BACKGROUND AND OBJECTIVES:Recently the highest level of evidence indicated the prognostic value of isolated tumor cells (ITC) in bone marrow of patients with breast cancer, both at primary diagnosis and during recurrence-free follow-up. The aim of the present study was to investigate the therapeutic efficacy of zoledronate in reducing persistence of ITC in the bone marrow of patients with breast cancer after they had completed primary therapy.PATIENTS AND METHODS:In a non-randomized phase II pilot study, 4 mg of zoledronate were administered once every four weeks for six months, after a initial loading dose of 8 mg, to 31 patients with persisting ITC in bone marrow. All patients had completed surgery and adjuvant chemotherapy, if indicated, at least 6 months previously. The bone marrow was re-examined after 7.9 months (std 0,89). ITC were detected by immunocytochemical staining, using the monoclonal pan-cytokeratin antibody A45-B/B3 and the APAAP technique. Patients were followed-up prospectively for a median of 39 months after the first aspiration.RESULTS:ITC were detected in all 31 patients at the time of first bone marrow aspiration, but 27 of them (87 %) were free of ITC 6 months after the end of zoledronate therapy. The reduction in cell numbers between first and second aspiration were statistically significance (P < 0,0001). Ten of 12 patients without detection of ITC in bone marrow after treatment and who had undergone additional aspirations, still had no ITC a median time of 19 months (range 4.7 - 38.7 months) after the end of treatment. Zoledronate treatment was well tolerated, bone pain having been the most common side effect in 45 % of patients (n = 14).CONCLUSION:These results indicate a potential antineoplastic effect of zoledronate, a cell-cycle independent drug, on persisting ITC in a dormant state. Our data provide the basis for investigating the efficacy of zoledronate on ITC in treating primary breast cancer in prospectively randomized trials. ITC in bone marrow represents a useful marker in selecting patients at risk for recurrence and for monitoring therapeutic efficacy.

Fragestellung: In der Therapie von Patientinnen mit metastasiertem Mammakarzinom haben sich Behandlungsschemata mit einerseits möglichst hoher Ansprechrate und andererseits bestmöglicher Verträglichkeit durchgesetzt. Bisher gibt es jedoch keine Standardtherapie in der metastasierten Situation.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Ältere Patientinnen mit Brustkrebs sind in Studien unterrepräsentiert. Werden sie deswegen unzureichend behandelt? Haben sie prognostisch günstigere Tumore? Und spiegelt sich das im Überleben und der Rezidivfeiheit wider?

