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2. Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients

Author

Harbeck, N., Schmitt, M., Meisner, C., Friedel, C., Untch, M., Schmidt, M., Sweep, C.G.J., Lisboa, B.W., Lux, M.P., Beck, T., Hasmuller, S., Kiechle, M., Janicke, F., and Thomssen, C.

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Decision Making, Breast Neoplasms, Enzyme-Linked Immunosorbent Assay, Disease-Free Survival, Metastasis, law.invention, Breast cancer, Drug Therapy, Randomized controlled trial, Risk Factors, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Plasminogen Activator Inhibitor 1, Biomarkers, Tumor, medicine, Humans, Prospective Studies, Prospective cohort study, Cyclophosphamide, Aged, Neoplasm Staging, Gynecology, Chemotherapy, business.industry, Cancer, Middle Aged, Prognosis, medicine.disease, Urokinase-Type Plasminogen Activator, Methotrexate, Treatment Outcome, Chemotherapy, Adjuvant, Hormonal regulation Aetiology, screening and detection [IGMD 6], Female, Fluorouracil, business, Risk assessment, Plasminogen activator
Abstract

Item does not contain fulltext AIM: Final 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer (EORTC) pooled analysis (n=8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynakologische Onkologie (AGO) guidelines recommend invasion and metastasis markers urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) for risk assessment and treatment decision in node-negative (N0) breast cancer (BC). METHODS: The final Chemo-N0 trial analysis (recruitment 1993-1998; n=647; 12 centres) comprises 113 (5-167) months of median follow-up. Patients with low-uPA and PAI-1 tumour tissue levels (n=283) were observed. External quality assurance guaranteed uPA/PAI-1 enzyme-linked immunosorbent assay (ELISA) standardisation. Of 364 high uPA and/or PAI-1 patients, 242 agreed to randomisation for CMF chemotherapy (n=117) versus observation (n=125). RESULTS: Actuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high-uPA/PAI-1 observation group patients (randomised and non-randomised) was 23.0%, in contrast to only 12.9% for low-uPA/PAI-1 patients (plog-rank=0.011). High-risk patients randomised to cyclophosphamide-methotrexate-5-fluorouracil (CMF) therapy had a 26.0% lower estimated probability of disease recurrence than those randomised for observation (intention-to-treat (ITT)-analysis: hazard ratio (HR) 0.74 (0.44-1.27); plog-rank=0.28). Per-protocol analysis demonstrated significant treatment benefit: HR 0.48 (0.26-0.88), p=0.019, disease-free survival (DFS) Cox regression, adjusted for tumour stage and grade. CONCLUSIONS: Chemo-N0 is the first prospective biomarker-based therapy trial in early BC defining patients reaching good long-term DFS without adjuvant systemic therapy. Using a standardised uPA/PAI-1 ELISA, almost half of N0-patients could be spared chemotherapy, while high-risk patients benefit from adjuvant chemotherapy. These 10-year results validate the long-term prognostic impact of uPA/PAI-1 and the benefit from adjuvant chemotherapy in the high-uPA/PAI-1 group at highest level of evidence. They thus support the guideline-based routine use of uPA/PAI-1 for risk-adapted individualised therapy decisions in N0 breast cancer.

Published
2013
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3. Combined Tamoxifen and Luteinizing Hormone-Releasing Hormone (LHRH) Agonist Versus LHRH Agonist Alone in Premenopausal Advanced Breast Cancer: A Meta-Analysis of Four Randomized Trials

Author

Klijn, J. G. M., Blamey, R. W., Boccardo, F., Tominaga, T., Duchateau, L., Sylvester, R., Beex, L. V. A. M., Mauriac, L., Zijl, J. A., Veyret, C., Wildiers, J., Jassem, J., Piccart, M., Burghouts, J., Becqaert, D., Seynaeve, C., Mignolet, F., Namer, M., Julien, J. P., Garcia Conde, J., Dunser, M., Margreiter, R., Tjabbes, T., Roozendaal, K. J., Velden, P. C., Nortier, J. W. R., Blamey, R., Howell, A., Forbes, J., Kaufmann, M., Nordenskjold, B., Kvinnsland, S., Wilson, R. G., Jonat, W., Kleeberg, U. R., Eiermann, W., Hilfrich, J., Weitzel, H. K., Glas, U., Rutqvist, L. E., Rudenstam, C., Sander, S., Ryden, S., Honsson, P., Lonning, P. E., Loven, L., Russell, I. S., Olweny, C., Byrne, J. J., Snyder, R. D., Coates, A. S., Lowenthal, R. M., Jeal, P. N., Dalley, D. N., Janicke, F., Kleine, W., Michel, R. Th, Canobbio, L., Amoroso, D., Rubagotti, A., Bumma, C., D Aprile, M., Matteis, A., Di Carlo, A., Francini, G., Petrioli, R., Folco, U., Calligioni, E., Gallotti, P., Lopez, M., Mesiti, M., Pacini, P., Sassi, M., Sismondi, P., Paolo Zola, Ogita, M., Okazaki, M., Watanabe, T., Satomi, T., Hatazawa, C., Okuyama, N., Koyama, T., Kobayashi, M., Shimizu, T., Tabei, T., Sano, M., Makino, H., Ando, J., Kimura, M., Takeuchi, T., Aoyama, H., Koyama, H., Shin, E., Chou, G., and Medical Oncology

