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  • 1
    Electronic Resource
    Electronic Resource
    The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 89-95 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The acquired ability of tamoxifen to stimulate tumor growth has been suggested as one mechanism for the development of treatment failure in breast cancer. We have reported that tamoxifen-stimulated MCF-7 breast tumors in nude mice display reduced tamoxifen levels as compared with tamoxifen-inhibited tumors and an altered metabolite profile with isomerization oftrans-4-hydroxytamoxifen to a weak antiestrogen and the production of metabolite E, an estrogenic metabolite. To investigate further the importance of tamoxifen metabolism in this model, we quantified levels of tamoxifen and major metabolites in tamoxifen-stimulated as compared with tamoxifen-inhibited MCF-7 tumors growing in nude mice and employed tamoxifen analogs resistant to metabolism. Tamoxifen-stimulated tumors have a relative abundance ofcis-4-hydroxytamoxifen and metabolite E. However, in vivo treatment of mice carrying tamoxifen-stimulated tumors with fixed-ring nonisomerizable tamoxifen analogs or with nafoxidine, a nonsteroidal antiestrogen with a different structure, nonetheless resulted in tumor growth stimulation. Tumors were also stimulated by a deoxytamoxifen analog resistant to conversion to metabolite E. Growth of tamoxifen-stimulated tumors was inhibited by a pure steroidal antiestrogen, ICI 182, 780, suggesting the need for clinical trials of this drug in patients with tamoxifen resistance. Growth of tamoxifen-stimulated tumors was further stimulated by estrogen replenishment, and this estrogen stimulation could be blocked by tamoxifen indicating that tamoxifen has both agonist and antagonist properties in these tumors. This study suggests that tamoxifen-stimulated tumor growth in this model is not due to isomerization or metabolism of tamoxifen to less antiestrogenic or more estrogenic metabolities. The mechanisms by which tamoxifen acquires more potent in vivo agonist properties, resulting in tumor growth stimulation over time, remain to be defined.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685924
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  • 2
    Electronic Resource
    Electronic Resource
    The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 89-95 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The acquired ability of tamoxifen to stimulate tumor growth has been suggested as one mechanism for the development of treatment failure in breast cancer. We have reported that tamoxifen-stimulated MCF-7 breast tumors in nude mice display reduced tamoxifen levels as compared with tamoxifen-inhibited tumors and an altered metabolite profile with isomerization of trans-4-hydroxytamoxifen to a weak antiestrogen and the production of metabolite E, an estrogenic metabolite. To investigate further the importance of tamoxifen metabolism in this model, we quantified levels of tamoxifen and major metabolites in tamoxifen-stimulated as compared with tamoxifen-inhibited MCF-7 tumors growing in nude mice and employed tamoxifen analogs resistant to metabolism. Tamoxifen-stimulated tumors have a relative abundance of cis-4-hydroxytamoxifen and metabolite E. However, in vivo treatment of mice carrying tamoxifen-stimulated tumors with fixed-ring nonisomerizable tamoxifen analogs or with nafoxidine, a nonsteroidal antiestrogen with a different structure, nonetheless resulted in tumor growth stimulation. Tumors were also stimulated by a deoxytamoxifen analog resistant to conversion to metabolite E. Growth of tamoxifen-stimulated tumors was inhibited by a pure steroidal antiestrogen, ICI 182,780, suggesting the need for clinical trials of this drug in patients with tamoxifen resistance. Growth of tamoxifen-stimulated tumors was further stimulated by estrogen replenishment, and this estrogen stimulation could be blocked by tamoxifen indicating that tamoxifen has both agonist and antagonist properties in these tumors. This study suggests that tamoxifen-stimulated tumor growth in this model is not due to isomerization or metabolism of tamoxifen to less antiestrogenic or more estrogenic metabolites. The mechanisms by which tamoxifen acquires more potent in vivo agonist properties, resulting in tumor growth stimulation over time, remain to be defined.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685924
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    A demonstration that breast cancer recurrence can be predicted by Neural Network analysis (1992)
    Springer
    Breast cancer research and treatment 21 (1992), S. 47-53 
    Details
    ISSN: 1573-7217
    Keywords: neural networks ; breast cancer ; prognosis ; survival analysis ; Cox regression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Neural Network Analysis, a form of artificial intelligence, was successfully used to predict the clinical outcome of node-positive breast cancer patients. A Neural Network was trained to predict clinical outcome using prognostic information from 1008 patients. During training, the network received as input information tumor hormone receptor status, DNA index and S-phase determination by flow cytometry, tumor size, number of axillary lymph nodes involved with tumor, and age of the patient, as well as lengtl of clinical followup, relapse status, and time of relapse. The ability of the trained Network to determine relapse probability was then validated in a separate set of 960 patients. The Neural Network was as powerful as Cox Regression Modeling inidentifying breast cancer patients at high and low risk for relapse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01811963
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  • 4
    Electronic Resource
    Electronic Resource
    Making the most of your prognostic factors: Presenting a more accurate survival model for breast cancer patients (1992)