Material und Methodik: Von 1999 bis 2005 wurden 10 Pat. im Rahmen der Dolphin-0-Studie (Carboplatin AUC6/Paclitaxel 175mg/m2 kombiniert mit Ganzkörperhyperthermie (GKHT) bei prim. oder rezidiv. Ovarial-Ca) und 29 Pat. im Rahmen der Dolphin-1-Studie (Carboplatin AUC5/Ifosfamid 3g/m2 kombiniert mit GKHT bei rezidiv. Ovarial-Ca) behandelt. Ergebnisse: Durchschnittl. 1,8 vorangegangene Chemotherapien (0–6). Im Durchschnitt 4,8 Zyklen pro Patientin, hierbei 58 Zyklen bei Dolphin-0 und 131 bei Dolphin-1. Die mittl. Nachbeobachtungszeit betrug 24,5 Monate (2,4–69,6 Monate). Ansprechraten von Dolphin-0 nach Abschluss der Therapie: CR 80%, PR 10%, SD 10%, von Dolphin-1: CR 10,3%, PR 13,8%, SD 20,7% und PD 55,2%. Med. Überlebenszeit der Pat. der Dolphin-0-Studie: 50,9 Mon., Dolphin-1-Studie: 12,4 Mon. 5-J-Überlebensrate Dolphin-0-Studie 50%. Dolphin-1-Studie: 2-J-Überlebensrate 25,2%. Toxizität: Neutropenie: Dolphin-0: 17,8% Grad 1, 26,7% Grad 2, 3,5% Grad 3, 1,8% Grad 4, Dolphin-1: 20,5 Grad 1, 14,2% Grad 2, 21,4% Grad 3, 20,5% Grad 4. Thrombozytopenie: Dolphin-0: 17,9% Grad 2, 3,6% Grad 3, 1,8% Grad 4, Dolphin-1: 9% Grad 2, 24,1% Grad 3, 10,5% Grad 4. Anämie: Dolphin-0: 41,5% Grad 1, 16% Grad 2, 2% Grad 4, Dolphin-1: 46,5% Grad 1, 30% Grad 2, 3% Grad 3, 3% Grad 4. Infektionen: Dolphin-0: 22,4% Grad 1–2, kein Grad 3, Dolphin-1: 17,6% Grad 1–3, hiervon 2 x Pneumonie, 3 x schwere erosive Mucositis. Emesis: Dolphin-0: Grad 1 17,9%, Grad 2 4,5%, Dolphin-1: Grad 1 19,5%, Grad 2 18%, Grad 3 und 4 jeweils 2%. Verbrennung: Dolphin-0: 6,8% Grad 1, Dolphin-1: 3,7% Grad 1, 1,5% Grad 2, 2,3% Grad 3. Dosisreduktion: Dolphin-0: 2 Zyklen (Myelotox.), 1 Zyklus (Emesis), Dolphin-1: 24 Zyklen (Myelotox.), 2 Zyklen (Nephrotox.). Intervallverlängerung: Dolphin-0: 6.9%, Dolphin-1: 18,3% Fazit: Die GKHT kombiniert mit Chemotherapie beim Ovarialkarzinom zeigte eine akzeptable Ansprechrate und tolerable Toxizität. Sie sollte jedoch weiterhin im Rahmen klinischer Studien überprüft werden.

Aims: If the persistence of ITC after adjuvant therapy is associated with risk for recurrence, it would be an indication to consider secondary adjuvant treatment. Cell-cycle independent agents might be effective in the elimination of dormant cells. Methods: We analyzed BM aspirates from 228 pts during recurrence-free follow-up at a median interval of 21.3mon after primary diagnosis. ITC were detected by monoclonal antibody A45-B/B3 against cytokeratin. Pts were followed for a median of 49.8mon. In a pilot study on 14 pts with evidence of persisting ITC, zoledronate was applied (4mg q4wx6mon, loading dose 8mg). Pts were to have completed surgery (R0) and adjuvant chemotherapy for at least 6mon. In a matched pair analysis, these pts were compared to 14 pts with persisting ITC in the BM, who received no further therapy. The BM was re-examined after a median of 8mon in the treatment group and 9mon in the control group. Results: Persistent ITC in BM were detected in 12.7% of pts. Positive BM status was more frequent (15.7%) within the first 21mon after primary diagnosis than after a follow-up>21mon (9.7%). Recurrence-free survival was 149mon in pts with negative and 86mon in pts with positive BM status (P=.0003). Pts who were without evidence of persistent ITCs had a significantly longer overall survival (162.1 vs. 98.7mon; P=.0008). In multivariate analysis ITC was an independent predictor for disease-free (RR 4.57; P<.0001) and overall survival (RR 5.57; P=.002). While ITC were detected in all 28 pts of the therapeutic intervention study at initial BM aspiration, no pt showed ITC in the BM after 6mon of zoledronate. ITC were detected in 4 pts (29%) of the control group (P=.03). Conclusions: Evidence of persistent ITCs in BM from pts with breast carcinoma indicated an increased risk for subsequent recurrence. Secondary adjuvant treatment intervention with zoledronate might have a potential antineoplastic effect on persisting ITC in dormant state.