Subjects
Agonist, Oncology, endocrine system, Cancer Research, medicine.medical_specialty, Neoplasms, Hormone-Dependent, Antineoplastic Agents, Hormonal, medicine.drug_class, medicine.medical_treatment, Antineoplastic Agents, Breast Neoplasms, Buserelin, Gonadotropin-Releasing Hormone, Drug Therapy, SDG 3 - Good Health and Well-being, Neoplasms, Internal medicine, medicine, Humans, Neoplasm Metastasis, Hormone-Dependent, Randomized Controlled Trials as Topic, Hormonal, business.industry, Standard treatment, Goserelin, Oophorectomy, Cancer, Antiestrogen, medicine.disease, Survival Analysis, Drug Therapy, Combination, Female, Premenopause, Tamoxifen, Endocrinology, Combination, business, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract

PURPOSE: The logic behind the application of luteinizing hormone-releasing hormone (LHRH) agonists in combination with tamoxifen in premenopausal women is that LHRH agonists on the one hand suppress the tamoxifen-induced stimulation of the pituitary-ovarian function and, on the other hand, seem as effective as surgical castration. This meta-analysis combines all randomized evidence to compare the combined treatment with LHRH agonist alone with respect to overall survival, progression-free survival, and objective response in premenopausal women with advanced breast cancer. PATIENTS AND METHODS: Four clinical trials randomizing a total of 506 premenopausal women with advanced breast cancer to LHRH agonist alone or to the combined treatment of LHRH agonist plus tamoxifen were identified. Meta-analytic techniques were used to analyze individual patient data from these trials. RESULTS: With a median follow-up of 6.8 years, there was a significant survival benefit (stratified log-rank test, P = .02; hazards ratio [HR] = 0.78) and progression-free survival benefit (stratified log-rank test, P = .0003; HR = 0.70) in favor of the combined treatment. The overall response rate was significantly higher on combined endocrine treatment (stratified Mantel Haenszel test, P = .03; odds ratio = 0.67). CONCLUSION: The combination of LHRH agonist plus tamoxifen is superior to LHRH agonist alone in premenopausal women with advanced breast cancer. Therefore, if a premenopausal woman with advanced breast cancer is thought to be suitable for endocrine treatment, it is proposed that the combination of a LHRH agonist plus tamoxifen be considered as the new standard treatment.

Published
2001
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4. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

