer patients. Follow-up is needed to evaluate the value of serum HER2 and MMP-9 as prognostic markers.     

CNS complications of breast cancer: current and emerging treatment options

In general, the development of CNS metastases of breast cancer depends on several prognostic factors, including younger age and a negative hormone receptor status. Also, the presence of a breast cancer 1, early onset (BRCA1) germline mutation and expression of the human epidermal growth factor receptor 2 (Her2/neu) proto-oncogene seem to contribute to an increased rate of development of CNS metastases.The choice of appropriate therapy for brain metastases also depends on prognostic factors, including the age of the patient, the Karnofsky performance score, the number of brain metastases and the presence of systemic disease. Surgery followed by whole brain radiation therapy (WBRT) is generally restricted to ambulant patients with a single brain metastasis without active extracranial disease. In patients who have two to four metastases, stereotactic focal radiotherapy (i.e. radiosurgery) with or without WBRT is usually indicated. In the remainder of patients, WBRT alone provides adequate palliation. Although breast carcinoma is sensitive to chemotherapy, the role of chemotherapy in the treatment of brain metastases is still unclear. Objective responses after cyclophosphamide-based therapies were reported in studies performed in the 1980s. Subgroup analysis of data from a randomised study indicates that survival may improve if WBRT is combined with the radiosensitiser efaproxiral. Interestingly, the Her2/neu antibody trastuzumab, which does not cross the blood-brain barrier, produces systemic responses and enhanced survival, without a clear effect on brain metastases.Breast cancer constitutes the most common solid primary tumour leading to leptomeningeal disease. Clinical symptoms such as cranial nerve dysfunction or a cauda equina syndrome can be treated with local radiotherapy. A randomised study in patients with leptomeningeal disease secondary to breast cancer has revealed that intrathecal chemotherapy is associated with substantially more adverse effects than non-intrathecal treatment, without a clear benefit in terms of response or survival.Intramedullary metastasis is rare but often presents with a rapidly progressive myelopathy. Local radiotherapy may preserve neurological function.Epidural spinal cord metastasis occurs in approximately 4% of patients and can lead to paraplegia. A randomised study has shown that surgical intervention together with local radiotherapy is superior to local radiotherapy alone.     

Serum big endothelin-1 levels in female patients with breast cancer

Endothelin-1[ET-1] acts as a growth factor in various malignancies. Big endothelin-1 (big ET-1) is the precursor of ET-1. The aim of this study was to determine the importance of serum big ET-1 levels as a novel marker of disease in female patients with breast cancer of various clinical stages. The study consisted of 75 female patients with breast cancer who were diagnosed and treated at the Gazi University Department of Medical Oncology and 20 controls. The patients were classified as follows: group A [n=26], patients with newly diagnosed primary breast cancer but without metastasis; group B [n=33], patients with metastatic breast cancer who had undergone treatment for their diseases and in whom metastasis was detected during follow-up; group C [n=16], off-therapy patients whose cancer had been in remission for at least 5 years; and group D [n=20] healthy controls. Serum big ET-1 level were measured with an enzyme immunoassay kit. The median serum big ET-1 levels of the 75 patients with breast cancer [10.96+/-1.36 ng/ml] were statistically significantly higher than those of controls [8.97+/-1.55 ng/ml]. The median serum big ET-1 levels of the patients with primary breast cancer patients [group A] were statistically significantly different from those in the controls, the off-therapy patients and the patients with metastatic disease [11.56+/-0.78 ng/ml, 8.97+/-1.55 ng/ml, 9.76+/-1.52 ng/ml, and 10.83+/-1.18 ng/ml respectively, P=.001]. There was no statistically significant difference in the serum big ET-1 levels of patients in group A in terms of tumor stage, hormone receptor status or lymph node status. Serum big ET-1 levels were statistically significantly higher in patients with metastatic disease than in controls or off-therapy patients (P=.001). The serum big ET-1 levels of off-therapy patients whose disease was in remission were not statistically significantly different from those in controls (P>.05). Serum big ET-1 levels seemed to represent the activation of ET-1 in female patients with breast cancer. Serum big ET- 1 levels can be an indicator of the breast cancer. Further studies are needed to demonstrate the prognostic importance of serum big ET-1 in patients with breast cancer.     

Trastuzumab : in HER2 and hormone receptor co-positive metastatic breast cancer

Trastuzumab is a humanised IgG1 monoclonal antibody, which selectively binds to the human epidermal growth factor receptor 2 (HER2), inhibiting cell proliferation and survival in HER2-dependent tumours. In a randomised phase III trial in postmenopausal women with HER2 and hormone receptor (HR) co-positive metastatic breast cancer, median progression-free survival (primary endpoint) was significantly longer in patients receiving intravenous trastuzumab plus oral anastrozole than in those receiving anastrozole alone. Overall response rate and clinical benefit rate were also significantly higher, and median time to disease progression was significantly longer with trastuzumab plus anastrozole versus anastrozole alone. There were no reports of new or unexpected adverse events with trastuzumab plus anastrozole combination therapy in the randomised phase III trial. In a noncomparative phase II study of trastuzumab plus letrozole in postmenopausal women with HER2 and HR co-positive metastatic breast cancer, the majority of adverse events were mild or moderate in severity.     

Phase II trial of vinorelbine and trastuzumab in patients with HER2-positive metastatic breast cancer. A prospective, open label, non-controlled, multicenter phase II trial (to investigate efficacy and safety of this combination chemotherapy)

Summary  The purpose of this study was to evaluate the efficacy (progression free survival (PFS) and response rate) and safety of vinorelbine and trastuzumab combination chemotherapy in patients with HER2-overexpressing, metastatic breast cancer as a first line chemotherapy regimen. Patients with histologically confirmed, HER2-positive (immunohistochemistry (ICH) 3+, or 2+ and FISH+) metastatic breast cancer who had nor received prior vinorelbine or anti-HER2 therapy in the adjuvant setting, received at least eight weeks of vinorelbine i.v. (25 mg/g weekly) and trastuzumab (4 mg/kg on day 1 followed by 2 mg/kg weekly). Forty-one women from six participating centers were enrolled into the trial. The overall response rate, was 43.9% (18 of 41 patients), (CI 28–60.3%), 30% of patients were progression free after 1 year. Four patients reached complete remission, 14 partial remission and five had stable disease for at least 18 weeks. Six patients developed primary progression. 35 patients (85%) experienced progression after a median time of 235 days. Therapy was in general well-tolerated. There were two CTC grade 4 infusion syndromes and two patients experienced cardiotoxicity at least grade 2. This phase II trial of vinorelbine and trastuzumab demonstrated an effective and well-tolerated regimen with a favourable safety profile.