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)

Herceptin is the first therapy for breast cancer which targets an oncogene product. This humanized antibody to HER-2 has been shown to have activity as a single agent in a phase II trial of heavily pre-treated patients with advanced breast cancer and, in phase III studies, its use with chemotherapy is associated with higher response rates, longer time to progression and improved survival when compared with chemotherapy alone. Retrospective analysis of data from these pivotal trials suggests that attributable benefit of herceptin is greater in those patients who express HER-2 at the highest levels, that is 3+ expression by immunohistochemistry. Further analysis also implies that cases which are positive for HER-2 by fluorescent in situ hybridization may also benefit from treatment regardless of whether they express HER-2 at the 2+ or 3+ level. Use of herceptin as first-line therapy for metastatic disease in early studies suggest that response rates and clinical benefit rate similar to chemotherapy may be achievable and that survival using this sequential approach may not be compromized. Other combinations of herceptin and chemotherapy have been investigated with phase II data suggesting considerable activity with weekly taxol and when combined with navelbine. The non-linear pharmacokinetics of herceptin suggest that, as doses increased, half-life increases and may be feasible on a 3-weekly schedule. The role of herceptin in the adjuvant setting in the management of breast cancer will be tested in randomized studies of patients who express HER-2 at the highest levels; two of these studies have already begun.
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PMID:Update on HER-2 as a target for cancer therapy: herceptin in the clinical setting. 1173 89

The most prominent secondary organs screened for the presence of occult disseminated tumor cells are regional lymph nodes and bone marrow. The current data suggest that micrometastatic cells represent a selected population of dormant cancer cells, which still express a considerable degree of heterogeneity. The analysis of micrometastatic cells will open a new avenue to assess the molecular determinants of both early tumor cell dissemination and subsequent outgrowth into overt metastases. Moreover, identifying therapeutic target structures (e.g., HER2), monitoring the elimination of bone marrow micrometastases, and assessing treatment-resistant tumor cell clones may help in understanding the current limitations of adjuvant systemic therapy. This review summarizes the current knowledge on the biological characteristics of micrometastatic cancer cells in bone marrow and lymph nodes of cancer patients.
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PMID:Characterization of disseminated tumor cells. 1174 67

This is a case report of a 57-year-old woman with a history of primary carcinoma of the right breast with metastases to the contralateral axillary lymph node. After a partial response (PR) was induced by high-dose chemotherapy with peripheral blood stem cell transplantation, she underwent mastectomy with biopsy of the bilateral axillary lymph nodes. Six months after surgery, the patient had multiple lung metastases. She was then treated with five cycles of fluorouracil, mitoxantrone and vindesine. Although a PR was achieved, further chemotherapy could not be given because of cardiac dysfunction. Since immunohistochemical staining for the HER2 gene product was strongly positive on the surface of primary tumor cells, humanized anti-HER2 monoclonal antibody (trastuzumab) was given intravenously. The metastatic lesion decreased in size and finally appeared to be only cicatricial. Twenty-one months after the initial administration of trastuzumab, the pulmonary lesion was excised. The pathological examination revealed no tumor cells in the resected specimen so further treatment was stopped. The relapse-free state has continued for 24 months after the pulmonary resection.
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PMID:A case with HER2-overexpressing breast cancer completely responded to humanized anti-HER2 monoclonal antibody. 1177 64

HER-2 has a well-established role as a prognostic indicator in breast cancer and as a predictor for response to trastuzumab. Recent studies have also suggested that it may serve as a predictor of response to anthracycline-based therapies. This article argues that the data are insufficient to accept this hypothesis as scientifically established. The argument is developed along several lines: first, that the trials used to support a predictive role for HER-2 have real flaws with regard to this hypothesis; second, that HER-2 is a remarkably inconsistent predictor of anthracycline response when examined in a broader context that includes preoperative and metastatic disease; third, that preclinical data fail to support the hypothesis; and finally, that even if accepted, the hypothesis is difficult to extrapolate to the everyday world of breast cancer.
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PMID:Is HER-2/neu a predictor of anthracycline utility? No. 1177 98