Author

EBCTCG, Abe, O., Abe, R., Enomoto, K., Kikuchi, K., Koyama, H., Masuda, H., Nomura, Y., Sakai, K., Sugimachi, K., Tominaga, T., Uchino, J., Yoshida, M., Haybittle, Jl, Davies, C., Harvey, Vj, Holdaway, Tm, Kay, Rg, Mason, Bh, Forbes, Jf, Wilcken, N., Gnant, M., Jakesz, R., Ploner, M., Yosef, Hma, Focan, C., Lobelle, Jp, Peek, U., Oates, Gd, Powell, J., Durand, M., Mauriac, L., Di Leo, A., Dolci, S., Piccart, Mj, Masood, Mb, Parker, D., Price, Jj, Hupperets, Psgj, Jackson, S., Ragaz, J., Berry, D., Broadwater, G., Cirrincione, C., Muss, H., Norton, L., Weiss, Rb, Abu-Zahra, Ht, Portnoj, Sm, Baum, M., Cuzick, J., Houghton, J., Riley, D., Gordon, Nh, Davis, Hl, Beatrice, A., Mihura, J., Naja, A., Lehingue, Y., Romestaing, P., Dubois, Jb, Delozier, T., Mace-Lesec H, J., Rambert, P., Andrysek, O., Barkmanova, J., Owen, Jr, Meier, P., Howell, A., Ribeiro, Gc, Swindell, R., Alison, R., Boreham, J., Clarke, M., Collins, R., Darby, S., Elphinstone, P., Evans, V., Godwin, J., Gray, R., Harwood, C., Hicks, C., James, S., Mackinnon, E., Mcgale, P., Mchugh, T., Mead, G., Peto, R., Wang, Y., Albano, J., Oliveira, Cf, Gervasio, H., Gordilho, J., Johansen, H., Mouridsen, Ht, Gelman, Rs, Harris, Jr, Henderson, Ic, Shapiro, Cl, Andersen, Kw, Axelsson, Ck, Blichert-Toft, M., Moller, S., Overgaard, J., Overgaard, M., Rose, C., Cartensen, B., Palshof, T., Trampisch, Hj, Dalesio, O., Vries, Ege, Rodenhuis, S., Tinteren, H., Comis, Rl, Davidson, Ne, Robert, N., Sledge, G., Tormey, Dc, Wood, W., Cameron, D., Chetty, U., Forrest, P., Jack, W., Rossbach, J., Klijn, Jgm, Treurniet-Donker, Ad, Putten, Wlj, Costa, A., Veronesi, U., Bartelink, H., Duchateau, L., Legrand, C., Sylvester, R., Hage, Ja, Velde, Cjh, Cunningham, Mp, Catalano, R., Creech, Rh, Bonneterre, J., Fargeot, P., Fumoleau, P., Kerbrat, P., Namer, M., Jonat, W., Kaufmann, M., Schumacher, M., Minckwitz, G., Bastert, G., Rauschecker, H., Sauer, R., Sauerbrei, W., Schauer, A., Schryver, A., Vakaet, L., Belfiglio, M., Nicolucci, A., Pellegrini, F., Sacco, M., Valentini, M., Mcardle, Cs, Smith, Dc, Galligioni, E., Boccardo, F., Rubagotti, A., Dent, Dm, Gudgeon, Ca, Hacking, A., Erazo, A., Medina, Jy, Izuo, M., Morishita, Y., Takei, H., Fentiman, Is, Hayward, Jl, Rubens, Rd, Skilton, D., Graeff, H., Janicke, F., Meisner, C., Scheurlen, H., Fournier, D., Dafni, U., Fountzilas, G., Klefstrom, P., Blomqvist, C., Saarto, T., Margreiter, R., Asselain, B., Salmon, Rj, Vilcoq, Jr, Rodrigo Arriagada, Hill, C., Laplanche, A., Le, Mg, Spielmann, M., Bruzzi, P., Montanaro, E., Rosso, R., Sertoli, MR, Venturini, M., Amadori, D., Benraadt, J., Kooi, M., Velde, Ao, Dongen, Ja, Vermorken, Jb, Castiglione, M., Cavalli, F., Coates, A., Collins, J., Forbes, J., Gelber, Rd, Goldhirsch, A., Lindtner, J., Price, Kn, Rudenstam, Cm, Senn, Hj, Bliss, Jm, Chilvers, Ced, Coombes, Rc, Hall, E., Marty, M., Borovik, R., Brufman, G., Hayat, H., Robinson, E., Wigler, N., Bonadonna, G., Camerini, T., Palo, G., Del Vecchio, M., Formelli, F., Valagussa, P., Martoni, A., Pannuti, F., Cocconi, G., Colozza, A., Camisa, R., Aogi, K., Takashima, S., Ikeda, T., Inokuchi, K., Sawa, K., Sonoo, H., Korzeniowski, S., Skolyszewski, J., Ogawa, M., Yamashita, J., Bonte, J., Christiaens, R., Paridaens, R., Den Boegart, W., Martin, P., Romain, S., Hakes, T., Hudis, Ca, Wittes, R., Giokas, G., Kondylis, D., Lissaios, B., La Huerta, R., Sainz, Mg, Altemus, R., Cowan, K., Danforth, D., Lichter, A., Lippman, M., O Shaughnessy, J., Pierce, Lj, Steinberg, S., Venzon, D., Zujewski, J., Paradiso, A., Lena, M., Schittulli, F., Myles, Jd, Pater, Jl, Pritchard, Ki, Anderson, S., Bass, G., Brown, A., Bryant, J., Costantino, J., Dignam, J., Fisher, B., Redmond, C., Wieand, S., Wolmark, N., Jackson, Im, Palmer, Mk, Ingle, Jn, Suman, Vj, Bengtsson, No, Jonsson, H., Larsson, Lg, Lythgoe, Jp, Kissin, M., Erikstein, B., Hannisdal, E., Jacobsen, Ab, Varhaug, Je, Gundersen, S., Hauer-Jensen, M., Host, H., Nissen-Meyer, R., Blamey, Rw, Mitchell, Ak, Morgan, Dal, Robertson, Jfr, Di Palma, M., Mathe, G., Misset, Jl, Clark, Rm, Levine, M., Morimoto, K., Takatsuka, Y., Crossley, E., Harris, A., Talbot, D., Taylor, M., Di Blasio, B., Ivanov, V., Semiglazov, V., Brockschmidt, J., Cooper, MR, Ueo, H., Falkson, Ci, A Hern, R., Ashley, S., Powles, Tj, Smith, Ie, Yarnold, Jr, Gazet, Jc, Cocoran, N., Deshpande, N., Di Martino, L., Douglas, P., Lindtner, A., Notter, G., Bryant, Ajs, Ewing, Gh, Firth, La, Krushen-Kosloski, Jl, Foster, L., George, Wd, Stewart, Hj, Stroner, P., Malmstrom, P., Moller, Tr, Ryden, S., Tengrup, I., Tennvall-Nittby, L., Carstenssen, J., Dufmats, M., Hatschek, T., Nordenskjold, B., Soderberg, M., Carpenter, Jt, Albain, K., Crowley, J., Green, S., Martino, S., Osborne, Ck, Ravdin, Pm, Glas, U., Johansson, U., Rutqvist, Le, Singnomklao, T., Wallgren, A., Maibach, R., Thurlimann, B., Brenner, H., Hercbergs, A., Yoshimoto, M., Deboer, G., Paterson, Ahg, Meakin, Jw, Panzarella, T., Shan, Y., Shao, Yf, Wang, X., Zhao, Db, Chen, Zm, Pan, Hc, Bahi, J., Reid, M., Spittle, M., Deutsch, Gp, Senanayake, F., Kwong, Dlw, Bianco, Ar, Carlomagno, C., Laurentiis, M., Placido, S., Buzdar, Au, Smith, T., Bergh, J., Holmberg, L., Liljegren, G., Nilsson, J., Seifert, M., Sevelda, P., Zielinsky, Cc, Buchanan, Rb, Cross, M., Royle, Gt, Dunn, Ja, Hills, Rk, Lee, M., Morrison, Jm, Spooner, D., Litton, A., Chlebowski, Rt, Caffier, H., Faculteit Medische Wetenschappen/UMCG, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Early Breast Cancer Trialists' Collaborative, Group, DE LAURENTIIS, Michelino, and DE PLACIDO, Sabino