    Springer
    Breast cancer research and treatment 22 (1992), S. 251-262 
    Details
    ISSN: 1573-7217
    Keywords: logistic regression ; predictive assessment ; prognostic factors ; transformations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Determining an appropriate level of adjuvant therapy is one of the most difficult facets of treating breast cancer patients. Although the myriad of prognostic factors aid in this decision, often they give conflicting reports of a patient's prognosis. What we need is a survival model which can properly utilize the information contained in these factors and give an accurate, reliable account of the patient's probability of recurrence. We also need a method of evaluating these models' predictive ability instead of simply measuring goodness-of-fit, as is currently done. Often, prognostic factors are broken into two categories such as positive or negative. But this dichotomization may hide valuable prognostic information. We investigated whether continuous representations of factors, including standard transformations — logarithmic, square root, categorical, and smoothers — might more accurately estimate the underlying relationship between each factor and survival. We chose the logistic regression model, a special case of the commonly used Cox model, to test our hypothesis. The model containing continuous transformed factors fit the data more closely than the model containing the traditional dichotomized factors. In order to appropriately evaluate these models, we introduce three predictive validity statistics — the Calibration score, the Overall Calibration score, and the Brier score — designed to assess the model's accuracy and reliability. These standardized scores showed the transformed factors predicted three year survival accurately and reliably. The scores can also be used to assess models or compare across studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01840838
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  • 5
    Electronic Resource
    Electronic Resource
    Igf system components as prognostic markers in breast cancer (1998)
    Springer
    Breast cancer research and treatment 47 (1998), S. 295-302 
    Details
    ISSN: 1573-7217
    Keywords: IGF ; breast cancer ; prognosis ; IGFBP ; treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The insulin-like growth factor (IGF) family of ligands, receptors, and binding proteins can regulate breast cancer cell proliferation in vitro, and interruption of these pathways inhibits IGF-mediated cell proliferation. If the IGF family members are key regulators of breast cancer growth and progression in vivo, we would expect their expression to be an indicator of the prognosis of the disease. Thus, measurement of IGF expression may provide an indicator of the growth effect within a tumor, and provide new targets for treatment of the disease. In this review we will summarize the data generated thus far indicating that IGF family members are indicators of prognosis of breast cancer, and that measurement of the whole IGF family in concert may provide useful information for treatment strategies of breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005915420341
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  • 6
    Electronic Resource
    Electronic Resource
    Time-dependence of hazard ratios for prognostic factors in primary breast cancer (1998)
    Springer
    Breast cancer research and treatment 52 (1998), S. 227-237 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; Cox models ; nonproportional hazards ; prognostic factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Some prognostic factors, such as steroid receptors, appear strongly related to outcome in early studies with short follow-up, but as follow-up matures the relationships appear to weaken. We investigated this phenomenon for several factors (tumor size, axillary lymph nodes, S-phase fraction, estrogen receptor (ER) status, and adjuvant therapy) in a large sample of breast cancer cases (N=2,873) with up to 17 years of follow-up for disease-free survival (DFS). Subjects in the study were identified from patients who had hormone receptor assays performed in our laboratory. Analysis of DFS included fitting a multivariate Cox proportional hazards model, testing for nonproportionality, and examining diagnostic plots. The assumption of proportional hazards was violated for several factors including ER, tumor size, and S-phase fraction. For ER, the hazard ratio was initially less than 1.0, indicating a good effect on prognosis, but increased at later times to values greater than 1.0, indicating a bad effect on prognosis. In contrast, the hazard ratios for tumor size and S-phase were initially high and decreased asymptotically toward 1.0 over time. Analysis of p53 expression in a subset of cases yielded qualitatively similar results. We conclude that several standard prognostic factors (ER, tumor size, S-phase fraction) and possibly other investigational factors have important but nonproportional effects on hazard. It is likely that violation of proportional hazards is common and not limited to breast cancer. Failure to recognize violations of proportional hazards can lead to both over- and under-estimation of the effects of important prognostic factors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006133418245
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  • 7
    Electronic Resource
    Electronic Resource
    Hsp27 overexpression inhibits doxorubicin–induced apoptosis in human breast cancer cells (1999)
    Springer
    Breast cancer research and treatment 56 (1999), S. 185-194 
    Details