Based largely on studies of cell lines in vitro and of transgenic mouse models, disruptions of transforming growth factor (TGF) beta signaling are thought to contribute to the development and progression of human breast cancer. However, whether and how TGF-beta signaling becomes disrupted during human breast cancer development in vivo remains largely unknown. To address this question, we have compared the patterns of expression and activation of the postreceptor components of the TGF-beta signaling pathway, the so-called Smads, in human breast cancer cell lines with those in breast carcinoma specimens. None of the breast carcinoma cell lines were growth arrested by TGF-beta in vitro. Each of the tumor cell lines expressed normal levels of Smad2 and -3. Moreover, TGF-beta treatment induced phosphorylation of Smad2 (Smad2P) in each of these lines, except those that lacked TGF-beta type II receptors. Moreover, only one of the cell lines failed to express Smad4. Among 456 cases of human breast carcinoma assembled in tissue microarrays, the majority (92%) expressed Smad2, Smad2P, as well as Smad4, indicating their ability to proliferate within a microenvironment that contains bioactive TGF-beta. Thirty cases (6.6%) failed to express Smad2P, suggesting the loss of TGF-beta receptor signaling. Nine cases (2%) failed to express Smad4, and 3 of these also failed to express Smad2P. Thus, the phenotypes of breast tumors in vivo paralleled that of human breast cancer cell lines in terms of Smad2P and Smad4 expression. Loss of Smad signaling was not associated with any particular histological subtype, histological or nuclear grade, estrogen- or progesterone receptor expression, or HER2/neu expression. Loss of Smad4 was inversely correlated with the presence of axillary lymph node metastases. Most importantly, among patients with stage II breast cancer, lack of Smad2P expression in the tumor was strongly associated with shorter overall survival. Finally, analysis of a small cohort of hereditary breast cancers failed to reveal any association between BRCA1 or BRCA2 genotype and alterations in Smad signaling.
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PMID:Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. 1180 1

Cyclooxygenase-2 (Cox-2) expression can induce mammary tumorigenesis in transgenic mice, and selective Cox-2 inhibitors are both chemopreventive and chemotherapeutic in rat models of breast cancer. We analyzed the expression of Cox-2 protein by immunohistochemistry in tissue array specimens of 1576 invasive breast cancers. Moderate to strong (elevated) expression of Cox-2 protein was observed in 37.4% of the tumors, and it was associated with unfavorable distant disease-free survival (P < 0.0001). Elevated Cox-2 expression was associated with a large tumor size, a high histological grade, a negative hormone receptor status, a high proliferation rate (identified by Ki-67), high p53 expression, and the presence of HER-2 oncogene amplification (P < 0.0001 for all comparisons), along with axillary node metastases and a ductal type of histology (P = 0.0001 and P = 0.0017, respectively). Interestingly, association with the unfavorable outcome was especially apparent in the subgroups defined by estrogen receptor positivity, low p53 expression, and no HER-2 amplification (P < 0.0001 for all comparisons). These results indicate that elevated Cox-2 expression is more common in breast cancers with poor prognostic characteristics and is associated with an unfavorable outcome. The present findings support efforts to initiate clinical trials on the efficacy of Cox-2 inhibitors in adjuvant treatment of breast cancer.
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PMID:Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. 1183 May 10

Human epidermal growth factor receptor 2 (p185 HER2) oncoprotein immunohistochemical expression and DF3 antigen distribution were evaluated in 129 patients with primary breast cancer. p185 HER2 overexpession was positively correlated with the degree of differentiation, metastatic disease, progesterone receptors, and cytoplasmic distribution of DF3 antigen. p185 HER2 overexpression had prognostic significance for the disease-free interval.
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PMID:Immunohistochemical study of p185 HER2 and DF3 in primary breast cancer and correlation with CA-15-3 serum tumor marker. 1186 May 39