Subjects
Oncology, medicine.medical_specialty, Antineoplastic Agents, Hormonal, DEATHS, Ovariectomy, Antineoplastic Agents, Breast Neoplasms, Aged, Anthracyclines, Antineoplastic Combined Chemotherapy Protocols, Cause of Death, Chemotherapy, Adjuvant, Female, Humans, Middle Aged, Neoplasm Metastasis, Neoplasm Recurrence, Local, Ovary, Randomized Controlled Trials as Topic, Receptors, Estrogen, Survival Rate, Tamoxifen, Medicine (all), Breast cancer, MammaPrint, Internal medicine, Receptors, medicine, Chemotherapy, TAMOXIFEN, skin and connective tissue diseases, Survival rate, Adjuvant, Gynecology, Hormonal, medicine.diagnostic_test, Oncotype DX Breast Cancer Assay, business.industry, General Medicine, medicine.disease, Estrogen, Neoplasm Recurrence, Local, Hormonal therapy, Oncotype DX, business, medicine.drug, Epirubicin
Abstract

Background Quinquennial overviews (1985–2000) of the randomised trials in early breast cancer have assessed the 5 year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxorubicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modern aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50–69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0·0001 for recurrence, 2p For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age ( These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1–2 years of tamoxifen versus none (33 000); and about 5 years versus 1–2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.

Published
2005

6. Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients.

Author

Look, M.P., Putten, W.L.J. van, Duffy, M.J., Harbeck, N., Christensen, I.J., Thomssen, C., Kates, R., Spyratos, F., Ferno, M., Eppenberger-Castori, S., Sweep, C.G.J., Ulm, K., Peyrat, J.P., Martin, P.M., Magdelenat, H., Brunner, N., Duggan, C., Lisboa, B.W., Bendahl, P.O., Quillien, V., Daver, A., Ricolleau, G., Meijer-van Gelder, M.E., Manders, P., Fiets, W.E., Blankenstein, M.A., Broet, P., Romain, S., Daxenbichler, G., Windbichler, G., Cufer, T., Borstnar, S., Kueng, W., Beex, L.V.A.M., Klijn, J.G.M., O'Higgins, N., Eppenberger, U., Janicke, F., Schmitt, M., Foekens, J.A., Look, M.P., Putten, W.L.J. van, Duffy, M.J., Harbeck, N., Christensen, I.J., Thomssen, C., Kates, R., Spyratos, F., Ferno, M., Eppenberger-Castori, S., Sweep, C.G.J., Ulm, K., Peyrat, J.P., Martin, P.M., Magdelenat, H., Brunner, N., Duggan, C., Lisboa, B.W., Bendahl, P.O., Quillien, V., Daver, A., Ricolleau, G., Meijer-van Gelder, M.E., Manders, P., Fiets, W.E., Blankenstein, M.A., Broet, P., Romain, S., Daxenbichler, G., Windbichler, G., Cufer, T., Borstnar, S., Kueng, W., Beex, L.V.A.M., Klijn, J.G.M., O'Higgins, N., Eppenberger, U., Janicke, F., Schmitt, M., and Foekens, J.A.

Abstract

Item does not contain fulltext, In this report we present an extension of the pooled analysis of the prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I in breast cancer patients. We analyzed a different endpoint, metastasis-free survival (MFS). We checked the consistency of the estimates for uPA and PAI-1 for relapse-free survival (RFS) and MFS exploring possible sources of heterogeneity. Nodal status, the most important prognostic factor for breast cancer, introduced heterogeneity in the uPA/PAI-1 survival analyses, reflecting the interaction between nodal status and uPA/PAI-1. The estimates for uPA and PAI-1 were found to be consistent, even when a different transformation of their values was used. The heterogeneity of the separate data sets decreased if the levels of uPA and PAI-1 were ranked, data sets were pooled, and the analyses corrected for the base model that included all traditional prognostic factors, and stratified by data set. We conclude that uPA and PAI-1 are ready to be used in the clinic to help classify breast cancer patients into high and low risk groups.

