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

Mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, are associated with the pathogenesis of medullary thyroid carcinoma (MTC). Somatic mutations in RET, predominantly at codon 918, and very rarely at codon 883, have been found in a proportion of sporadic MTC. We have previously shown that approximately 80% of sporadic MTCs had at least one subpopulation with a somatic RET mutation. Uneven distribution of somatic mutation within a single tumor or among metastases from a single individual was notable. In the present study, we sought to correlate RET expression, as demonstrated by RET immunohistochemistry, with mutation status in sporadic MTC for each tumor. Seventy evaluable subpopulations, belonging to 28 unrelated sporadic cases, comprising primary MTC and metastases, were immunostained with two different polyclonal antibodies raised against the C-terminus of RET. The regional presence of codon 918 or 883 seemed to coincide with increased RET immunopositivity in at least 62 of 70 (89%, P < 0.000001) tumor subpopulations. The reasons for this concordance are not entirely clear but could be related to either RNA or protein stability. Preliminary studies have suggested that the presence of somatic codon 918 mutation in MTC has a prognostic significance. If these preliminary results prove true, then given our data, we can further explore the feasibility of RET immunocytochemistry as a rapid assessment for the presence of somatic codon 918 for molecular diagnostic and prognostic purposes.
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PMID:Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma. 985 69

Medullary thyroid carcinomas (MTC) metastasize early into the regional lymph nodes. Calcitonin is a highly specific and sensitive marker for these tumors, which is feasible for follow-up and for screening. Additionally, in families with hereditary MTC the responsible mutations of the RET-proto-oncogene can be identified, and prophylactic surgery can be provided. We operated on 127 patients for MTC, 114 of whom had diagnosed carcinomas; 13 operations were performed with prophylactic intention. A total of 101 patients needed microsurgical dissection of the cervical compartments. Of these, 31% could be cured, and a further 46% showed postoperatively normalized basal calcitonin concentrations. Thirteen patients who needed mediastinal dissection had persistent increased levels of pentagastrin-stimulated or basal calcitonin values. All patients who underwent prophylactic surgery could be cured.
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PMID:[The concept of "microsurgical" technique in medullary thyroid carcinoma]. 993 10

Prostate cancer development and progression is driven by the accumulation of genetic changes, the nature of which remains incompletely understood To facilitate high-throughput analysis of molecular events taking place in primary, recurrent, and metastat prostate cancer, we constructed a tissue microarray containing small 0.6-mm cylindrical samples acquired from 371 formalin-fixed blocks, including benign prostatic hyperplasia (n = 32) and primary tumors (n = 223), as well as both locally recurrent tumors (n = 54) and metastases (n = 62) from patients with hormone-refractory disease. Fluorescence in situ hybridization (FISH) was applied to the analysis of consecutive tissue microarray sections with probes for five different genes. High-level (> or =3X) amplifications were very rare (<2%) in primary prostate cancers However, in metastases from patients with hormone-refractory disease, amplification of the androgen receptor gene was seen in 22%, MYC in 11%, and Cyclin-D1 in 5% of the cases. In specimens from locally recurrent tumors, the corresponding percentages were 23, 4, and 8%. ERBB2 and NMYC amplifications were never detected at any stage of prostate cancer progression. In conclusion, FISH to tissue microarray sections enables high-throughput analysis of genetic alterations contributing to cancer development and progression. Our results implicate a role for amplification of androgen receptor in hormonal therapy failure and that of MYC in the metastatic progression of human prostate cancer.
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PMID:Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. 1002 66

Detecting and/or monitoring changes in circulating tumor markers might assist in evaluating cancer risk, diagnosis, prognosis, or response to treatment. Several categories of circulating tumor markers have been investigated in breast cancer. These categories include classical tumor-associated antigens, such as CEA and CA 15-3, markers of tumor biology, including markers of angiogenesis, adhesion, and invasion, and antibody response to tumor-associated antigens such as HER2/neu and p53. We used a recently proposed Tumor Marker Utility Grading System to evaluate the use of several circulating tumor markers for different clinical utilities in breast cancer. While there are no tumor markers with established clinical utilities for most uses, tumor-associated antigens can be used for monitoring patients with metastatic disease. In addition, markers of tumor biology such as the circulating extracellular domain of HER2/neu might be useful in determining not only prognosis, but also response to specific treatments. However, further investigations are required to further assess the utility of individual tumor markers for specific clinical uses.
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PMID:Circulating tumor markers in breast cancer: accepted utilities and novel prospects. 1006 86