The success of mammographic screening for breast cancer is that it involves increasingly more patients with small primary tumors formerly thought to have an overall excellent prognosis. Yet, only approximately two thirds of these patients actually have this favorable prognosis, while the remaining third develops metastatic disease. Thus, there is emerging evidence that epithelial tumor cells can disseminate into secondary organs at an earlier stage of primary tumor development than appreciated by current risk classifications. Bone marrow is one of the most prominent secondary organs screened for the presence of disseminated tumor cells. The current data suggest that bone marrow micrometastases represent a selected population of dormant and heterogeneous cancer cells. The analysis of micrometastatic cells opens a new avenue by which to assess the molecular determinants of both early tumor cell dissemination and subsequent outgrowth into overt metastases. Moreover, identifying therapeutic target structures (e.g., HER2/neu), monitoring the elimination of bone marrow micrometastases, and assessing treatment-resistant tumor cell clones might help to understand the current limitations of adjuvant systemic therapy. This review summarizes the current knowledge of the biological characteristics of micrometastatic cancer cells in bone marrow of breast cancer patients.
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PMID:Molecular determinants of occult metastatic tumor cells in bone marrow. 1189 16

The efficacy of trastuzumab for metastases coupled with the relatively poor prognosis of patients with node-positive, HER2-positive breast cancer has led to the evaluation of trastuzumab as an adjuvant therapy. A prospective, randomized, three-arm, phase III trial is being conducted by the Breast Intergroup (N9831) for women with primary, operable, histologically confirmed, node-positive breast carcinoma that strongly overexpresses (3+) HER2 protein and/or displays HER2/neu gene amplification, as determined by local laboratory testing. The protocol requires confirmatory central testing of HER2 status using the HercepTest immunohistochemistry and the Vysis PathVysion fluorescence in situ hybridization (FISH) assays. Tumor specimens from the first 119 patients enrolled in N9831 were centrally tested; 74% were found to be HercepTest 3+ and 66% were found to have HER2 gene amplification. Only six of nine (67%) of the specimens submitted by local laboratories as FISH positive could be confirmed by central assays. The concordance for central HercepTest and central FISH assays was 92%. The poor concordance (74%) between local and central testing for HER2 status has led to modifications in the eligibility criteria for N9831.
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PMID:Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. 1269 58

More than 40,000 women in the United States die each year from metastatic breast cancer. Elucidation of HER2 and its role in malignant transformation has helped define a subset of aggressive breast cancer that may be relatively resistant to non-anthracycline-based therapies and hormonal agents, but responds to targeted molecular therapy. Trastuzumab, an antibody against HER2, has proven effective as single agent therapy in women with HER2 overexpressed metastatic breast cancer. Moreover, in combination with chemotherapy, trastuzumab has been shown to delay disease progression and improve overall survival for women with HER2-positive advanced breast cancer. The combination of chemotherapy and trastuzumab is emerging as a standard of care in women with HER2 overexpressed metastatic breast cancer. Several combination regimens using trastuzumab with taxanes, vinca alkaloids, or platinum compounds have demonstrated efficacy in first- and second-line treatment settings. However, the development of anthracycline-based combinations has been limited by concerns of related cardiotoxicity. Newer multi-agent regimens are in development. The optimal combination, duration, and sequence of trastuzumab therapy remain unknown in patients with HER2-positive metastatic disease. The role of continuing treatment after disease progression is also unclear. Evidence from some retrospective analyses suggest HER2-positive tumors are relatively resistant to tamoxifen and perhaps more responsive to aromatase inhibitors, although such data are inconclusive. HER2 status should not be used routinely for clinical decision making regarding hormonal therapy options. Several ongoing trials are attempting to address these and other issues related to HER2 testing to select the most appropriate candidates for these emerging therapies. While many questions remain, the treatment of HER2 overexpressing metastatic breast cancer is rapidly evolving, and represents a new approach to treatment in oncology.
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PMID:HER2 overexpressing metastatic breast cancer. 1205 79


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