Published
2003

7. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients

Author

Look, M.P. (Maxime), Kueng, W., Klijn, J.G.M. (Jan), Broet, P., Eppenberger, U., Putten, W.L.J. (Wim) van, Ferno, M., Christensen, I.J., Lisboa, B.W., Thomssen, C. (Christoph), Kates, R. (Ronald), Magdelenat, H., Martin, P.M., Beex, L.V. (Louk), Windbichler, G., Janicke, F., Spyratos, F., Peyrat , J.P., Ricolleau, G., Cufer, T., Brunner, N., Meijer van Gelder, M.E. (Marion), Bendahl, P.O., Ulm, K., Schmitt, M. (Manfred), Sweep, C.G., Fiets, W.E., Duggan, C., Blankenstein, M.A. (Marinus), Borstnar, S., Daxenbichler, G., Eppenberger-Castori, S. (Serenella), Foekens, J.A. (John), O'Higgins, N., Duffy, M.J. (Michael), Daver, A., Manders, P. (Peggy), Romain, S., Quillien, V., Harbeck, N. (Nadia), Look, M.P. (Maxime), Kueng, W., Klijn, J.G.M. (Jan), Broet, P., Eppenberger, U., Putten, W.L.J. (Wim) van, Ferno, M., Christensen, I.J., Lisboa, B.W., Thomssen, C. (Christoph), Kates, R. (Ronald), Magdelenat, H., Martin, P.M., Beex, L.V. (Louk), Windbichler, G., Janicke, F., Spyratos, F., Peyrat , J.P., Ricolleau, G., Cufer, T., Brunner, N., Meijer van Gelder, M.E. (Marion), Bendahl, P.O., Ulm, K., Schmitt, M. (Manfred), Sweep, C.G., Fiets, W.E., Duggan, C., Blankenstein, M.A. (Marinus), Borstnar, S., Daxenbichler, G., Eppenberger-Castori, S. (Serenella), Foekens, J.A. (John), O'Higgins, N., Duffy, M.J. (Michael), Daver, A., Manders, P. (Peggy), Romain, S., Quillien, V., and Harbeck, N. (Nadia)

Abstract

BACKGROUND: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). METHODS: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. RESULTS: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). CONCLUSIONS: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especial

Published
2002

8. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients.

Author

Look, M.P., Putten, W.L.J. van, Duffy, M.J., Harbeck, N., Christensen, I.J., Thomssen, C., Kates, R., Spyratos, F., Ferno, M., Eppenberger-Castori, S., Sweep, C.G.J., Ulm, K., Peyrat, J.P., Martin, P.M., Magdelenat, H., Brunner, N., Duggan, C., Lisboa, B.W., Bendahl, P.O., Quillien, V., Daver, A., Ricolleau, G., Meijer-van Gelder, M.E., Manders, P., Fiets, W.E., Blankenstein, M.A., Broet, P., Romain, S., Daxenbichler, G., Windbichler, G., Cufer, T., Borstnar, S., Kueng, W., Beex, L.V.A.M., Klijn, J.G.M., O'Higgins, N., Eppenberger, U., Janicke, F., Schmitt, M., Foekens, J.A., Look, M.P., Putten, W.L.J. van, Duffy, M.J., Harbeck, N., Christensen, I.J., Thomssen, C., Kates, R., Spyratos, F., Ferno, M., Eppenberger-Castori, S., Sweep, C.G.J., Ulm, K., Peyrat, J.P., Martin, P.M., Magdelenat, H., Brunner, N., Duggan, C., Lisboa, B.W., Bendahl, P.O., Quillien, V., Daver, A., Ricolleau, G., Meijer-van Gelder, M.E., Manders, P., Fiets, W.E., Blankenstein, M.A., Broet, P., Romain, S., Daxenbichler, G., Windbichler, G., Cufer, T., Borstnar, S., Kueng, W., Beex, L.V.A.M., Klijn, J.G.M., O'Higgins, N., Eppenberger, U., Janicke, F., Schmitt, M., and Foekens, J.A.

Abstract

Item does not contain fulltext, BACKGROUND: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). METHODS: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. RESULTS: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). CONCLUSIONS: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especial

Published
2002

9. Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1.

Author

Janicke, F., Prechtl, A., Thomssen, C., Harbeck, N., Meisner, C., Untch, M., Sweep, C.G.J., Selbmann, H.K., Graeff, H., Schmitt, M., Janicke, F., Prechtl, A., Thomssen, C., Harbeck, N., Meisner, C., Untch, M., Sweep, C.G.J., Selbmann, H.K., Graeff, H., and Schmitt, M.

