ADEBAR Trial Research Articles

Impact of Granulocyte Colony-Stimulating Factor (G-CSF) and Epoetin (EPO) on Hematologic Toxicities and Quality of Life in Patients During Adjuvant Chemotherapy in Early Breast Cancer: Results From the Multi-Center Randomized ADEBAR Trial

BackgroundHematologic toxicities are one of the greatest challenges in adjuvant chemotherapy for breast cancer. This analysis of the ADEBAR trial aims to evaluate application and effect of granulocyte colony-stimulating factor (G-CSF) and epoetin alfa (EPO) on hematologic parameters and fatigue in patients with breast cancer during chemotherapy. Patients and MethodsIn the ADEBAR trial, 1493 patients with node-positive primary breast cancer were randomized to either 6 × 5-fluorouracil, epirubicin, and cyclophosphamide (FEC120) or 4 × epirubicin and cyclophosphamide followed by 4 × docetaxel (EC-DOC). Co-medication with G-CSF or EPO was applied to treat chemotherapy-induced leukopenia or anemia. Fatigue was assessed at baseline and after one-half of the chemotherapy. ResultsIn total, 899 patients could be included in the analysis. There was no evidence for an association between leucocyte or hemoglobin levels and application of G-CSF and EPO in the preceding cycle, respectively. Hemoglobin levels (B = −0.41; P < .001) were affected by treatment regimen. Fatigue during chemotherapy was mostly affected by the level of fatigue before the start of chemotherapy (B = 0.41; P < .001). Patients with G-CSF application in the preceding cycle showed an increased fatigue score (B = 5.43; P = .02). ConclusionWe showed that fatigue during adjuvant chemotherapy was mostly affected by the level of fatigue present before the start of chemotherapy. This result suggests that the level of fatigue before the start of treatment should be included as an important factor when deciding on type and toxicity of chemotherapy in early breast cancer.

Prognostic Impact of Weight Change During Adjuvant Chemotherapy in Patients With High-Risk Early Breast Cancer: Results From the ADEBAR Study

BackgroundIn addition to established prognostic factors, individual lifestyle-associated factors, such as obesity, physical activity, and diet, seem to modulate the course of breast cancer. The aim of this analysis was to evaluate the influence of weight changes during adjuvant chemotherapy on outcome in a large multicenter prospectively randomized trial. Patients and MethodsThe ADEBAR trial compares a sequential chemotherapy consisting of epirubicin/cyclophosphamide followed by docetaxel to an epirubicin/5-fluorouracil/cyclophosphamide regimen in patients with lymph node–positive early breast cancer. Body weight was measured before each cycle of chemotherapy. According to the relative weight change (≥ 5%) between the first and the last cycle, patients were categorized into the weight gain, weight loss, or stable weight group. Overall survival (OS) and disease-free survival were assessed by univariate Kaplan-Meier and multivariate Cox regression analyses. ResultsConcise data from 1080 of 1493 participants who completed all cycles of chemotherapy were available for analysis. Of 307 patients (24.8%) whose weight changed by ≥ 5%, 120 patients (11.1%) lost and 187 (17.3%) gained weight. Multivariate analysis showed a significant independent effect of weight change on OS (P = .039), but not on disease-free survival (P = .111). Both weight change groups had a worse OS compared to patients with stable weight (weight gain: hazard ratio, 1.55; 95% confidence interval, 1.01-2.40; P = .047; weight loss: hazard ratio, 1.55; 95% CI, 0.97-2.47; P = .067). ConclusionWeight change of > 5% during adjuvant chemotherapy in patients with high-risk early breast cancer is associated with poor OS.

The Impact of Age on Quality of Life in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Comparative Analysis From the Prospective Multicenter Randomized ADEBAR trial

