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author:("hoober, Jens")
1.  Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial 
BMC Cancer  2013;13:480.
Background
The presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome. Bisphosphonate treatment was shown to eradicate DTC from BM in several studies. This controlled randomized open-label multi-center study aimed to investigate the influence of zoledronic acid (ZOL) on DTC and survival of breast cancer patients (Clinical Trial Registration Number: NCT00172068).
Methods
Patients with primary breast cancer and DTC-positive bone marrow were randomized to treatment with ZOL plus adjuvant systemic therapy (n = 40) or adjuvant systemic therapy alone (n = 46) between 03/2002 and 12/2004. DTC were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. The change in DTC numbers at 12 months and 24 months versus baseline, as well as patient outcomes were evaluated.
Results
86 patients could be included into survival analysis (median follow-up: 88 months, range: 8–108 mths). Patients in the control group were more likely to die during follow-up than those in the ZOL-group (11% vs. 2%, p = 0.106). 15% of patients in the control group presented with relapse whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p = 0.205). At 24 months, 16% of patients from the control group were still DTC positive, whereas all patients treated with ZOL became DTC negative (p = 0.032). Patients presenting with persistent DTC 12 months after diagnosis had significantly shorter overall survival (p = 0.011).
Conclusions
Bisphosphonate therapy contributes to eradication of disseminated tumor cells. The positive influence of bisphosphonates on survival in the adjuvant setting may be due to their effects on DTC.
Trial registration
ClinicalTrials.gov Identifier: NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)].
doi:10.1186/1471-2407-13-480
PMCID: PMC4015285  PMID: 24128322
Breast cancer; Bisphosphonates; Zoledronate; Disseminated tumor cells; Survival
2.  Adding Epoetin Alfa to Intense Dose-Dense Adjuvant Chemotherapy for Breast Cancer: Randomized Clinical Trial 
Background
The AGO-ETC trial compared 5-year relapse-free survival of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks vs conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC→T) (every 3 weeks) as adjuvant treatment in high-risk breast cancer patients. The objective of this study was to evaluate the safety and efficacy of epoetin alfa in a second randomization of the intense dose-dense arm.
Methods
One thousand two hundred eighty-four patients were enrolled; 658 patients were randomly assigned to the IDD-ETC treatment group. Within the IDD-ETC group, 324 patients were further randomly assigned to the epoetin alfa group, and 319 were randomly assigned to the non–erythropoiesis-stimulating agent (ESA) control group. Primary efficacy endpoints included change in hemoglobin level from baseline to Cycle 9 and the percentage of subjects requiring red blood cell transfusion. Relapse-free survival, overall survival, and intramammary relapse were secondary endpoints estimated with Kaplan-Meier and Cox regression methods. Except for the primary hypothesis, all statistical tests were two-sided.
Results
Epoetin alfa avoided the decrease in hemoglobin level (no decrease in the epoetin alfa group vs –2.20g/dL change for the control group; P < .001) and statistically significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8% vs 28.1%; P < .0001). The incidence of thrombotic events was 7% in the epoetin alfa arm vs 3% in the control arm. After a median follow-up of 62 months, epoetin alfa treatment did not affect overall survival, relapse-free survival, or intramammary relapse.
Conclusions
Epoetin alfa resulted in improved hemoglobin levels and decreased transfusions without an impact on relapse-free or overall survival. However, epoetin alfa had an adverse effect, resulting in increased thrombosis.
doi:10.1093/jnci/djt145
PMCID: PMC3714019  PMID: 23860204
3.  HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer 
Introduction
Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial.
Methods
HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro.
Results
Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P <0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P <0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors.
Conclusions
Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group.
Introduction The human epidermal growth factor receptor 2 (HER2) is the prototype of a predictive biomarker for targeted treatment [1-8]. International initiatives have established the combination of immunohistochemistry (IHC) and in situ hybridization as the current gold standard [9,10]. As an additional approach determination of HER2 mRNA expression is technically feasible in formalin-fixed paraffin-embedded (FFPE) tissue [11-13]. Crosstalk between the estrogen receptor (ER) and the HER2 pathway has been suggested based on cell culture and animal models [14]. Consequently, the 2011 St Gallen panel has pointed out that HER2-positive tumors should be divided into two groups based on expression of the ER [15].
A retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 study has suggested that mRNA levels of HER2 and ESR1 might be relevant for the degree of benefit from adjuvant trastuzumab. By subpopulation treatment effect pattern plot (STEPP) analysis in ER-positive tumors, benefit from trastuzumab was shown to be restricted to those with higher levels of HER2 mRNA (S Paik, personal communication, results summarized in [15]).