Abstract

Item does not contain fulltext, BACKGROUND: Most patients with lymph node-negative breast cancer are cured by locoregional treatment; however, about 30% relapse. Because traditional histomorphologic and clinical factors fail to identify the high-risk patients who may benefit from adjuvant chemotherapy, other prognostic factors are needed. In a unicenter study, we have found that levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the primary tumor are predictive of disease recurrence. Thus, we designed the Chemo N(0) prospective randomized multicenter therapy trial to investigate further whether uPA and PAI-1 are such prognostic factors and whether high-risk patients identified by these factors benefit from adjuvant chemotherapy. After 4.5 years, we present results of the first interim analysis. METHODS: We studied 556 patients with lymph node-negative breast cancer. The median follow-up was 32 months. All patients with low tumor levels of uPA (< or = 3 ng/mg of protein) and of PAI-1 (< or = 14 ng/mg of protein) were observed. Patients with high tumor levels of uPA (> 3 ng/mg of protein) and/or of PAI-1 (> 14 ng/mg of protein) were randomly assigned to combination chemotherapy or subjected to observation only. All statistical tests were two-sided. RESULTS: A total of 241 patients had low levels of uPA and PAI-1, and 315 had elevated levels of uPA and/or PAI-1. The estimated 3-year recurrence rate for patients with low tumor levels of uPA and PAI-1 (low-risk group) was 6.7% (95% confidence interval [CI] = 2.5% to 10.8%). This rate for patients with high tumor levels of uPA and/or PAI-1 (high-risk group) was 14.7% (95% CI = 8.5% to 20.9%) (P = 0.006). First interim analysis suggests that high-risk patients in the chemotherapy group benefit, with a 43.8% lower estimated probability of disease recurrence at 3 years than high-risk patients in the observation group (intention-to-treat analysis: relative risk = 0.56; 95% CI = 0.25 to 1.28), but furth

Published
2001

11. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients

Author

Foekens, J.A. (John), Henzen-Logmans, S.C. (Sonja), Klijn, J.G.M. (Jan), Putten, W.L.J. (Wim) van, Peters, H.A. (Harry), Look, M.P. (Maxime), Portengen, H. (Henk), Schmitt, M. (Manfred), Kramer, M.D., Brunner, N., Janicke, F., Meijer van Gelder, M.E. (Marion), Foekens, J.A. (John), Henzen-Logmans, S.C. (Sonja), Klijn, J.G.M. (Jan), Putten, W.L.J. (Wim) van, Peters, H.A. (Harry), Look, M.P. (Maxime), Portengen, H. (Henk), Schmitt, M. (Manfred), Kramer, M.D., Brunner, N., Janicke, F., and Meijer van Gelder, M.E. (Marion)

Abstract

The antigen levels of components of the urokinase-type plasminogen activator (uPA) system of plasminogen activation are correlated with prognosis in several types of cancers, including breast cancer. In the present study involving 2780 patients with primary invasive breast cancer, we have evaluated the prognostic importance of the four major components of the uPA system [uPA, the receptor uPAR (CD87), and the inhibitors PAI-1 and PAI-2]. The antigen levels were determined by ELISA in cytosols prepared from primary breast tumors. The levels of the four factors significantly correlated with each other; the Spearman rank correlation coefficients (r(s)) ranged from 0.32 (between PAI-2 and PAI-1 or uPAR) to 0.59 (between uPA and PAI-1). The median duration of follow-up of patients still alive was 88 months. In the multivariate analyses for relapse-free survival (RFS) and overall survival (OS), we defined a basic model including age, menopausal status, tumor size and grade, lymph node status, adjuvant therapy, and steroid hormone receptor status. uPA, uPAR, PAI-1, and PAI-2 were considered as categorical variables, each with two cut points that were established by isotonic regression analysis. Compared with tumors with low levels, those with intermediate and high levels showed a relative hazard rate (RHR) and 95% confidence interval (95% CI) of 1.22 (1.02-1.45) and 1.69 (1.39-2.05) for uPA, and 1.32 (1.14-1.54) and 2.17 (1.74-2.70) for PAI-1, respectively, in multivariate analysis for RFS in all patients. Compared with tumors with high PAI-2 levels, those with intermediate and low levels showed a poor RFS with a RHR (95% CI) of 1.30 (1.14-1.48) and 1.76 (1.38-2.24), respectively. Similar results were obtained in the multivariate analysis for OS in all patients. Furthermore, uPA and PAI-1 were independent predictive factors of a poor RFS and OS in node-negative and node-positive patients. PAI-2 also added to the multivariate models for RFS in node-negative and node-positiv

Published
2000

12. Biological and clinical relevance of the urokinase-type plasminogen activator (uPA) in breast cancer

Author

Schmitt, M., Goretzki, L., Janicke, F., Juan Calvete, Eulitz, M., Kobayashi, H., Chucholowski, N., and Graeff, H.

