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1.  Tumor-infiltrating lymphocytes in breast cancer 
Oncoimmunology  2014;3:e27926.
We have prospectively validated in an independent clinical cohort the finding that elevated amounts of tumor-infiltrating lymphocytes in breast carcinoma tissues predict the response of patients to neoadjuvant chemotherapy. These results suggest that a robust tumor infiltration by T and B cells is a promising biomarker to define patients who might benefit from neoadjuvant chemotherapy.
doi:10.4161/onci.27926
PMCID: PMC4203634  PMID: 25340002
biological marker; breast cancer; neoadjuvant chemotherapy; response predictor
2.  Cost-Effectiveness Analysis of Prognostic Gene Expression Signature-Based Stratification of Early Breast Cancer Patients 
Pharmacoeconomics  2014;33:179-190.
Background
The individual risk of recurrence in hormone receptor-positive primary breast cancer patients determines whether adjuvant endocrine therapy should be combined with chemotherapy. Clinicopathological parameters and molecular tests such as EndoPredict® (EPclin) can support decision making in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancer.
Objective
Using a life-long Markov state transition model, we determined the health economic impact and incremental cost effectiveness of EPclin-based risk stratification in combination with clinical guidelines [German-S3, National Comprehensive Cancer Center Network (NCCN), and St. Gallen] to decide on chemotherapy use.
Methods
Information on overall and metastasis-free survival came from Austrian Breast & Colorectal Cancer Study Group clinical trials 6/8 (n = 1,619) and published literature. Effectiveness was assessed as quality-adjusted life-years (QALYs). Costs (2010) were assessed from a German third-party payer perspective.
Results
Lifetime costs per patient ranged from €28,268 (St.Gallen and EPclin) to €33,756 (NCCN). Due to an imperfect prognostic value and differences in chemotherapy use, strategies achieved between 13.165 QALYs (NCCN) and 13.173 QALYs (EPclin alone) per patient. Using German-S3 as reference, three strategies showed dominant results (St. Gallen and EPclin, German-S3 and EPclin, EPclin alone). Compared to German-S3, the addition of EPclin saved €3,388 and gained 0.002 QALYs per patient. Combining guidelines with EPclin remained preferable in sensitivity analysis.
Conclusion
Our study suggests that molecular markers can be sensibly combined with clinical guidelines to determine the risk profile of adjuvant breast cancer patients. Compared with the current German best practice (German-S3), combinations of EPclin with the St. Gallen, German-S3 or NCCN guideline and EPclin alone were dominant from the perspective of the German healthcare system.
Electronic supplementary material
The online version of this article (doi:10.1007/s40273-014-0227-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s40273-014-0227-x
PMCID: PMC4305105  PMID: 25404424
3.  Deciphering clonality in aneuploid breast tumors using SNP array and sequencing data 
Genome Biology  2014;15(9):470.
Intra-tumor heterogeneity concerns the existence of genetically different subclones within the same tumor. Single sample quantification of heterogeneity relies on precise determination of chromosomal copy numbers throughout the genome, and an assessment of whether identified mutation variant allele fractions match clonal or subclonal copy numbers. We discuss these issues using data from SNP arrays, whole exome sequencing and pathologist purity estimates on several breast cancers characterized by ERBB2 amplification. We show that chromosomal copy numbers can only be estimated from SNP array signals or sequencing depths for subclonal tumor samples with simple subclonal architectures under certain assumptions.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0470-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0470-7
PMCID: PMC4220069  PMID: 25270265
4.  Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences 
Oncotarget  2014;5(20):9952-9965.
Mutational profiling of triple-negative breast cancer (TNBC) by whole exome sequencing (WES) yielded a landscape of genomic alterations in this tumor entity. However, the clinical significance of these findings remains enigmatic. Further, integration of WES in routine diagnostics using formalin-fixed paraffin-embedded (FFPE) material is currently not feasible.
Therefore, we designed and validated a breast cancer specific gene panel for semiconductor-based sequencing comprising 137 amplicons covering mutational hotspots in 44 genes and applied this panel on a cohort of 104 well-characterized FFPE TNBC with complete clinical follow-up.
