Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trastuzumab/chemotherapy combinations have already shown superior results in metastatic breast cancer patients. The purpose of this study is to determine the clinical efficacy of neoadjuvant trastuzumab and docetaxel in women with locally advanced breast cancer, with or without metastatic disease. Treatment-naive women with HER2-overexpressing locally advanced breast cancer, with or without metastatic disease, were included. Patients received trastuzumab 4 mg/kg loading dose intravenously then 2 mg/kg weekly. On day 22, docetaxel 100 mg/m2 every 3 weeks for 4 cycles was added to weekly trastuzumab. Patients then underwent surgery and subsequent 4 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m2) without trastuzumab. Weekly trastuzumab was resumed 1 month after completion of AC and continued for a year. Preliminary results from the first 22 patients with median follow-up of 15.5 months (range, 2-38 months) are reported. Of these, 9 patients (40.9%) had inflammatory breast cancer, and 6 patients (27.3%) had stage IV breast cancer. Seventeen of 22 patients (77.3%) had objective clinical response, with a clinical complete response in 9 patients (40.9%). Two patients (9.1%) had decline in cardiac function and 7 patients (31.8%) experienced neutropenia, with 2 deaths (9.1%) from neutropenic sepsis. Eight patients (36.4%) have relapsed, 3 with local skin recurrence (13.6%) and 5 with distant recurrence, of whom 1 had liver metastasis (4.5%) and 4 had brain metastasis (18.2%). Combined neoadjuvant trastuzumab and docetaxel induced high clinical response rates for HER2-overexpressing breast cancer, in particular for inflammatory breast cancer. A high rate of brain metastasis was noted, particularly in patients with baseline metastatic disease.
 ...
PMID:Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. 1471 10

Central nervous system (CNS) metastases from breast cancer are common and can present as the first or solitary site of disease progression. The CNS has been reported to act as a sanctuary site that denies access to many chemotherapeutic agents. We present here, a series of 10 metastatic breast cancer patients who developed CNS metastases after an initial response to trastuzumab treatment. Forty one patients with metastatic HER2-overexpressing breast cancer, without evidence of CNS involvement prior to the initiation of trastuzumab treatment, were followed during trastuzumab treatment. A neurological evaluation was performed in those patients who developed neurological signs or symptoms during the course of treatment. The clinical course and pattern of CNS involvement in these patients are discussed. Thirty two patients (78%) showed an initial response to trastuzumab treatment. Ten (31%) of the responding patients developed either isolated CNS relapse or concurrent CNS and systemic progression at a median of 43 weeks after the initiation of trastuzumab treatment. Trastuzumab as a single agent was continued following control of brain symptoms in three patients, two showed signs of systemic disease progression at 11 and 15 weeks following the diagnosis of CNS metastases, respectively. In two other patients, trastuzumab in combination with weekly chemotherapy was continued for more than 20 weeks after CNS relapse without evidence of disease progression. The incidence of CNS involvement in our group of patients was higher than expected. With more successful and prolonged systemic anti-tumour effects achieved by novel drug combinations, the risk of developing CNS metastases might be even greater. Evaluation of prophylactic cranial irradiation strategies might be studied for high-risk patients.
 ...
PMID:Central nervous system progression among patients with metastatic breast cancer responding to trastuzumab treatment. 1474 56

Gemcitabine (Gemzar) and paclitaxel show good activity as single agents and combined in metastatic breast cancer, and the combination of paclitaxel/trastuzumab (Herceptin) has been shown to prolong time to disease progression and survival significantly in this setting. Preclinical data indicate additive or synergistic effects of gemcitabine and trastuzumab in HER2-positive human breast cancer cell lines. In a phase II trial, patients with HER2-overexpressing metastatic breast cancer who had received no prior chemotherapy for metastatic disease received gemcitabine at 1,200 mg/m2 on days 1 and 8 and paclitaxel at 175 mg/m2 on day 1 every 21 days for six cycles plus trastuzumab at an initial loading dose of 4 mg/kg followed by 2 mg/kg weekly; patients without progressive disease after six cycles continued to receive trastuzumab until disease progression. Overall, objective response was observed in 28 (67%) of 42 evaluable patients, including complete response in 4 (10%) and partial response in 24 (57%); stable disease was observed in 7 (17%) and progressive disease was observed in 6 (14%). Median time to treatment failure was 9+ months. Median overall survival has not yet been reached, but is estimated at approximately 27 months. Significant toxicities apart from neutropenia were uncommon. The triplet combination of gemcitabine, paclitaxel, and trastuzumab is highly active and well tolerated in patients with HER2-overexpressing metastatic breast cancer.
 ...
PMID:Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer. 1476 3

Overexpression of HER-2/neu in breast cancer has been associated with more aggressive disease and poor overall survival. Trastuzumab, a recombinant humanized monoclonal antibody with high affinity for the HER-2 protein, inhibits the growth of breast cancer cells overexpressing HER-2. Trastuzumab showed, as second-line treatment, 15% of objective response in metastatic breast cancer. Bone marrow metastases are detectable in 23% of the patients with advanced breast cancer at first relapse and this rate increases in patients with metastatic disease. We report a case of a complete response of bone marrow metastases from breast cancer using a 3-weekly trastuzumab schedule, in a heavily pretreated patient with severe symptomatic pancytopenia.
 ...
PMID:Complete response of severe symptomatic bone marrow metastases from heavily pretreated breast cancer with a 3-weekly trastuzumab schedule. A clinical case. 1501 14

