Dokument: Molekulare Klassifikation des Hochrisiko-Mammakarzinoms als Prädiktor des Benefits der Dosis-Intensivierung der adjuvanten Chemotherapie: Ergebnisse der randomiserten WSG-AM-01 Studie
| Titel: | Molekulare Klassifikation des Hochrisiko-Mammakarzinoms als Prädiktor des Benefits der Dosis-Intensivierung der adjuvanten Chemotherapie: Ergebnisse der randomiserten WSG-AM-01 Studie | |||||||
| Weiterer Titel: | Molecular classification of high risk breast cancer as predictor of benefit from dose intensification of adjuvant chemotherapy: Results of randomized WSG AM-01 trial. | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=12857 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20090928-134138-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Gluz, Oleg [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Nitz, Ulrike [Gutachter] Prof. Dr. Janni Wolfgang [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Purpose: This work evaluates the prognostic and predictive impact of protein expression
of various molecular markers in addition to conventional prognostic factors in high-risk breast cancer (HRBC) patients from a randomized trial. Patients received different chemotherapy dose-intensification strategies. The molecular classification of breast cancer should be evaluated in this selected population. Methods: 403 patients were randomly assigned to dose-dense conventional chemotherapy with 4 cycles of E90C600 followed by 3 cycles of C600M40F600q2w (DD) or a rapidly cycled tandem high-dose regimen with 2 cycles E90C600q2w followed by 2 cycles of E90C3000Thiotepa400q3w (HD). Paraffin-embedded tumors from 236 patients were available for retrospective central pathology review (116 HD /120 DD). Expression of 34 molecular markers was evaluated immunohistochemically using tissue microarrays. Cluster groups were analyzed by unsupervised k-clustering (k=5). Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). Results: After a median follow-up of 61.7 months, 5-year event-free (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% vs. 41%; OS: 76 % vs. 61%. 5 stable molecular subgroups could be identified by cluster analysis using 24 proteins: luminal A (27%) and B (12%), multiple marker negative (27%), Her-2/neu (21%) and basal-like (13%). Basal-like and Her-2/neu subtypes had significant inferior survival rates than luminal subtypes. Basal-like and Her- 2/neu subtypes, but not luminal subtypes had a significant benefit from HDC in terms of EFS and OS. In multivariate analysis, HD, tumor size <2 cm and positive PR, as conventional factors and luminal A/B subtypes as new marker were associated with favorable outcome. Interaction analysis showed that triple negativity (ER/PR/HER-2/neu) and G3 status of tumors, but not basal-like cluster group predicted benefit from HD. Conclusion: For the first time molecular subtypes of BC could be reconfirmed in the HRBC population. Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple negative tumors and /or G3. Patients with basal-like and Her-2/neu subtypes derived the most benefit from HD, compared to luminal subgroups, but the predictive value was inferior compared to “conventional” factors such as triple-negative subtype or G3 status.Purpose: This work evaluates the prognostic and predictive impact of protein expression of various molecular markers in addition to conventional prognostic factors in high-risk breast cancer (HRBC) patients from a randomized trial. Patients received different chemotherapy dose-intensification strategies. The molecular classification of breast cancer should be evaluated in this selected population. Methods: 403 patients were randomly assigned to dose-dense conventional chemotherapy with 4 cycles of E90C600 followed by 3 cycles of C600M40F600q2w (DD) or a rapidly cycled tandem high-dose regimen with 2 cycles E90C600q2w followed by 2 cycles of E90C3000Thiotepa400q3w (HD). Paraffin-embedded tumors from 236 patients were available for retrospective central pathology review (116 HD /120 DD). Expression of 34 molecular markers was evaluated immunohistochemically using tissue microarrays. Cluster groups were analyzed by unsupervised k-clustering (k=5). Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). Results: After a median follow-up of 61.7 months, 5-year event-free (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% vs. 41%; OS: 76 % vs. 61%. 5 stable molecular subgroups could be identified by cluster analysis using 24 proteins: luminal A (27%) and B (12%), multiple marker negative (27%), Her-2/neu (21%) and basal-like (13%). Basal-like and Her-2/neu subtypes had significant inferior survival rates than luminal subtypes. Basal-like and Her- 2/neu subtypes, but not luminal subtypes had a significant benefit from HDC in terms of EFS and OS. In multivariate analysis, HD, tumor size <2 cm and positive PR, as conventional factors and luminal A/B subtypes as new marker were associated with favorable outcome. Interaction analysis showed that triple negativity (ER/PR/HER-2/neu) and G3 status of tumors, but not basal-like cluster group predicted benefit from HD. Conclusion: For the first time molecular subtypes of BC could be reconfirmed in the HRBC population. Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple negative tumors and /or G3. Patients with basal-like and Her-2/neu subtypes derived the most benefit from HD, compared to luminal subgroups, but the predictive value was inferior compared to “conventional” factors such as triple-negative subtype or G3 status. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 30.09.2009 | |||||||
| Dateien geändert am: | 29.09.2009 | |||||||
| Promotionsantrag am: | 14.11.2008 | |||||||
| Datum der Promotion: | 30.06.2009 |