TP53 mutations were present in more than 80% of cases. PI3K pathway alterations (29.8%) comprising mainly PIK3CA mutations (22.1%) but also mutations and/or amplifications/deletions in other PI3K-associated genes (7.7%) were far more frequently observed, when compared to WES data. Alterations in MAPK signaling genes (8.7%) and cell-cycle regulators (14.4%) were also frequent. Mutational profiles were linked to TNBC subgroups defined by morphology and immunohistochemistry. Alterations in cell-cycle pathway regulators were linked with better overall (p=0.053) but not disease free survival.
Taken together, we could demonstrate that breast cancer targeted hotspot sequencing is feasible in a routine setting and yields reliable and clinically meaningful results. Mutational spectra were linked to clinical and immunohistochemically defined parameters.
PMCID: PMC4259450  PMID: 25296970
triple-negative breast cancer; next generation sequencing; immunohistochemistry; mutation profiling
5.  Gross cystic disease fluid protein 15 (GCDFP-15) expression in breast cancer subtypes 
BMC Cancer  2014;14(1):546.
Background
Gross cystic disease fluid protein 15 (GCDFP-15), which is regulated by the androgen receptor (AR), is a diagnostic marker for mammary differentiation in histopathology. We determined the expression of GCDFP-15 in breast cancer subtypes, its potential prognostic and predictive value, as well as its relationship to AR expression.
Methods
602 pre-therapeutic breast cancer core biopsies from the phase III randomized neoadjuvant GeparTrio trial (NCT00544765) were investigated for GCDFP-15 expression by immunohistochemistry. Expression data were correlated with disease-free (DFS) and overall survival (OS) time as well as pathological complete response (pCR) to neoadjuvant chemotherapy.
Results
239 tumors (39.7%) were GCDFP-15 positive. GCDFP-15 expression was positively linked to hormone receptor (HR) and HER2 positive tumor type, while most triple negative carcinomas were negative (p < 0.0001). GCDFP-15 was also strongly correlated to AR expression (p 0.001), and to the so-called molecular apocrine subtype (HR-/AR+, p < 0.0001). Higher rates of GCDFP-15 positivity were seen in tumors of lower grade (<0.0001) and negative nodal status (p = 0.008). GCDFP-15 positive tumors tended to have a more favourable prognosis than GCDFP-15 negative tumors (DFS (p = 0.052) and OS (p = 0.044)), which was not independent from other factors in multivariate analysis. GCDFP-15 expression was not linked to pCR. Histological apocrine differentiation was frequent in molecular apocrine carcinomas (60.7%), and was associated with GCDFP-15 within this group (p = 0.039).
Conclusions
GCDFP-15 expression is higher in tumors with favorable prognostic features. GCDFP-15 expression is further a frequent feature of AR positive tumors and the molecular apocrine subtype. It might have reduced sensitivity as a diagnostic marker for mammary differentiation in triple negative tumors as compared to HR or HER2 positive tumor types.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-546) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-546
PMCID: PMC4122770  PMID: 25070172
GCDFP-15; Breast cancer; Neoadjuvant chemotherapy; Apocrine; CUP
6.  13th St. Gallen International Breast Cancer Conference 2013: Primary Therapy of Early Breast Cancer Evidence, Controversies, Consensus – Opinion of a German Team of Experts (Zurich 2013) 
Breast Care  2013;8(3):221-229.
Summary
The International Consensus Conference on the treatment of primary breast cancer takes place every two years in St. Gallen, Switzerland. The panel in St. Gallen is composed of international experts from different countries. From a German perspective, it seems reasonable to interpret the voting results in the light of AGO-recommendations and S3-guidelines for everyday practice in Germany. Consequently, a team of eight breast cancer experts, of whom two are members of the international St. Gallen panel, commented on the voting results of the St. Gallen Consensus Conference (2013). The main topics at this year's St. Gallen conference were surgical issues of the breast and axilla, radio-therapeutic and systemic treatment options, and the clinical relevance of tumour biology. The clinical utility of multigene assays for supporting individual treatment decisions was also intensively discussed.
doi:10.1159/000351692
PMCID: PMC3728634  PMID: 24415975
St. Gallen Consensus; Early breast cancer; Adjuvant therapy; Multigene signatures; Targeted therapy
7.  Side Effects of Standard Adjuvant and Neoadjuvant Chemotherapy Regimens According to Age Groups in Primary Breast Cancer 
Breast Care  2013;8(1):60-66.