BackgroundElderly breast cancer patients are affected by poorer quality of life (QoL) compared to younger patients. Because QoL has a relevant impact on guideline-adherent treatment, elderly breast cancer patients are often undertreated, especially with regard to adjuvant chemotherapy, and overall survival is decreased. Thus, understanding the impact of chemotherapy on QoL in elderly patients is crucial. This study compared QoL in patients aged < 65 years and 65 to 70 years receiving adjuvant chemotherapy as a secondary outcome in the prospective randomized multicenter ADEBAR trial. Patients and MethodsPatients with lymph node–positive breast cancer were prospectively randomized for either sequential anthracycline–taxane or epirubicin/fluorouracil/cyclophosphamid chemotherapy (FEC) therapy. QoL was assessed at baseline (t1), before cycle 4 FEC, and cycle 5 epirubicin/cyclophosphamid–docetaxel (EC-DOC) (t2), 4 weeks after chemotherapy (t3), and 6 weeks after radiation (t4) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer–Specific Module (QLQ-BR23). We compared patients aged < 65 years and 65 to 70 years with respect to QoL and discontinuation of chemotherapy. ResultsA total of 1363 patients were enrolled onto the ADEBAR trial, with 16.7% of the patients aged 65 to 70 years. In elderly patients, Eastern Cooperative Oncology Group performance status was higher and global health status and physical functioning were lower at baseline. Global health status decreased between t1 and t3 by 7 points in patients < 65 years and by 11 points in patients 65 to 70 years, and physical functioning decreased in the same period by 13.4 points in patients aged < 65 years and by 15.9 points in patients 65 to 70 years. In both groups, at t4 global health status exceeded baseline by 6 points, and physical functioning was 1.3 points under baseline in patients < 65 years old and 3 points under baseline in patients 65 to 70 years. There was a trend to more fatigue in elderly patients and to more nausea and vomiting while receiving chemotherapy in younger patients at t3. There was a higher dropout rate in patients aged 65 to 70 years (25.7%) than in patients aged < 65 years (16.2%). ConclusionThere were only small or trivial differences in QoL in patients aged < 65 years versus 65 to 70 years who were receiving adjuvant chemotherapy, although the dropout rate from chemotherapy was notably higher in elderly breast cancer patients.

Short term quality of life with epirubicin-fluorouracil-cyclophosphamid (FEC) and sequential epirubicin/cyclophosphamid-docetaxel (EC-DOC) chemotherapy in patients with primary breast cancer – Results from the prospective multi-center randomized ADEBAR trial

BackgroundThe recommendation for adjuvant dose-dense chemotherapy in high risk primary breast cancer is heterogeneous among guidelines. Understanding the impact on QoL is thereby a crucial factor, especially if the benefit is potentially low. This study aims to assess QoL as a secondary outcome in the prospective randomized multi-center ADEBAR trial. MethodsQoL was assessed at baseline (t1), before cycle 4 FEC and cycle 5 EC-DOC (t2), 4 weeks after chemotherapy (t3) and 6 weeks after radiation (t4) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer-Specific Module (QLQ-BR23). Results1306 patients were enrolled into the ADEBAR trial. 675 were assigned to the FEC and 688 to the EC-DOC arm. After the beginning of treatment, global QoL dropped in both arm by 3–4 points. In the EC-DOC arm, QoL dropped further at t3 by 7 points and stayed stable in the FEC arm. 6 weeks after radiation, QoL exceeded baseline in both arms by 6–8 points. The differences between treatment arms were strongest at t3 (53.0 vs. 49.5) but did not reach clinical relevance at any point in time. Physical functioning, nausea and vomiting, fatigue and systemic therapy side effects followed with some minor exceptions similar patterns but showed higher amplitudes. ConclusionIn conclusion, we could not detect a clinically relevant difference between the two treatment arms in global QoL, although the results consistently show that patients on EC-DOC report worse scores during the treatment.

Abstract P1-12-03: Short term quality of life with epirubicin-fluorouracil-cyclophosphamid (FEC) and sequential epirubicin/cyclophosphamid-docetaxel (EC-DOC) chemotherapy in patients with primary breast cancer – Results from the prospective multi-center randomized Adebar trial

