Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a comparative study of CA 15.3 and EMCA (epithelial mucin core antigen) in 77 consecutive women with newly diagnosed UICC assessable metastatic breast cancer, 59 patients received hormones and 18 chemotherapy. Assessments of response were made prior to commencing therapy and repeated 2 monthly. Sites of metastatic disease included bone (34), pulmonary (8), bone and pulmonary (14) and visceral (21). Using a cut-off of 33 U ml-1 changes in EMCA at 2, 4 and 6 months showed a highly significant correlation (P < 0.001) with UICC assessed response at 6 months; selectivity 70%, sensitivity 80%, specificity 91%, positive predictive value 84%; negative predictive value 89% at 2 months. Corresponding values for CA 15.3: selectivity 89%, sensitivity 85%, specificity 91%, PPV 92% and NPV 91%. Four of eight patients unassessable by CA 15.3 were assessable by EMCA; four patients expressed neither marker. EMCA appears to reflect tumour bulk and may be useful in monitoring therapy in patients with advanced breast cancer. With an easier and more robust assay format than CA 15.3, EMCA is potentially a more useful marker.
 ...
PMID:Epithelial mucin core antigen (EMCA) in assessing therapeutic response in advanced breast cancer--a comparison with CA15.3. 821 8

We determined the concentration and effusion/serum ratio of mucin-like carcinoma-associated antigen (MCA) in comparison to carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125, and cancer antigen 15-3 in 80 sera and 99 effusions from 64 patients with histologically confirmed malignancies (4 patients out of this group showed various effusions simultaneously, which were analyzed separately) and 31 patients with various nonneoplastic diseases. Tumor cells were detected by cytological examination in 41 effusions (60.3%) from patients with neoplastic diseases, while in another 27 cases this method failed to demonstrate the malignant origin of the effusion. Of the cytological "positive" malignant effusions 90% were also correctly identified by an elevated MCA concentration at a cutoff level of 10 U/ml, whereas only one effusion of benign origin (3%) showed a slightly elevated MCA concentration of 10.5 U/ml. In 33% of cytologically "negative" effusions of patients with neoplastic diseases, the MCA concentration was also elevated, with a maximum of 453 U/ml. Increased MCA levels in cytologically confirmed malignant effusions were not restricted to metastatic breast cancer. All 17 cytologically "positive" "non-breast cancer" effusions were correctly identified by their MCA concentrations. None of the other tumor markers reached this high sensitivity at the same level of specificity. The ratio of effusion/serum concentration of all tumor markers as well as the concentration of cancer antigen 125 in effusions was of little diagnostic value. Our results indicate that the MCA concentration in an effusion correlates very closely with its malignant origin and is superior to all the other antigens tested.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Tumor-associated antigens in effusions of malignant and benign origin. 835 2

We have synthesized various formulations that have potential for active specific immunotherapy (ASI) of human cancers. Sialyl-Tn (STn) is a potentially important target structure for ASI because its expression on mucins is a strong, independent predictor of poor prognosis, suggesting that it may have functional significance in the metastatic process. In this first pilot study of synthetic sialyl-Tn hapten conjugated to keyhole limpet hemocyanin (STn-KLH), with Detox adjuvant, toxicity and humoral immunogenicity were assessed in 12 patients with metastatic breast cancer. Toxicity was minimal, restricted to local cutaneous reactions (apart from transient nausea and vomiting following single low-dose cyclophosphamide treatment). Using STn-conjugated human serum albumin in a solid-phase enzyme-linked immunosorbent assay, it was shown that all patients developed IgM and IgG specific for the synthetic STn hapten. Following immunization, most patients were shown to develop increased titres of complement-mediated cytotoxic antibodies, partially inhibited by synthetic STn hapten, but not by the related TF hapten. We also detected IgM and IgG antibodies reactive with natural STn determinants expressed on ovine submaxillary mucin, the STn specificity of this reactivity being confirmed by hapten inhibition. Evaluation of clinical efficacy in a small pilot study is difficult. Five patients are alive 12 or more months after entry, and another 4 patients are alive 6 or more months after entry into the study. All 3 patients with known widespread bulky disease progressed despite ASI, 2 having died from widespread cancer. Two patients had partial responses, each lasting 6 months. While several patients had disease stability for 3-10 months, 1 patient with pulmonary metastases remains stable 15 months after entry into the program.
 ...
PMID:Immunization of breast cancer patients using a synthetic sialyl-Tn glycoconjugate plus Detox adjuvant. 843 84