Summary
Background
Elderly breast cancer patients are underrepresented in clinical trials and this leads to a lack of knowledge regarding the tolerance and side effects of modern chemotherapy regimens, especially in dose-dense (dd) or dose-intensified combination.
Patients and Methods
In this analysis, data from 4 German, randomized (neo-)adjuvant trials, including anthracycline-based chemotherapy, were evaluated for toxicity, compliance and feasibility. Patients were grouped according to age.
Results
Of the 4,775 patients, 73.6% were < 60 years, 15.8% were 60–64 years and 10.6% were > 64 years. The patients’ compliance decreased with increasing age, the rate of therapy discontinuations was 10.3%; 16.0% were > 64 years old (p < 0.001). The rate of dose reductions also increased with increasing age in the docetaxel/doxorubicin/cyclophosphamide (TAC) (p overall = 0.02) and 5-fluorouracil/epirubicin-cyclophosphamide (FE120C) (p overall < 0.001) treatment groups. Neutropenia grade 3 + 4 in patients of > 64 years was 77% in FE120C- compared to 55% in TAC-treated patients (with primary granulocyte colony-stimulating factors (G-CSFs)). The incidence of febrile neutropenia (FN) was lowest in the regimens without additional taxanes. FN in patients aged > 64 years was lower in the FE120C- than in TAC-and dd-doxorubicin/docetaxel-treated groups.
Conclusion
The range and intensity of toxicity increased with age. Neutropenia did not increase significantly in the dd groups; the highest rate was seen in FE120C-treated patients. FE120C without G-CSFs is not an option in patients older than 64 years.
doi:10.1159/000346834
PMCID: PMC3971817  PMID: 24715845
Elderly; Chemotherapy; Side effect; Tolerability; Breast cancer
8.  Prospective Validation of Immunological Infiltrate for Prediction of Response to Neoadjuvant Chemotherapy in HER2-Negative Breast Cancer – A Substudy of the Neoadjuvant GeparQuinto Trial 
PLoS ONE  2013;8(12):e79775.
Introduction
We have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy (NACT). The aim of this study was to prospectively validate the tumor-associated lymphocyte infiltrate as predictive marker for response to anthracycline/taxane-based NACT.
Patients and Methods
The immunological infiltrate was prospectively evaluated in a total of 313 core biopsies from HER2 negative patients of the multicenter PREDICT study, a substudy of the neoadjuvant GeparQuinto study. Intratumoral lymphocytes (iTuLy), stromal lymphocytes (strLy) as well as lymphocyte-predominant breast cancer (LPBC) were evaluated by histopathological assessment. Pathological complete response (pCR) rates were analyzed and compared between the defined subgroups using the exact test of Fisher.
Results
Patients with lymphocyte-predominant breast cancer (LPBC) had a significantly increased pCR rate of 36.6%, compared to non-LPBC patients (14.3%, p<0.001). LPBC and stromal lymphocytes were significantly independent predictors for pCR in multivariate analysis (LPBC: OR 2.7, p = 0.003, strLy: OR 1.2, p = 0.01). The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate (OR 1.2, p = 0.01) but not in multivariate logistic regression analysis (OR 1.2, p = 0.11).
Conclusion
Confirming previous investigations of our group, we have prospectively validated in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT. Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates. The lymphocytic infiltrate is a promising additional parameter for histopathological evaluation of breast cancer core biopsies.
doi:10.1371/journal.pone.0079775
PMCID: PMC3846472  PMID: 24312450
9.  Present Status of Adjuvant Chemotherapy for Elderly Breast Cancer Patients 
Breast Care  2012;7(6):439-444.