Abstract Background: The grade of recommendation for adjuvant dose-dense chemotherapy in patients with high risk primary breast cancer is heterogeneous among international guidelines. Understanding the impact on quality of life (QOL) by adjuvant dose dense chemotherapy in comparison to standard adjuvant chemotherapy is thereby a crucial factor, especially if the benefit is potentially low. This study aims to assess the impact on QOL by adjuvant dose dense chemotherapy in the prospective randomized multi-center ADEBAR trial. Methods: QOL was assessed at baseline (t1), before cycle 4 FEC (Epirubicin 60mg/m2 i.v. d 1 + 8, 5-Fluoruracil 500mg/m2 i.v. d 1 + 8, Cyclophosphamide 75mg/m2 p.o. d 1–14, q4w x 6) and cycle 5 EC-DOC (Epirubicin 90mg/m2 plus Cyclophosphamide 600mg/m2 q3w x 4, sequentially followed by Docetaxel 100mg/m2 q3w x 4) (t2), 4 weeks after chemotherapy (t3), 6 weeks after radiation (t4) and 1 year after baseline (t5) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer-Specific Module (QLQ-BR23). A multivariate mixed model was fitted to test for differences between the two treatment arms. Primary endpoint was global QOL, secondary endpoints physical functioning, nausea&amp;vomiting, fatigue and systemic therapy side effects. A minimum clinically meaningful difference was considered to be 10 points. Results: 1306 patients were recruited between 3/2002 and 5/2005 675 were assigned to the FEC and 688 to the EC-DOC arm. Compliance to QOL assessment was 74% at baseline and 58% four weeks after therapy, but dropped to 11% after one year follow up. After the beginning of treatment global QOL dropped in both arm by 3 to 4 points. In the EC-DOC arm QOL dropped further at t3 by 7 points and stayed stable in the FEC arm. 6 weeks after radiation QOL exceeded baseline in both arms by 6 to 8 points. The differences between treatment arms were strongest at t3 (54.1 vs. 49.7) but did not reach clinical relevance at any point in time. Physical functioning, nausea vomiting, fatigue and systemic therapy side effects followed with some minor exceptions similar patterns, but showed higher amplitudes. Conclusion: In conclusion we could not detect a statistically significant difference between the two treatment arms in QOL parameters, indicating that dose dense adjuvant chemotherapy did not impact QOL at a clinically relevant level compared to standard adjuvant chemotherapy. Citation Format: Schwentner L, Harbeck N, Singer S, Eichler M, Rack B, Forstbauer H, Wischnik A, Scholz C, Fink V, Huober J, Friedl T, Weissenbacher T, Härtl K, Kiechle M, Janni W. Short term quality of life with epirubicin-fluorouracil-cyclophosphamid (FEC) and sequential epirubicin/cyclophosphamid-docetaxel (EC-DOC) chemotherapy in patients with primary breast cancer – Results from the prospective multi-center randomized Adebar trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-03.

Obesity as an independent risk factor for decreased survival in node-positive high-risk breast cancer.

Obese breast cancer patients have a higher risk of lymph node metastasis and a poorer prognosis compared to patients with normal weight. For obese women with node-positive breast cancer, an association between body weight and prognosis remains unclear. In this retrospective study, we analyzed patient data from the Phase-III ADEBAR trial, in which high-risk breast cancer patients (pT1-4, pN2-3, pM0) were randomized into a docetaxel-based versus epirubicin-based chemotherapy regimen. Patients were grouped according to their BMI value as underweight/normal weight (BMI <25kg/m(2); n=543), overweight (BMI 25-29.9kg/m(2); n=482) or obese (BMI ≥30kg/m(2); n=285). Overweight and obese patients were older, had larger tumors and were more likely to be postmenopausal at the time of diagnosis compared to underweight/normal-weight patients (all p<0.001). Multivariate Cox regression analyses adjusting for age and histopathological tumor features showed that obese patients had a significantly shorter disease-free survival (DFS; HR 1.43; 95% CI 1.11-1.86; p=0.006) and overall survival (OS; HR 1.56; 95% CI 1.14-2.14; p=0.006) than non-obese patients. Subgroup analyses revealed that the differences in DFS and OS were significant for postmenopausal but not for premenopausal patients, and that the survival benefit of non-obese patients was more pronounced in women with hormone-receptor-positive disease. Obesity constitutes an independent, adverse prognostic factor in high-risk node-positive breast cancer patients, in particular for postmenopausal women and women with hormone-receptor-positive disease.

Toxicity Analysis in the ADEBAR Trial: Sequential Anthracycline-Taxane Therapy Compared with FEC120 for the Adjuvant Treatment of High-Risk Breast Cancer