THERATOPE (Biomira Inc., Edmonton, AB, Canada) STn-KLH cancer vaccine induces strong antibody titers against both the synthetic STn epitope and against a natural mucin, OSM, which expresses STn-like epitopes. In prospective, randomized studies in patients with metastatic breast cancer treated at two cancer centers, the effect of different low-dose, immunomodulatory cyclophosphamide (cyclo) pretreatments on the response to THERATOPE STn-KLH was compared. Patients were randomized to receive either intravenous cyclo 300 mg/m2 on day -3, or oral cyclo 50 mg daily from days -14 to -3 inclusive, or no cyclo, before THERATOPE treatments. The anti-STn and anti-OSM antibody titers were higher in the patients who received cyclo intravenously before THERATOPE. Patients treated with cyclo intravenously and THERATOPE STn-KLH cancer vaccine lived significantly longer (projected median survival of 19.7 months versus actual median survival of 12.6 months, p = 0.0176) than those treated with the same STn vaccine with oral or no cyclo. Although it is not clear how the anti-STn antibody response modifies tumor biology, we noted that patients in the intravenously administered cyclo group had a lower percentage of patients showing progressive disease at 9 weeks, and that there was an inverse correlation between serum anti-STN antibody titer and growth of measurable tumors. There was no correlation between tumor growth and anti-KLH antibody titers. These data are consistent with a therapeutic effect of THERATOPE STn-KLH cancer vaccine and support development of a phase III study to explore this further.
 ...
PMID:Enhancing the effect of THERATOPE STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide. 887 24

Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed.
 ...
PMID:A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer. 888 20

Active specific immunotherapy, the use of 'vaccines' to stimulate therapeutic tumor antigen-specific immune responses, holds promise as a complementary approach to chemotherapy, radiation and surgery for the treatment of patients with cancers that have a high risk of relapse or progressive disease. Important components of an agent used for active immunotherapy are immunogens in the form of tumor-associated antigen(s) and an adjuvant or carrier molecule to promote presentation of the antigen to the immune effector cells. Possible antigens include tumor-expressed proteins or carbohydrate structures such as the glycoprotein mucin and its epitopes. The Theratope vaccine, consisting of a synthetic mimic of the mucin-associated glycan epitope STn conjugated to the carrier molecule keyhole limpet hemocyanin, has been developed for immunizing patients with mucin-expressing tumors. In murine and human studies, the vaccine has been shown to stimulate anti-STn antibodies and mucin-specific T-cell responses. The immune response is augmented by pretreatment with intravenous cyclophosphamide that serves to inhibit suppressor T-cells. Phase II studies suggested a survival benefit for breast cancer patients who received the Theratope vaccine after intravenous cyclophosphamide. A multinational phase III study testing the Theratope vaccine in patients with metastatic breast cancer who have had a clinical response or stability of disease is ongoing. Other malignancies for which the vaccine may be applicable include ovarian and gastrointestinal cancers.
 ...
PMID:Technology evaluation: Theratope, Biomira Inc. 1124 77

Radioimmunotherapy (RIT) is a promising approach for treating metastatic breast cancer. Initial clinical trials using 131I radioimmunoconjugates, and more recent studies employing 90Y, have demonstrated objective, although transient, antitumor effects in heavily pretreated patients with minimal toxicity. Antibodies targeting unique epitopes of epithelial glycoprotein mucin (MUC-1) on breast cancer cell surfaces that have been studied in patients include BrE-3 (murine and humanized) and m170 (murine). Both antibodies react with at least 90% of breast cancers. In these and other RIT trials, myelosuppression has been the dose-limiting toxicity. However, this toxicity has been successfully circumvented with the use of autologous peripheral blood stem cell transplantation, and recent clinical trials have escalated 90Y doses up to 50 mCi/m(2). The therapeutic index indicates that using these agents with stem cell support should deliver 9000 to 18000 rads to metastatic tumors. Development of improved chelates that are readily metabolized in the liver may reduce doses to this organ, projected to be next in line as dose-limiting. Combination therapy will be required to produce durable benefits in metastatic breast cancer. Low dose taxanes are synergistic with RIT in preclinical studies and when administered in the optimal sequence could sensitize tumor cells to the continuous low dose radiation delivered by RIT, without increasing toxicity. The addition of systemically administered tumor targeting radiation therapy using RIT as part of combined modality therapy may enhance the rate of complete response and, in patients with minimal metastatic disease, could lead to curative therapy.
 ...
PMID:Systemic radiotherapy in metastatic breast cancer using 90Y-linked monoclonal MUC-1 antibodies. 1125 79