Summary
Elderly breast cancer patients are underrepresented in clinical trials, leading to a lack of knowledge regarding their tolerance of modern chemotherapy regimens. In addition, physicians are often reluctant to treat older patients with chemotherapy due to potential side effects. This article summarizes the up-to-date literature on chemotherapy in elderly patients with breast cancer, evaluates the impact of the patients’ comorbidities and treatment alterations and aims to encourage treating patients adequately according to their disease in combination with the biological age rather than the chronological age alone. Finally, a short overview is given of the recruiting studies in Europe evaluating chemotherapy in elderly patients.
doi:10.1159/000345867
PMCID: PMC3971796  PMID: 24715824
Adjuvant chemotherapy; Elderly patients; Breast cancer
10.  Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 
Annals of Oncology  2013;24(9):2206-2223.
The 13th St Gallen International Breast Cancer Conference (2013) Expert Panel reviewed and endorsed substantial new evidence on aspects of the local and regional therapies for early breast cancer, supporting less extensive surgery to the axilla and shorter durations of radiation therapy. It refined its earlier approach to the classification and management of luminal disease in the absence of amplification or overexpression of the Human Epidermal growth factor Receptor 2 (HER2) oncogene, while retaining essentially unchanged recommendations for the systemic adjuvant therapy of HER2-positive and ‘triple-negative’ disease. The Panel again accepted that conventional clinico-pathological factors provided a surrogate subtype classification, while noting that in those areas of the world where multi-gene molecular assays are readily available many clinicians prefer to base chemotherapy decisions for patients with luminal disease on these genomic results rather than the surrogate subtype definitions. Several multi-gene molecular assays were recognized as providing accurate and reproducible prognostic information, and in some cases prediction of response to chemotherapy. Cost and availability preclude their application in many environments at the present time. Broad treatment recommendations are presented. Such recommendations do not imply that each Panel member agrees: indeed, among more than 100 questions, only one (trastuzumab duration) commanded 100% agreement. The various recommendations in fact carried differing degrees of support, as reflected in the nuanced wording of the text below and in the votes recorded in supplementary Appendix S1, available at Annals of Oncology online. Detailed decisions on treatment will as always involve clinical consideration of disease extent, host factors, patient preferences and social and economic constraints.
doi:10.1093/annonc/mdt303
PMCID: PMC3755334  PMID: 23917950
surgery; radiation therapy; systemic adjuvant therapies; early breast cancer; St Gallen Consensus; subtypes
11.  Being Pregnant and Diagnosed with Breast Cancer 
Breast Care  2012;7(3):204-209.
Breast cancer during pregnancy (BCP) is an important subgroup within the young and very young breast cancer patients. It accounts for about 1% of all breast cancers. Due to an increased awareness, the attitude towards breast cancer during pregnancy has changed and, today, women with BCP are more likely to receive standard chemotherapy and have a term delivery instead of being advised to interrupt the pregnancy or undergo an early preterm delivery. This increased knowledge is based on small cohort studies and international collaborations such as the registry by the German Breast Group for BCP and the initiative of the European Society of Gynaecological Oncology (ESGO). Guidelines and recommendations such as the German guidelines by the AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, www.ago-online.org) and the National Comprehensive Cancer Network (NCCN) guidelines include recommendations for BCP. In general, surgery and chemotherapy (beyond the 13th week of gestation) can be safely performed during pregnancy. Chemotherapy should follow the treatment recommendations for breast cancer in young women. Trastuzumab, endocrine treatment, and radiotherapy are not indicated during pregnancy. Preterm delivery should be avoided as far as possible because it bears a higher risk of infant morbidity and mortality. The treatment of BCP should be planned within a multidisciplinary team including perinatologists, obstetricians and neonatologists.
doi:10.1159/000339674
PMCID: PMC3409382  PMID: 22872793
Breast cancer; Pregnancy; Chemotherapy; Guidelines
12.  Metabolomics of human breast cancer: new approaches for tumor typing and biomarker discovery 
Genome Medicine  2012;4(4):37.