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; doxorubicin ; hsp27 ; topoisomerase II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previously we demonstrated that heat shock protein 27 (hsp27) overexpression confers resistance to the chemotherapeutic agent doxorubicin in MDA–MB–231 breast cancer cells. Since induction of apoptosis is one underlying mechanism of chemotherapeutic drug action, we investigated the effect of hsp27 overexpression on doxorubicin–induced apoptosis, finding that hsp27 protects MDA–MB–231 cells from apoptosis. We also examined expression of the doxorubicin target, topoisomerase II (topo II), in control and hsp27–overexpressing stable transfectants, as topo II expression is important for both drug sensitivity and the initiation of apoptosis by doxorubicin. The relative levels of both topo IIα and β were higher in the controls than the hsp27–overexpressing clones, suggesting that the apoptotic protective effect of hsp27 overexpression in MDA–MB–231 cells is associated with altered topo II expression.abstract
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006207009260
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  • 8
    Electronic Resource
    Electronic Resource
    Heat shock proteins and drug resistance (1994)
    Springer
    Breast cancer research and treatment 32 (1994), S. 67-71 
    Details
    ISSN: 1573-7217
    Keywords: doxorubicin ; drug resistance ; heat shock ; hsp27 ; hsp70 ; prognosis ; stress response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Heat shock proteins (hsp's) are induced in cells when exposed to different environmental stressful conditions. We have found that breast cancer cells sometimes express high levels of several hsp's, which may both augment the aggressiveness of these tumors and make them more resistant to treatment. We have shown that hsp70 is an ominous prognostic sign as detected by Western blot assays in node-negative breast tumors, and that hsp27 increases specific resistance to doxorubicin in breast cancer cell lines. These findings have direct clinical application, and suggest that modulating hsp expression may be a therapeutic target for reversal of hsp-associated detrimental cellular effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00666207
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  • 9
    Electronic Resource
    Electronic Resource
    Prognostic significance of PAI-1 and uPA in cytosolic extracts obtained from node-positive breast cancer patients (1997)
    Springer
    Breast cancer research and treatment 43 (1997), S. 153-163 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; uPA ; PAI-1 ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cancer cell invasion is accomplished by the concertedaction of several extracellular proteolytic enzyme systems, oneof which is the urokinase plasminogen activation system.The different components of this system, e.g. urokinaseplasminogen activator (uPA), its receptor uPAR, as wellas its main inhibitor plasminogen activator inhibitor type1 (PAI-1) have all been shown to haveprognostic value in breast cancer, i.e. high tumorlevels are associated with a poor prognosis.In orderto further substantiate the prognostic value of uPAand PAI-1, we have tested the cutpoints (medianvalues and optimized cutpoints) from our first study(Cancer Res 53: 2513–2521, 1993) in an independentgroup of breast cancer patients. Breast cancer cytosolsfrom 100 premenopausal and 150 post-menopausal node positivepatients were included. The median observation time was80 months (range 49–145). Univariate analysis showed thathigh PAI-1 levels (above the median PAI-1 value)were significantly associated with short recurrence-free survival (RR:1.65; 95% CI: 1.04–2.63; P=0.03) andshort overall survival (RR: 2.46; 95% CI: 1.52–3.96;P=0.0001) in postmenopausal patients. Postmenopausal patientswith high uPA levels (above the median uPAvalue) had a significantly shorter recurrence-free survival (RR:2.04; 95% CI: 1.17–3.56; P=0.01) andoverall survival (RR: 2.07; 95% CI: 1.16–3.70; P= 0.01) than patients with low uPA values.Nearly identical results were obtained when using theoptimized PAI-1 or uPA value.In a Cox multivariateanalysis which included other established prognostic factors, highPAI-1 was found to be an independent prognosticvariable predicting short overall survival with a relativerisk of 2.27 in postmenopausal women, and highuPA was found to be an independent prognosticvariable predicting short recurrence-free survival with a relativerisk of 1.86 in postmenopausal women. The presentstudy indicates that uPA and PAI-1 are independentand significant prognostic variables in subsets of breastcancer patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005744914124
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  • 10
    Electronic Resource
    Electronic Resource
    Phase II study of flutamide as second line chemotherapy in patients with advanced pancreatic cancer (1997)
    Springer
    Investigational new drugs 15 (1997), S. 361-364 
    Details
    ISSN: 1573-0646
    Keywords: flutamide ; androgens ; pancreas cancer ; clinical benefit ; quality of life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Androgen receptors are present in both pancreatic cancer tissue and cell lines. Flutamide is a potent antiandrogen widely used in clinical practice for patients with metastatic prostate cancer. This Phase II trial was undertaken to evaluate the impact of flutamide in patients with advanced pancreatic adenocarcinoma who had developed progressive disease following therapy with one 5-FU-based regimen. Fourteen patients were treated with flutamide, 250 mg orally three times per day. Therapy was generally well tolerated. No patient achieved objective tumor response. No patient had improvement in tumor-related symptoms as measured by improvement in pain intensity, analgesic requirement, performance status, or nutritional status. Median survival was 4.7 months. We conclude that flutamide is ineffective second line therapy for patients with advanced pancreatic adenocarcinoma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005989519350
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