BACKGROUND. The prognostic significance of isolated turner cells (ITCs) in bone marrow (BM) from patients with breast carcinoma at the time of their primary diagnosis recently was been confirmed by a large pooled analysis. If the persistence of ITCs after adjuvant therapy centers a similar risk for recurrence, then it would be art indication to consider secondary adjuvant therapy.METHODS. The authors analyzed BM aspirates front 228 patients during recurrence-free follow-tip at a median interval +/- standard deviation (SD) of 21.3 +/- 29.1 months after a primary diagnosis of breast carcinoma (pathologic T1 [pT1]-pT2, pN0-pN3, pM0). Carcinoma cells were detected using a standardized immunoassay with monoclonal antibody A45-B/B3 directed against cytokeratin (CK). Patients were followed for a median +/- SD of 49.8 +/- 32.1 months after their primary, diagnosis.RESULTS. Persistent ITCs in BM were detected in 12.7% of patients (n = 29 patients). Positive BM status was itiore frequent (15.7%) within the first 21 months after primary diagnosis than after a follow-tip > 21 months (9.7%). The Kaplan-Meier estimate for mean recurrence-free survival was 149.7 months (95% confidence interval [95% CI], 139.6-159.8 months) in patients with negative BM status and 86.5 months (95% CI, 35.7-107.4 months; P = 0.0003) in patients with positive BM status at the time patients underwent follow-up BM aspiration. Patients who were without evidence of persistent ITCs had a significantly longer overall survival (162.1 months; 95% CI, 152.1-172.0 months) compared with patients who had positive BM status (overall Survival, 98.7 months; 95% CI, 79.7-117.9 months; P = 0.0008). In multivariate Cox regression analysis that included BM status, tumor size, lymph node status, and histopathologic grade, evidence of ITCs was an independent significant predictor for reduced disease-free survival (relative risk [RR], 4.57; P < 0.0001) and overall survival (RR, 5.57; P = 0.002). Persistent ITCs had the greatest prognostic relevance when they were detected between 25 months and 42 months after primary diagnosis (RR, 7.68).CONCLUSIONS. Evidence of Persistent ITCs in BM from patients with breast carcinoma indicated an increased risk for subsequent recurrence. Prospective trials should investigate the benefit of secondary adjuvant treatment on the basis of BM marrow status. Cancer 2005;103:884-91. (C) 2005 American Cancer Society.

Background: We assessed the prognostic significance of the presence of micrometastasis in the bone marrow at the time of diagnosis of breast cancer by means of a pooled analysis.Methods: We combined individual patient data from nine studies involving 4703 patients with stage I, II, or III breast cancer. We evaluated patient outcomes over a 10-year follow-up period (median, 5.2 years), using a multivariable piecewise Cox regression model.Results: Micrometastasis was detected in 30.6 percent of the patients. As compared with women without bone marrow micrometastasis, patients with bone marrow micrometastasis had larger tumors and tumors with a higher histologic grade and more often had lymph-node metastases and hormone receptor-negative tumors (P<0.001 for all variables). The presence of micrometastasis was a significant prognostic factor with respect to poor overall survival and breast-cancer-specific survival (univariate mortality ratios, 2.15 and 2.44, respectively; P<0.001 for both outcomes) and poor disease-free survival and distant-disease-free survival during the 10-year observation period (incidence-rate ratios, 2.13 and 2.33, respectively; P<0.001 for both outcomes). In the multivariable analysis, micrometastasis was an independent predictor of a poor outcome. In the univariate subgroup analysis, breast-cancer-specific survival among patients with micrometastasis was significantly shortened (P<0.001 for all comparisons) among those receiving adjuvant endocrine treatment (mortality ratio, 3.22) or cytotoxic therapy (mortality ratio, 2.32) and among patients who had tumors no larger than 2 cm in diameter without lymph-node metastasis and who did not receive systemic adjuvant therapy (mortality ratio, 3.65).Conclusions: The presence of micrometastasis in the bone marrow at the time of diagnosis of breast cancer is associated with a poor prognosis.