Background: Data from meta-analyses have shown taxane-containing therapies to be superior to anthracycline-based treatments for high-risk breast cancer. Patients and Methods: The ADEBAR trial was a multicenter phase III trial in which patients with lymph node-positive breast cancer were prospectively randomized for either sequential anthracycline-taxane or FEC120 therapy. Patients received 4× epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks (q3w), followed by 4× docetaxel (100 mg/m²) q3w (EC-Doc arm), or 6× epirubicin (60 mg/m²) and 5-fluorouracil (500 mg/m²) on days 1 and 8 and cyclophosphamide (75 mg/m²) on days 1–14, q4w (FEC arm). We compared both arms with respect to toxicity and feasibility. Results: Hematological toxicity was found significantly more often in the FEC arm. Febrile neutropenia was seen in 11.3% of patients in the FEC arm and in 8.4% of patients in the EC-Doc arm (p = 0.027). Non-hematological side effects of grade 3/4 were rarely seen in either arm. Therapy was terminated due to toxicity in 3.7% of the patients in the EC-Doc arm and in 8.0% of the patients in the FEC arm (p = 0.0009). Conclusion: The sequential anthracycline-taxane regimen is a well-tolerated and feasible alternative to FEC120 therapy.

Prognostic impact of weight change during chemotherapy.

1072 Background: Besides established prognostic factors such as tumor size or nodal status, individual host factors of the patient such as obesity, physical activity and diet seem to modulate the course of breast cancer (BC) as well. However, the specific impact of weight change during adjuvant chemotherapy remains unclear. The aim of this analysis was to evaluate the influence of weight change during chemotherapy on BC survival in a large, multi-center prospectively randomized trial. Methods: The ADEBAR trial compares two anthracycline based adjuvant chemotherapy regimen in patients (pts) with lymph node positive ( &gt; 3 positive) early BC: 4 x epirubicin (E) 90 mg/m2 + cyclophosphamide (C) 600 mg/m2 q3w followed by 4 x docetaxel 100 mg/m2 q3w versus 6 x E 60 mg/m2 + 5-FU 500 mg/m2 d1+d8 and C 75 mg/m2 d1-14 q4w. Weight was measured before each cycle. The weight before the 1st and the 6th cycle was assessed. Significant weight change was defined as increase or decrease of &gt; 5% of the initial weight. Overall survival (OS), disease free survival (DFS), and BC specific survival (BCSS) were assessed by Kaplan-Meier analysis. Results: In total, 1502 pts were included in the study. 1177 of them completed 6 cycles of chemotherapy. Out of the 350 pts (29.7%) who changed weight 142 pts (12.1%) lost and 208 pts (17.7 %) gained weight. There was a significant correlation between weight change and menopausal status (p&lt;0.0001), indicating that more premenopausal pts gained and postmenopausal pts lost weight. All other tumor characteristics were similarly distributed across the groups. Pts with weight change &gt; 5% showed a significantly worse outcome with respect to OS (p = 0.0028) and BCSS (p = 0.0258). A difference in DFS was not observed (p = 0.1917). The difference in OS was limited to pts who lost weight (p = 0.0008), whereas pts with weight gain have no significant different OS (p = 0.1246) in comparison to pts with constant weight. Conclusions: Our results suggest that weight loss during anthracycline-based treatment of early stage BC is associated with poorer OS. While weight normalization has shown beneficial effects in lifestyle intervention trials, patients should be advised not to lose weight during chemotherapy.

Final multivariate analysis of obesity and survival in patients with node-positive primary breast cancer: The ADEBAR trial.

1020 Background: The prevalence of obesity increases throughout most industrialized countries. Epidemiological studies have shown not only an increase in breast cancer (BC) among obese women but al...

Abstract S2-2: Multivariate Analysis of Obesity and Disease Free Survival in Patients with Nodal Positive Primary Breast Cancer — The ADEBAR Trial