Subjects
Enzyme Precursors, Plasminogen Activators, Binding Sites, Humans, Breast Neoplasms, Female, Neoplasm Invasiveness, Prognosis, Urokinase-Type Plasminogen Activator, Peptide Fragments, Recombinant Proteins
Abstract

Tumor cell invasion and metastasis is a multifactorial process, which at each step may require the action of proteolytic enzymes such as collagenases, cathepsins, plasmin, or plasminogen activators. An enzymatically inactive proenzyme form of the urokinase-type plasminogen activator (pro-uPA) is secreted by tumor cells which may be converted to an enzymatically active two-chain uPA-molecule (HMW-uPA) by plasmin-like enzymes. Action of proteases on pro-uPA may generate the enzymatically active or inactive high-molecular-weight form of uPA (HMW-uPA). Some proteases (plasmin, cathepsin B and L, kallikrein, trypsin or thermolysin) activate pro-uPA by cleaving the peptide bond Lys158 and IIe159. Other proteases (elastase, thrombin) cleave pro-uPA at different positions to yield enzymatically inactive HMW-uPA. HMW-uPA may be split into the enzymatically active LMW-uPA and the enzymatically inactive ATF (amino terminal fragment). ATF may be cleaved between peptide sequence 20 and 40 within the receptor binding domain of uPA (GFD). Such impaired ATF does not bind to uPA-receptors. Action of the bacterial endoproteinase Asp-N from Pseudomonas fragi mutant on pro-uPA or HMW-uPA, however, generates intact ATF which efficiently competes for binding of HMW-uPA or pro-uPA to receptors on tumor cells. High uPA-antigen content (pro-uPA, HMW-uPA, or LMW-uPA) in breast cancer tissue (not in plasma) indicates an elevated risk for the patient of recurrences and shorter overall survival. Thus pro-uPA/uPA-antigen content in breast cancer tissue serves as an independent prognostic parameter for the outcome of the disease. Cathepsin D is also an independent prognostic factor for recurrences and overall survival. High content of cathepsin D in breast cancer tumors is, however, not correlated with elevated levels of pro-uPA/uPA indicating that synthesis and release of cathepsin D and pro-uPA/uPA are independent events.

Published
1991

14. HER-2/neu Gene Amplification and Response to Paclitaxel in Patients With Metastatic Breast Cancer

Author

Konecny, G. E., primary, Thomssen, C., additional, Luck, H. J., additional, Untch, M., additional, Wang, H.-J., additional, Kuhn, W., additional, Eidtmann, H., additional, Bois, A. d., additional, Olbricht, S., additional, Steinfeld, D., additional, Mobus, V., additional, Minckwitz, G. v., additional, Dandekar, S., additional, Ramos, L., additional, Pauletti, G., additional, Pegram, M. D., additional, Janicke, F., additional, and Slamon, D. J., additional

Published
2004
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15. Pooled Analysis of Prognostic Impact of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in 8377 Breast Cancer Patients

Author

Look, M. P., primary, van Putten, W. L. J., additional, Duffy, M. J., additional, Harbeck, N., additional, Christensen, I. J., additional, Thomssen, C., additional, Kates, R., additional, Spyratos, F., additional, Ferno, M., additional, Eppenberger-Castori, S., additional, Sweep, C. G. J. F., additional, Ulm, K., additional, Peyrat, J.-P., additional, Martin, P.-M., additional, Magdelenat, H., additional, Brunner, N., additional, Duggan, C., additional, Lisboa, B. W., additional, Bendahl, P.-O., additional, Quillien, V., additional, Daver, A., additional, Ricolleau, G., additional, Meijer-van Gelder, M. E., additional, Manders, P., additional, Fiets, W. E., additional, Blankenstein, M. A., additional, Broet, P., additional, Romain, S., additional, Daxenbichler, G., additional, Windbichler, G., additional, Cufer, T., additional, Borstnar, S., additional, Kueng, W., additional, Beex, L. V. A. M., additional, Klijn, J. G. M., additional, O'Higgins, N., additional, Eppenberger, U., additional, Janicke, F., additional, Schmitt, M., additional, and Foekens, J. A., additional

Published
2002
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16. Letrozole (femara) is a more effective inhibitor of estrogen activity than tamoxifen: Evidence from a randomized phase III trial of 4 months preoperative endocrine therapy for postmenopausal women with primary invasive breast cancer

Author

Ellis, M.J., primary, Sing, B., additional, Miller, W.R., additional, Llombart-Cussac, A., additional, Janicke, F., additional, Evans, D.B., additional, Borgs, M., additional, Quebe-Fehling, E., additional, Brady, C., additional, Dugan, M., additional, and Coop, A., additional

Published
2001
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18. Randomized Adjuvant Chemotherapy Trial in High-Risk, Lymph Node-Negative Breast Cancer Patients Identified by Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1

Author

Janicke, F., primary, Prechtl, A., additional, Thomssen, C., additional, Harbeck, N., additional, Meisner, C., additional, Untch, M., additional, Sweep, C. G. J. F., additional, Selbmann, H.-K., additional, Graeff, H., additional, and Schmitt, M., additional

Published
2001
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26. Urokinase-type plasminogen activator and its inhibitor type 1 predict disease outcome and therapy response in primary breast cancer.