To assess the importance of Neu activation during mammary tumorigenesis, altered receptors harboring in-frame deletions within the extracellular domain were expressed in transgenic mice. Females from several independent lines develop multiple mammary tumors that frequently metastasize to the lung. Tumor progression in these strains was associated with elevated levels of tyrosine-phosphorylated Neu and ErbB-3. Consistent with these observations, a survey of primary human breast tumors revealed frequent co-expression of both erbB-2 and erbB-3 transcripts. The ability of altered Neu receptors to induce mammary tumorigenesis in transgenic mice prompted us to examine whether similar mutations occurred in ErbB-2 during human breast cancer progression. Interestingly, an alternatively spliced form of erbB-2, closely resembling spontaneous activated forms of neu, was detected in human breast tumors. The ErbB-2 receptor encoded by this novel transcript harbors an in-frame deletion of 16 amino acids in the extracellular domain and can transform Rat-1 fibroblasts. Together, these observations argue that co-expression of ErbB-2 and ErbB-3 may play a critical role in the induction of human breast tumors, and raise the possibility that activating mutations in the ErbB-2 receptor may also contribute to this process.
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PMID:Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. 1020 69

The progression of breast cancer growth and its ability to metastasize are associated with the process of angiogenesis. In this study, we examined the protein expression of vascular endothelial growth factor (VEGF) and its specific and functional receptor KDR in human breast tissue. We investigated a total of 13 mammary carcinomas, 3 fibroadenomas, 5 specimens with fibrocystic breast disease as well as normal (adjacent to malignant) breast tissue using immunohistochemistry and Western blot analysis. In all carcinomas examined, functional KDR protein was present independent of tumor type, tumor stage and histological grade as demonstrated by tyrosine phosphorylation analysis of KDR. When malignant tissues were compared with their neighboring non-neoplastic regions, activated KDR was found to be expressed to a much higher extent within the malignant tissue samples. In fibroadenomas, KDR was barely detectable, whereas in fibrocystic breast disease KDR expression was variable. Immunostaining of KDR was localized to endothelium and epithelium of mammary ducts in malignant and benign breast tissue, while VEGF immunoreactivity was primarily found in the endothelium and also in tumor cells and macrophages. Our data demonstrate that KDR activation is enhanced in breast cancer in vivo and emphasize the functional role of VEGF and KDR in the development of malignant breast disease.
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PMID:Molecular mediators of tumor angiogenesis: enhanced expression and activation of vascular endothelial growth factor receptor KDR in primary breast cancer. 1037 49

Much remains to be learned about drug resistance in the biology of RCC and its metastases. We measured MDR-1/P-glycoprotein expression in 19 tumor samples from patients with metastatic RCC by RNase protection and quantitative PCR assays. The median level of the 16 tumor metastases was 4.9 (range: 0.10 to 156.2) relative to the level of 10 assigned to a reference cell line, SW620, which has been characterized as expressing a minimum level of MDR-1. Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC. In 8/10 lines, MDR-1 expression was >10. Relative to the level in the primary line, MDR-1 expression was decreased (3 to 50-fold) in 3 metastatic lines, was increased in 1, and unchanged in 1. MRP mRNA expression was lower in the metastatic lines while EGFR expression was variable. IC50 values for 6 compounds (including 4 standard agents and one new Phase 1 agent) were determined for the paired lines. Rhodamine and calcein efflux assays were performed as measures of P-glycoprotein and MRP function. Rhodamine efflux correlated with MDR-1 mRNA expression (r = 0.87) and with the IC50s (r = 0.60) for paclitaxel in the paired cell lines. In contrast, calcein efflux did not correlate with MRP expression. Lastly, MDR-1 expression correlated with cytokeratin 8 (CK8) protein levels, a measure of cellular differentiation. In sum, these data suggest renal cell carcinoma (RCC) metastases have altered MDR-1 expression potentially due to altered differentiation relative to the primary tumor. Thus, the drug resistance phenotype of primary RCC tumors may not reflect that of their metastases.
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PMID:Intrinsic drug resistance in primary and metastatic renal cell carcinoma. 1037 90