Abstract Background: The prevalence of obesity increases throughout all evolved civilizations. On the other hand several epidemiological studies have shown not only an increase in breast cancer among obese women but also an adverse impact of obesity on survival of breast cancer patients. This analysis focuses on the impact of obesity on patients (pts) treated within the ADEBAR study protocol. Methods: The ADEBAR Trial compared 4 cycles of EC followed by 4 cycles of Doc vs. 8 cycles of FEC (120) in pts with primary breast cancer (&amp;gt;=4LN). 1500 pts have been accrued from sep/01 through may/05. For this analysis data of 1361 pts has been analyzed about the impact of obesity on disease free survival. Therefore pts have been grouped to either “underweight” (BMI&amp;lt;18.5kg/m2), “normal weight” (BMI18.5-25kg/m2), “overweight” (25kg/m2&amp;lt;BMI&amp;gt;30kg/m2) or “obese” (BMI&amp;gt;30). Results: 13 pts (1.0%) were “underweight”, 557 pts (40.9%) were normal weight, 491 pts (36.1%) were overweight, 300 pts (22.0%) were obese at the time of study enrollment. After a follow up period of 60 months 87.5% of the underweight group, 70.4% of the normal weight group, 70.7% of the overweight group and 58.6% of the obese group were alive with no signs of recurrent disease. This difference was significant (Chi-square=9.355; p&amp;lt; 0.0249). The tumor size at clinical diagnosis was strongly associated to the patient's weight (&amp;lt; 0.0001). There was no significant difference in the number of positive lymph nodes (p = 0.2890), tumor histology (p = 0.9750), grading (p = 0.9520), ER and PR hormone receptors (ER p = 0.9708, PR p = 0.7785) and the expression of HER2 (p = 0.1710) regarding underweight, normal, overweight and obese patients. In a multivariate analysis obesity was an independent prognostic factor with a hazard ratio of 1,007 per 1kg/m2 increase (P&amp;lt;0,0167). Conclusion: This analysis strongly implicates an impact of obesity on disease free survival in patients with early stage node positive breast cancer in the prospectively randomized ADEBAR multicenter trial. It is therefore in line with earlier findings in epidemiological research and raises the question whether a weight reduction might be an additional approach on breast cancer therapy. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-2.

Obesity and disease-free survival in patients with nodal-positive early-stage breast cancer: The ADEBAR trial.

541 Background: The prevalence of obesity increases throughout all evolved civilizations. On the other hand several epidemiological studies have shown not only an increase in breast cancer among obese women but also an adverse impact of obesity on survival of breast cancer patients. This analysis focuses on the impact of obesity on patients (pts) treated within the ADEBAR study protocol. Methods: The ADEBAR Trial compared 4 cycles of EC followed by 4 cycles of Docetaxel vs. 8 cycles of FEC (120) in pts with primary breast cancer (> = 4LN). 1500 pts have been accrued from sep/01 through may/05. For this analysis data of 1,361 pts has been analyzed about the impact of obesity on disease free survival. Therefore pts have been grouped to either “underweight” (BMI < 18.5 kg/m2), ”normal weight” (BMI 18.5-25 kg/m2), ”overweight” (25 kg/m2<bmi<30kg m2)=“ “obese”=“ or=“ (bmi=“>30). Results: 13 pts (1.0%) were “underweight”, 557 pts (40.9%) were normal weight, 491 pts (36.1%) were overweight, 300 pts (22.0%) were obese at the time of study enrollment. After a follow up period of 60 months 87.5% of the underweight group, 70.4% of the normal weight group, 70.7% of the overweight group and 58.6% of the obese group were alive with no signs of recurrent disease. This difference was significant (Chi- square = 9.355; p < 0.0249). Conclusions: This analysis strongly implicates an impact of obesity on disease free survival in patients with early stage node positive breast cancer in the prospectively randomized ADEBAR multicenter trial. It is therefore in line with earlier findings in epidemiological research and raises the question whether a weight reduction might be an additional approach on breast cancer therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis Amgen, Johnson & Johnson, Novartis, sanofi-aventis Amgen, sanofi-aventis

The ADEBAR trial: Final toxicity analysis of a phase III study evaluating the role of docetaxel in the adjuvant therapy of breast cancer patients with extensive lymph node involvement

585 Background: Taxane based adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. However, toxicity concerns of combined anthracycline-taxane regimens have compromised its acceptance. We analyzed the toxicity of a sequential anthracycline-taxane chemotherapy compared to a conventional anthracycline regimen. Patients and Methods: ADEBAR was a multicenter phase III trial (n=1,502) to evaluate whether breast cancer (BC) pts with &gt; 3 axillary lymph metastases benefit from a sequential anthracycline-docetaxel regimen (E90C-D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21 days followed by 4 cycles docetaxel [D] 100mg/m2 q21 days) compared to dose-intensive anthracycline-containing polychemotherapy (FE120C: 6 cycles E 60 mg/m2 d 1+8, 5-FU 500mg/m2 d 1+8 and C 75 mg/m2 d 1–14, q4 weeks). We present the final toxicity analysis. Results: Complete toxicity data were available from 1,338 pts. Treatment was stopped prematurely in 3.7% of the pts in the E90C-D arm and in 8.0% in the FE120C arm due to toxicity (p=0.0009). Antibiotic treatment was given in 10.4% (E90C-D) vs. 19.7% (FE120C), G-CSF support in 39.2% vs 61.4 % and erythropoietin stimulation in 8.7% vs. 20.0%, respectively (p&lt;0.0001). Hematologic and non-hematological grade 3–4 toxicities are summarized in the table . In summary, haematological toxicity (leucopenia, infection thrombocytopenia, anemia) was significantly greater in the FE120C-arm. Skin toxicity, edema and vomiting occurred significantly more often in pts treated with E90C-D. Conclusion: Different toxicity profiles given, overall toxicity of a sequential anthracycline-taxane regimen is not necessarily greater than that of an adequately dosed anthracycline chemotherapy, which needed to be interrupted more frequently due to toxicity. [Table: see text] No significant financial relationships to disclose.