9612 Background BCT is the most frequently performed surgical treatment for primary breast cancer resulting in optimal cosmetic outcome. Aim of this study was to evaluate safety and outcome in comparison to mastectomy in a large population-based southern German breast cancer database with a long follow-up. Methods In a retrospective matched pair analysis on 1574 women with primary operable breast cancer, we compared local recurrence rates, DDFS and OAS after BCT and mastectomy. 787 pairs of pts with comparable tumor size, nodal status, grading, age and menopausal status were selected. The significance of various prognostic parameters at the time of primary diagnosis was evaluated, by multivariate analyses, with respect to locoregional recurrence, DDFS and OAS. The median follow-up was 58 months. Results Risk factors at primary diagnosis, such as tumor size and lymph node status, were comparable between both groups. Mastectomy resulted in a five-year survival rate of 93% compared to 94% with BCT (p=.29) and a DDFS rate of 89%, compared to 91% (p=.09), respectively. 92% of pts treated with mastectomy were free of loco-regional recurrence five years after primary diagnosis, while 93% of pts showed no sign of local recurrence after BCT (p=.13). However, node-negative pts showed an increased risk for loco-regional recurrence, when treated with BCT (p=.02). Multivariate analysis, allowing for type of surgery, tumor size, nodal status, grading, hormone receptor status and menopausal status showed that lymph node status (p<.001) and grading (p=.04) were the most significant single prognostic factors for survival, while DDFS was only predicted by nodal status (p<.001) and loco-regional recurrence by grading (p=.03), respectively. The primary surgical therapy was shown to be of no statistical influence (p=.17). Conclusions This analysis confirms previously published data which show equivalence of BCT and mastectomy in terms of OAS, DFS and local recurrence rate. These reassuring data are part of repeated regional quality assurance evaluations, monitoring adverse treatment effects. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, AstraZeneca, Aventis, Novartis, Pfizer

579 Background: The prognostic significance of ITC in the BM of breast cancer patients at the time of primary diagnosis has recently been confirmed by a large pooled analysis (Braun S, SABCS 2003). If the persistence of ITC after adjuvant therapy confers a similar risk for relapse, there would be an indication to consider secondary adjuvant therapy. Methods: We analyzed BM aspirates of 228 patients during recurrence-free follow-up at a median interval of 21.3 months (standard deviation [std] 29.1 mon) after primary diagnosis of breast cancer pT1–2 pN0–3 pM0. Carcinoma cells were detected using a standardized immunoassay with monoclonal antibody A45-B/B3, directed against cytokeratin (CK). Patients were followed for a median of 49.8 months (std 32.1 mon) after primary diagnosis. Results: Persistent ITC in the BM were detected in 12.7% of the patients (n=29). Positive BM status was more frequent (15.7%) within the first 21 months after primary diagnosis, than after a follow-up longer than 21 mon (9.7%). The Kaplan-Meier estimate for mean relapse-free survival was 149.7 mon (139.6 –159.8 95%CI) in patients with negative and 86.5 mon (65.7 –107.4 95% CI, p= .0003, log rank test) in patients with positive BM status Patients without evidence of persistent ITC had a significantly longer overall survival (162.1 mon, [152.1 –172.0]), than patients with positive BM status (98.7 mon, [79.7 –117.9], p= .0008). In multivariate Cox regression analysis, allowing for bone marrow status, tumor size, nodal status, and histopathological grading, evidence for ITC was an independent significant predictor for reduced survival (RR 5.57, p= .002). Persistent ITC had the greatest prognostic relevance when detected between 25 and 42 months after primary diagnosis (RR 7.68). Conclusion: Evidence of persistent ITC in the bone marrow of breast cancer patients indicates an increased risk for subsequent relapse, and may serve as follow-up tool in future. Prospective trials should investigate the benefit of secondary adjuvant treatment on the basis of the bone marrow status. No significant financial relationships to disclose.