Active specific immunotherapy (ASI) is a promising approach to treating cancer. Numerous studies in the laboratory have demonstrated that various cancer vaccines can stimulate antibody and cell mediated immune responses against tumour-associated antigens [1-9]. Yet few studies have demonstrated convincing clinical responses. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on a number of human cancer cells and is associated with more aggressive disease. Consequently, STn is an ideal candidate for ASI therapy. Theratope vaccine is a cancer vaccine that was designed by Biomira, Inc. (Edmonton, Alberta, Canada) by incorporating a synthetic STn antigen that emulates the carbohydrate seen on human tumours. The clinical trials conducted to date with Theratope vaccine are outlined in this report. Overall, Theratope vaccine has been well-tolerated with minimal toxicity. The most common side effects have been in duration and erythema at the site of injections. Both in a non-transplant setting following low dose iv. cyclophosphamide and high dose autologous transplant setting, there has been a trend toward Theratope vaccine decreasing the risk for relapse, prolonging the time to relapse and thus impacting on overall survival. The definitive Phase III trial comparing the outcome of patients with metastatic breast cancer receiving vaccinations with Theratope vaccine versus vaccination with the nonspecific immune stimulants Keyhole Limpet Hemocyanin (KLH) and Detox -B stable emulsion (Detox-B) (now called Enhanzyn Immunostimulant) was closed to enrolment on March 30, 2001. Over 1000 women with distant metastatic breast cancer were enrolled into the program.
 ...
PMID:Theratope vaccine (STn-KLH). 1172 22

The success of high-dose chemotherapy followed by autologous stem-cell rescue as treatment for breast and ovarian cancer is limited by a high incidence of relapse. After autologous transplantation, patients are likely to have a low tumor burden and thus would be more likely to respond immunologically to a cancer vaccine. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on breast and ovarian cancer and is an ideal candidate for vaccine immunotherapy. Sialyl-Tn-keyhole limpet hemocyanin (STn-KLH) vaccine (Theratope) incorporates a synthetic STn antigen that mimics the unique tumor-associated STn carbohydrate and is designed to stimulate tumor antigen-specific immune responses in patients with mucin-expressing tumors. Between 1995 and 2000, 70 patients (16 with stage II/III breast cancer, 17 with stage III/IV ovarian cancer, and 37 with stage IV breast cancer) were treated with 2 different formulations of STn-KLH. Toxicity, outcome, and immune response data are reported. STn-KLH was well-tolerated with minimal toxicity. The most common side effects were indurations and erythema at the sites of injections. Humoral and cellular responses were elicited in the majority of patients. Overall, these data indicate that post-autologous transplant patients are able to mount an effective immune response to vaccine immunotherapy with minimal side effects, and that vaccine immunotherapy may be a useful addition to high-dose chemotherapy regimens.
 ...
PMID:The role of cancer vaccines following autologous stem cell rescue in breast and ovarian cancer patients: experience with the STn-KLH vaccine (Theratope). 1262 Jan 52