Influence of sequencing of chemotherapy and radiotherapy regarding adverse effects of the cytostatic treatment: Results of the ADEBAR trial

559 Background: The ADEBAR-trial was designed as a multicenter randomised phase III study for high risk primary breast cancer (BC) pts., i.e. with more than 3 axillary lymph node metastases. Primary objective of the trial was to evaluate the benefit of a sequential anthracycline-docetaxel regimen (E90C-D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21 days followed by 4 cycles docetaxel [D] 100mg/m2 q21 days) compared to dose-intensive anthracycline- containing polychemotherapy (FE120C: 6 cycles E 60 mg/m2 d 1+8, 5-FU 500mg/m2 d 1+8 and C 75 mg/m2 d 1–14, q4 weeks). Patients and Methods: The study started in 2001 and was closed in 2005. By this time 200 actively participating sites had recruited a total number of 1,502 patients. One of the stratification issues was the sequencing of chemotherapy and radiotherapy. All patients were required to receive adjuvant radiotherapy. However the timing of irradiation, either in a sandwich setting after the first half of chemotherapy cycles or after completion of the entire cytostatic treatment was at the discretion of the study sites. In a toxicity-analysis in December 2006, the influence of sequencing of chemotherapy and radiotherapy was analyzed in 980 patients. Results: In 223 pts. radiotherapy was performed midtime after the first half of chemotherapy cycles, 757 pts. received radiotherapy only after completing the entire cytostatic treatment and before starting endocrine treatment, if applicable. Hospitalisation occurred in 32.7 % (73 pts.) of the sandwich group and in 27.9% (211 pts.) of the sequential group (p-value = 0.160). Interval prolongation was necessary in 37.7% (84 pts.) versus 31.6% (239 pts.) in the sequential group, (p-value = 0.089). The target dose was reduced in 15.7% (35 pts.) in the sandwich group and in 20.2% (153 pts.) of the sequential group, (p-value = 0.132). SAEs occurred in 29.6% (66 pts.) in the sandwich group versus 23.1% (175 pts.), (p-value = 0.048). Conclusion: No consistent association between treatment toxicity and the timing of chemotherapy and radiotherapy was observed. Because in this high risk patient group, the prevention of systemic relapse is most important, chemotherapy should be completed before the start of radiotherapy. No significant financial relationships to disclose.

U-Plasminogen activator (urinary plasminogen activator, urokinase) (uPA) and its PA-1 type 1 inhibitor are not only prognostically but also predictively significant and support clinical decisions on therapy in primary carcinoma of the breast

uPA and PAI-1 are the first novel tumor biological prognostic factors in breast cancer for which the prognostic impact has been validated at the highest level of evidence and hence all evaluation criteria for transfer into clinical practice have been fullfilled. Breast cancer patients with high uPA and/or PAI-1 levels in their primary tumor tissue have a significantly lower chance for cure than patients with low levels of both uPA and PAI-1. Our research that was honored with the Schmidt-Matthiesen-Award 2002 shows for the first time that uPA and PAI-1 are not only prognostic factors but also have a predictive impact with regard to response to adjuvant chemotherapy. Patients with high uPA/PAI-1 derive a significantly greater benefit from adjuvant chemotherapy than patients with low uPA/PAI-1. Benefit from adjuvant endocrine therapy is independent of uPA/PAI-1 status. The resulting question about the optimal chemotherapy for patients with high uPA/PAI-1 is currently being addressed in Germany by the NNBC-3 trial in node-negative breast cancer (AGO, EORTC-RBG) as well as the ADEBAR trial in patients with 4 or more involved axillary lymph nodes. Moreover, our results suggest the use of novel therapeutic agents interfering with the uPA system together with conventional chemotherapy in patients with high uPA/PAI-1 already in early stage disease.