HER-2 has been implicated in the oncogenesis of human prostate cancer (CaP) and is the target of a new treatment for metastatic breast cancer using the humanised monoclonal antibody (MAb) trastuzumab (Herceptin). In this study, a novel alpha-particle emitting [213Bi]Herceptin construct, which targets the HER-2 extracellular domain on CaP cells, was prepared and evaluated in vitro. We used immunocytochemistry, flow cytometry and Western blot analysis to examine the expression of HER-2 in a panel of established human CaP cell lines, used the MTS assay to evaluate the cytotoxicity of 213Bi-Herceptin on these cell lines and the TUNEL assay to document apoptosis. The results indicate that LNCaP-LN3 cells express high levels of HER-2 protein, in contrast, DU 145 cells express low to medium levels, and PC-3 cells express an undetectable level of HER-2 protein. 213Bi-Herceptin was specifically cytotoxic to LNCaP-LN3 cells in a concentration-dependent fashion, cause the cells to undergo apoptosis, whereas DU 145 showed an HER-2 level-dependent response to 213Bi-Herceptin cytotoxicity. In contrast, PC-3 cells were resistant to 213Bi-Herceptin-induced cytotoxicity. The 213Bi-Herceptin induced apoptosis in LNCaP-LN3 cells could be inhibited by incubation with unlabeled Herceptin. Our results suggest that 213Bi-Herceptin alpha-conjugate might be a promising new agent for the treatment of preangiogenic cancer cell clusters or micro-metastases with high levels of HER-2 expression.
 ...
PMID:Cytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate. 1503 48

Expanding knowledge about basic biology and a detailed understanding of the signaling pathways that participate in the growth and metastasis of breast cancer have identified opportunities for diagnostic and therapeutic intervention. Endocrine therapy represents the first and most successful example of targeted therapy in breast cancer. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is now part of the management of metastatic disease and is under evaluation as adjuvant therapy. Other pathways have been targeted, and several candidate drugs are being developed. While these developments represent opportunities for better therapies, they have also identified limitations in identification of targets and development of targeted therapies. Validation of targets is critical, and it is also critical to determine whether the putative target can be identified in a consistent, practical, and inexpensive manner. Finally, it is imperative that targeted therapies are devoid of toxicities secondary to the ubiquitous nature of the target, and we must improve our understanding of interactions that provide specificity of signaling under physiologic conditions.
 ...
PMID:Opportunities and challenges in the development of targeted therapies. 1505 40

The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in metastases. The HER2 expression in primary tumours and the corresponding lymph node metastases were evaluated in parallel samples from 47 patients. The HercepTest was used for immunohistochemical analyses of HER2 overexpression in all cases. CISH/FISH was used for analysis of gene amplification in some cases. HER2 overexpression (HER2-scores 2+ or 3+) was found in 55% of both the primary tumours and of the lymph node metastases. There were only small changes in the HER2-scores; six from 1+ to 0 and one from 3+ to 2+ when the metastases were compared to the corresponding primary tumours. However, there were no cases with drastic changes in HER2 expression between the primary tumours and the corresponding lymph node metastases. The literature was reviewed for similar investigations, and it is concluded that breast cancer lymph node metastases generally overexpress HER2 to the same extent as the corresponding primary tumours. This also seems to be the case when distant metastases are considered. It has been noted that not all patients with HER2 overexpression respond to HER2-targeted Trastuzumab treatment. The stability in HER2 expression is encouraging for efforts to develop complementary forms of therapy, for example, therapy with radionuclide-labelled Trastuzumab.
 ...
PMID:HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review. 1515 May 68

Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for > or =4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.
 ...
PMID:Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. 1516 42

Amplification and overexpression of the HER-2 oncogene in breast cancer is felt to be stable over the course of disease and concordant between primary tumor and metastases. Therefore, patients with HER-2-negative primary tumors rarely will receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive blood test was used to capture circulating tumor cells (CTCs) and evaluate their HER-2 gene status by fluorescence in situ hybridization. The HER-2 status of the primary tumor and corresponding CTCs in 31 patients showed 97% agreement, with no false positives. In 10 patients with HER-2-positive tumors, the HER-2/chromosome enumerator probe 17 ratio in each tumor was about twice that of the corresponding CTCs (mean 6.64 +/- 2.72 vs. 2.8 +/- 0.6). Hence, the ratio of the CTCs is a reliable surrogate marker for the expected high ratio in the primary tumor. Her-2 protein expression of 10 CTCs was sufficient to make a definitive diagnosis of the HER-2 gene status of the whole population of CTCs in 19 patients with recurrent breast cancer. Nine of 24 breast cancer patients whose primary tumor was HER-2-negative each acquired HER-2 gene amplification in their CTCs during cancer progression, i.e., 37.5% (95% confidence interval of 18.8-59.4%). Four of the 9 patients were treated with Herceptin-containing therapy. One had a complete response and 2 had a partial response.
 ...
PMID:HER-2 gene amplification can be acquired as breast cancer progresses. 1519 24

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.
 ...
PMID:Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. 1526 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>