Biomira is developing a therapeutic cancer vaccine [THERATOPE] for treatment of breast and other cancers. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. THERATOPE consists of the mucin antigen, sialyl-Tn (STn), a carbohydrate located on the surface of breast, colorectal and ovarian cancer cells, conjugated to keyhole limpet haemocyanin (KLH). Merck KGaA has acquired a worldwide licence to THERATOPE for treatment of breast cancer. Under the terms of the licence, Biomira and Merck KGaA, via its US affiliate, EMD Pharmaceuticals, will jointly market the vaccine in the US. Merck KGaA holds exclusive marketing rights for the rest of the world, except in Canada (where Biomira retains rights), Israel and the Palestine Autonomy Area. Merck KGaA is now collaborating on phase III development for breast cancer. Biomira stands to receive $US150 million in licence, milestone payments and equity investments. The development costs will be shared between the two companies in North America but Merck KGaA will be solely responsible for these costs in countries outside the US. Previously, Chiron Corporation had purchased a licence to THERATOPE in 1997; however, Chiron terminated this agreement in June 2000. Under the terms of the termination, Biomira paid Chiron $US2.25 million to compensate the company for its investment in the development of THERATOPE. In addition, Biomira will make another payment of $US3.25 million to Chiron upon FDA approval of the vaccine. No further payments or royalties will be made. In the third quarter of 2002, an independent review of interim data from the trial was conducted. This was the fifth scheduled review of the data by the Independent Data Safety Monitoring Board (DSMB), all of which produced a positive response. Following the completion of the review, the DSMB stated that the trial should continue and that it had no safety concerns regarding this trial. Although the data, to which Biomira and Merck KgaA are blinded, did not meet the predetermined statistical significance for either endpoint at the time of the review, both companies have chosen to continue with the trial. Biomira has since announced that the p-value for the interim survival analysis was set at 0.01, while it is set at 0.03 for final survival analysis. The tighter criteria was set for the interim analysis to potentially give the companies the opportunity of applying for marketing approval earlier than expected. Final analysis of the trial will take place in mid-2003. If these analyses indicate therapeutic efficacy, Biomira will meet the FDA and Canadian regulatory officials to obtain marketing approval for the vaccine for breast cancer under the accelerated review guidelines. Assuming a best-case scenario, the vaccine could be filed for approval in 2004. The phase III trial was initiated following positive preliminary results achieved in a bridging study in patients with metastatic breast cancer in the US and UK. Biomira announced final results of the bridging study in May 1999. The results confirmed that antibody titres against the STn antigen were significantly higher in patients treated with the improved formulation of THERATOPE, compared with the corresponding titres of patients in the phase II trials of the old formulation of THERATOPE. In September 2002, the first patient was enrolled in a phase II THERATOPE trial, which is enrolling patients with metastatic breast cancer who are taking either an aromatase inhibitor or fulvestrant. Approximately 95 patients will be enrolled in the trial at up to 12 US sites. The study is primarily designed to evaluate THERATOPE's ability to induce an immune response in these patients. However, the safety and tolerability of the aromatase inhibitor plus THERATOPE, and the fulvestrant plus THERATOPE combinations will also be evaluated. The trial has not been designed to evaluate the efficacy of the two combinations. The US FDA has granted fast-track status tranted fast-track status to THERATOPE for development as an adjunct to first-line combination chemotherapy in responding patients with metastatic breast cancer. A phase II trial in patients with metastatic colorectal cancer has been completed in the US; positive preliminary results from this trial were released in May 2001. On 24 November 1999, Biomira announced that it had licensed two patents covering methods of preventing growth of cancer cells expressing a mucin-type glycoprotein. The patents have been issued in the US and are pending in Japan and Canada. When issued in Japan, the patents will provide additional protection for THERATOPE in that country. The patents were licensed from Dr Sen-itiroh Hakomori of the Biomembrane Institute in Seattle, with whom Biomira has also entered into a research collaboration. Biomira announced in April 2003 that following examination of its re-issue application by the US Patent and Trademark Office, its patent 5798090 was re-issued (RE 38046) with additional claims. These additional claims represent broader patent coverage. The additional coverage will last until 2015. Earlier, in February 2000, Biomira announced an expansion of equity line for up to $US100 million; a 3-fold rise that was done without any additional shares of Biomira stock being issued. In June 2002, Biomira stated that it believes the market size for THERATOPE in the US, Europe and Japan to be approximately 184000 patients for the indication of metastatic breast cancer, of which the US would be 100000, Europe 75000 and Japan 9000. For the indication of colorectal cancer, the total market population for THERATOPE is expected to be 183000 patients, of which the US has been estimated at 100000, Europe 75000 and Japan 9000.
 ...
PMID:Cancer vaccine THERATOPE- Biomira. 1284 88


<< Previous 1 2 3 Next >>