Author

Harbeck N, Kates RE, Schmitt M, Gauger K, Kiechle M, Janicke F, Thomassen C, Look MP, and Foekens JA

Subjects
Breast Neoplasms diagnosis, Breast Neoplasms metabolism, Enzyme-Linked Immunosorbent Assay, Female, Humans, Neoadjuvant Therapy, Prognosis, Randomized Controlled Trials as Topic, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Plasminogen Activator Inhibitor 1 analysis, Urokinase-Type Plasminogen Activator analysis
Abstract

Combined determination of urokinase-type plasminogen activator (uPA) and its inhibitor, activator inhibitor type 1 (PAI-1), supports risk-adapted individualized therapy concepts, particularly in node-negative breast cancer. The prognostic impact of both factors in primary breast cancer was substantiated by a pooled analysis of > 8000 patients with breast cancer and a multicenter prospective randomized therapy trial in node-negative breast cancer; findings achieved the highest level of evidence for tumor biomarkers. Patients with node-negative breast cancer with low antigen levels of uPA and PAI-1 in their primary tumor tissue have a very good prognosis and therefore may be spared the burden of adjuvant chemotherapy, whereas those with elevated uPA/PAI-1 antigen levels carry an increased risk of disease recurrence. Recent retrospective analysis of > 3000 patients indicated that patients with breast cancer with high uPA/PAI-1 values derive a significantly greater benefit from adjuvant chemotherapy than patients with low uPA/PAI-1 levels. Similarly, in the multicenter prospective Chemo N0 trial, administration of cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy led to a substantial reduction in risk of disease recurrence in patients with high uPA/PAI-1. However, benefit from adjuvant endocrine therapy appears to be independent of a patient's uPA/PAI-1 status. In metastatic breast cancer, retrospective studies showed that elevated uPA or PAI-1 present in the primary tumor tissue are associated with a poor response to later palliative endocrine therapy. These findings suggest that high levels of uPA and/or PAI-1 do reflect an aggressive phenotype that may be overcome or suppressed by early systemic therapy in the adjuvant setting but may be too advanced for response to palliative therapy at a later stage.

Published
2004
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27. Interim Analysis of a Phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer.

Author

Luck HJ, Thomssen C, duBois A, Lisboa BW, Untch M, Kuhnle H, Konecny G, Janicke F, Meerpohl HG, Lindner C, Hecker D, and Diergarten K

Subjects
Adult, Aged, Alopecia chemically induced, Antibiotics, Antineoplastic administration & dosage, Antibiotics, Antineoplastic adverse effects, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Agents, Phytogenic adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms pathology, Epirubicin administration & dosage, Epirubicin adverse effects, Feasibility Studies, Female, Humans, Middle Aged, Neutropenia chemically induced, Paclitaxel administration & dosage, Paclitaxel adverse effects, Remission Induction, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms drug therapy
Abstract

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to be used routinely in clinical practice, has aroused considerable interest for its high single-agent activity in breast cancer and its novel mechanism of action. The 4' epimer of doxorubicin, epirubicin is an agent with high activity against breast cancer but a lower rate of toxic side effects, especially cardiotoxic events, than its parent compound. Although the paclitaxel/doxorubicin combination has yielded response rates between 63% and 94% in phase I/II studies, some severe cardiotoxic events were reported. The rationale for our study was to evaluate the paclitaxel/epirubicin combination, focusing mainly on cardiotoxicity. In all, 57 patients with metastatic breast cancer entered the study, 28% of whom had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication consisted of 60 mg/m2 epirubicin given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2 antagonists. The main toxicity was neutropenia (World Health Organization toxicity index grade 3/4, 72%). Other hematologic side effects were rare and no febrile neutropenia was reported. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grade 1 and 2). All patients had alopecia. The paclitaxel dose was escalated to 200 mg/m2 in eight patients, four of whom received a further escalation to 225 mg/m2. Severe neutropenia necessitated dose reductions in eight patients. No cardiac adverse events were reported. Of 41 patients evaluable for response, seven had complete remissions and 21 had partial remissions (68%). An additional 12 patients (29%) had stable disease. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of the role of this combination in the first-line treatment of metastatic breast cancer is warranted.

Published
1996

28. A randomized comparison of triptorelin and tamoxifen as treatment of progressive ovarian cancer.

Author

Jager W, Sauerbrei W, Beck E, Maassen V, Stumpfe M, Meier W, Kuhn W, and Janicke F

Subjects
Adult, Cystadenocarcinoma, Serous mortality, Cystadenocarcinoma, Serous pathology, Disease Progression, Female, Humans, Menopause, Middle Aged, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Salvage Therapy, Survival Rate, Treatment Failure, Antineoplastic Agents, Hormonal therapeutic use, Cystadenocarcinoma, Serous drug therapy, Estrogen Antagonists therapeutic use, Gonadotropin-Releasing Hormone antagonists & inhibitors, Ovarian Neoplasms drug therapy, Tamoxifen therapeutic use, Triptorelin Pamoate therapeutic use
Published
1995

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