In our study we evaluated this hypothesis in the neoadjuvant setting in a cohort of 217 patients from the neoadjuvant GeparQuattro trial [5]. All patients had been HER2- positive by local pathology assessment and had received 24 to 36 weeks of neoadjuvant trastuzumab plus an anthracycline/taxane-based chemotherapy. For central evaluation we used three different methods, HER2 IHC, and HER2 silver in situ hybridization (SISH), as well as measurement of HER2 mRNA by quantitative real-time (qRT)-PCR [11].
The primary objective of this analysis was to investigate if pathological complete response (pCR) rate in HER2-positive breast cancer would depend on the level of HER2 mRNA expression, with a separate analysis for HR-positive and -negative tumors. Central evaluation of the HER2 status showed that 27% of the tumors with HER2 overexpression by local pathology were HER2-negative. This enabled us to compare response rates in patients with HER2-positive and -negative tumors as a secondary objective.
doi:10.1186/bcr3384
PMCID: PMC3672694  PMID: 23391338
4.  Neoadjuvant Therapy – What Have We Achieved in the Last 20 Years? 
Breast Care  2011;6(6):419-426.
Neoadjuvant chemotherapy is the standard of care for patients with large, inoperable tumors or inflammatory breast cancer, but it is also increasingly considered for women with operable disease. Several randomized trials have demonstrated that anthracycline- and taxane-containing regimens in operable breast cancer were equally effective in terms of disease-free or overall survival regardless of whether they were administered postoperatively or preoperatively. Further neoadjuvant treatment allows for a higher rate of breast conserving surgery. Tumor responses in terms of pathologic complete remission after short-term chemotherapy will probably only serve as a surrogate marker for long-term outcome in some molecular breast cancer subtypes like the triple-negative, HER2-positive, and some luminal B subsets. Recent trials showed that in HER2-positive disease pCR rates were as high as 70% when 2 HER2-targeted agents were added to chemotherapy.
doi:10.1159/000335347
PMCID: PMC3290030  PMID: 22419894
Neoadjuvant chemotherapy; Pathologic complete remission; Molecular subtypes; HER2-positive breast cancer
6.  The Role of Combination Chemotherapy in the Treatment of Patients with Metastatic Breast Cancer 
Breast Care  2009;4(6):367-372.
Summary
Metastatic breast cancer (MBC) is usually not curable, and the primary goals of treatment are thus to control disease and symptoms, maintain quality of life, and prolong life while minimizing toxicity. Chemotherapy is still an important treatment option in MBC, and the decision whether polychemotherapy is preferable to sequential monochemotherapy is under debate. Data are quite consistent in that response rates and time to progression are significantly increased with combination chemotherapy compared to the use of a single agent in MBC patients. Data regarding overall survival with polychemotherapy are not conclusive; however, frequently this approach was associated with increased treatment toxicity and decreased quality of life. Nonetheless, in patients with symptomatic or acute, life-threatening disease, where maximum and quick tumor remission is important, polychemotherapy should be the preferred approach. Furthermore, since some of the newer combination regimens seem to increase toxicity only slightly and substantially prolong time to progression, this approach may also be an option in patients without symptomatic disease.
doi:10.1159/000262808
PMCID: PMC2941999  PMID: 20877671
Breast cancer; Metastasis; Polychemotherapy
7.  A multicentric observational trial of pegylated liposomal doxorubicin for metastatic breast cancer 
BMC Cancer  2010;10:2.
Background
Pegylated liposomal doxorubicin (PLD) is active in metastatic breast cancer. This observational study evaluated the efficacy and safety of PLD in patients treated during routine clinical practice.
Methods
Eligible patients had metastatic breast cancer and were treated with PLD according to the dose and schedule determined by their physician as part of routine practice. The primary objectives were to analyze the efficacy and toxicity of PLD therapy.
Results
125 patients were assessable. Median age was 62 years, 78% had performance status 0-1, and 60% had estrogen-receptor-positive disease. PLD treatment was second- or third-line in 69% of patients. Prior anthracyclines (adjuvant or metastatic) had been used in 56% of patients. The majority of patients (79%) received PLD every 4 weeks at a median dose of 40 mg/m2. Overall response rate was 43% in all patients and 34% in those previously treated with anthracyclines. The most common grade 3/4 adverse events were skin toxicity/hand-foot syndrome (6%), and leukopenia (3%).
Conclusions
This observational study supports the activity and tolerability of PLD in metastatic breast cancer as demonstrated in PLD clinical trials.
doi:10.1186/1471-2407-10-2
PMCID: PMC2806246  PMID: 20047698
8.  Dose-Dense Therapy 
Breast Care  2008;3(2):134-138.
doi:10.1159/000127220
PMCID: PMC2931089  PMID: 21373218

Results 1-8 (8)