Paclitaxel has emerged as an important agent in the treatment of breast cancer. The efficacy and tolerability of this agent, as well as its lack of cross-resistance with anthracyclines, have spurred intensive clinical investigation worldwide. Optimization of paclitaxel dose and scheduling and evaluation of the drug in combination regimens are a central focus of investigations. Recent clinical evidence suggests that optimal dose of single-agent paclitaxel by 3-h infusion is 175 mg/m&sup2;. Trials evaluating administration schedule have not found either a 24-h or 96-h infusion to be superior to a 3-h infusion. Weekly moderate-dose paclitaxel administration is also generating much interest, given the high relative dose intensity and dose density delivered, yet very modest myelosuppression and manageable neurotoxicity observed. As first-line therapy in metastatic disease, multiple studies have documented overall response rates in the range of 30%-60%. As second-line or salvage single-agent therapy in metastatic patients, paclitaxel generally affords an overall response rate of 20%-40%, even in anthracycline-resistant patients. The novel mechanism of action and manageable toxicity of paclitaxel has led to successful incorporation into combination chemotherapy regimens. The combination of paclitaxel and doxorubicin has been the most extensively studied, with the role of this regimen continuing to evolve. Other combination regimens that appear to hold substantial promise as first-line metastatic treatment are paclitaxel with carboplatin and paclitaxel with trastuzumab (anti-HER2 antibody). The favorable results obtained in the metastatic setting have prompted phase II and phase III investigations of paclitaxel in the adjuvant and neoadjuvant settings. In the adjuvant setting, a recent phase III study has indicated that the addition of sequential paclitaxel to standard therapy affords both disease-free and overall survival benefits. Current investigations with paclitaxel will continue to optimize the role of this agent in the treatment of early- and advanced-stage breast cancer, addressing not only response rates but also survival and quality-of-life issues. The use of paclitaxel on a weekly schedule or with new therapeutic modalities, such as monoclonal antibodies, is also receiving much attention. While it is clear that paclitaxel is a very active agent in the treatment of breast cancer, it is hoped that these innovative trials will further maximize the potential of this agent in patients with breast cancer.
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PMID:Paclitaxel in Breast Cancer. 1038 29

The HER2/neu proto-oncogene is overexpressed in 25% to 30% of patients with breast cancer. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a recombinant humanized monoclonal antibody with high affinity for the HER2 protein, inhibits the growth of breast cancer cells overexpressing HER2. In this phase II study the efficacy and toxicity of weekly administration of trastuzumab was evaluated in 46 patients with metastatic breast cancer whose tumors overexpressed HER2. A loading dose of 250 mg trastuzumab was administered intravenously, which was followed by 10 weekly doses of 100 mg each. Upon completion of this treatment period, patients with no disease progression could receive a weekly maintenance dose of 100 mg. Patients in this trial had extensive metastatic disease, and most had received prior anticancer therapy. Ninety percent of patients achieved adequate serum levels of trastuzumab. Toxicity was minimal, and no antibodies against trastuzumab could be detected. Objective responses were observed in 5 of the 43 evaluable patients, which included 1 complete remission and 4 partial remissions, for an overall response rate of 11.6%. Responses were seen in mediastinum, lymph nodes, liver, and chest wall lesions. Minor responses (seen in 2 patients) and stable disease (14 patients) lasted for a median of 5.1 months. These results demonstrate that trastuzumab is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers who have received extensive prior therapy. The regression of human cancer through the targeting of putative growth factor receptors such as HER2 warrants further evaluation of trastuzumab in the treatment of breast cancer.
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PMID:Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. 1048 97

Several recent publications have re-opened the question of whether HER2 status should be determined for all patients with newly diagnosed breast cancer. The barrier in the past to the use of HER2 has been the nonstandardization of HER2 status determination, which is the major caveat to its use today. Two test kits have been recently approved by the Food and Drug Administration for HER2 testing, one for determining HER2 amplification by fluorescence in situ hybridization and the other for measuring HER2 overexpression by immunohistochemistry. Neither of these tests, nor any of the other myriad tests used for HER2 determinations, has been validated in all the potential arenas for the use of HER2: refinement of estimates of prognosis of untreated low-risk patients, selection among treatment options for adjuvant therapy, and selection of patients for treatment with trastuzumab (Herceptin; Genentech, San Francisco, CA). The nonstandardization of testing has led to conflicting results and controversy as to the value of HER2 in evaluating breast cancer patient prognosis and the selection among therapeutic options. Thus, testing for HER2 is not yet routine for patients with newly diagnosed breast cancer, although it is of value for patients who develop metastatic disease and who need to know if they are candidates for trastuzumab.
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PMID:Should HER2 status be routinely measured for all breast cancer patients? 1048 3


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