Breast cancer is the most common cancer in women worldwide, and the development of new technologies for better understanding of the molecular changes involved in breast cancer progression is essential. Metabolic changes precede overt phenotypic changes, because cellular regulation ultimately affects the use of small-molecule substrates for cell division, growth or environmental changes such as hypoxia. Differences in metabolism between normal cells and cancer cells have been identified. Because small alterations in enzyme concentrations or activities can cause large changes in overall metabolite levels, the metabolome can be regarded as the amplified output of a biological system. The metabolome coverage in human breast cancer tissues can be maximized by combining different technologies for metabolic profiling. Researchers are investigating alterations in the steady state concentrations of metabolites that reflect amplified changes in genetic control of metabolism. Metabolomic results can be used to classify breast cancer on the basis of tumor biology, to identify new prognostic and predictive markers and to discover new targets for future therapeutic interventions. Here, we examine recent results, including those from the European FP7 project METAcancer consortium, that show that integrated metabolomic analyses can provide information on the stage, subtype and grade of breast tumors and give mechanistic insights. We predict an intensified use of metabolomic screens in clinical and preclinical studies focusing on the onset and progression of tumor development.
doi:10.1186/gm336
PMCID: PMC3446265  PMID: 22546809
breast cancer; metabolomics; lipidomics; biomarker analysis
13.  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
14.  Bevacizumab Treatment for Advanced Breast Cancer 
The Oncologist  2011;16(12):1684-1697.
The most promising breast cancer studies using bevacizumab combined with traditional cytotoxic agents in advanced breast cancer are outlined. The current indications for bevacizumab reviewed by the Oncologic Drug Advisory Committee are discussed and how benefit in patient clinical trials should be measured is proposed.
Significant advances in the treatment of patients with breast cancer have been made in the past 10 years. The current systemic treatment of breast cancer is characterized by the discovery of multiple cancer targets leading to treatments that are more sophisticated and specific than conventional cytotoxic chemotherapy. Two classes of compounds that have helped improve clinical outcomes are small molecules and monoclonal antibodies targeting specific tyrosine kinase receptors. Many novel targets have been discovered, and parallel multiple approaches to anticancer therapy have recently emerged from the literature. One promising strategy is targeting the proangiogenic vascular endothelial growth factors (VEGFs), either by ligand sequestration (preventing VEGF receptor binding) or inhibiting downstream receptor signaling. Bevacizumab, a monoclonal antibody directed against VEGF, has been shown to improve the efficacy of taxanes in frontline treatment of patients with metastatic breast cancer. This review outlines the most promising breast cancer studies using bevacizumab combined with traditional cytotoxic agents in advanced breast cancer. In addition, we discuss the current indications reviewed by the Oncologic Drug Advisory Committee and define our vision of how the benefit of patient clinical trials should be measured.
doi:10.1634/theoncologist.2011-0113
PMCID: PMC3248767  PMID: 21976315
Antiangiogenesis; Advanced breast cancer; Bevacizumab; FDA
15.  Multicenter Phase II Study with Weekly Bendamustine and Paclitaxel as First- or Later-Line Therapy in Patients with Metastatic Breast Cancer: RiTa II Trial 
Breast Care  2011;6(6):457-461.
The combination of bendamustine (B) and paclitaxel (P) as anthracycline-free treatment option in patients with advanced breast cancer has been evaluated in the previous RiTa I trial. The regimen of weekly B 70 mg/m2 and P 90 mg/m2 with a pause every 4th week was established as an effective regimen with low toxicity. The aim of the present RiTa II study was to investigate the potential of BP as anthracycline-free combination therapy. The primary objective was to determine the progression-free survival (PFS); secondary endpoints were safety, tolerability, overall response rate (ORR) and overall survival (OS). 26 patients were available, 15 received BP as first-line, 11 as beyond first-line treatment. 27% patients had triple-negative breast cancer (TNBC). Median PFS and OS were 7.3 months (95% confidence interval (CI): 5.5–10.9) and 14.9 months (95% CI: 9.9–22.9), respectively. The 1-year PFS rate was 20.3% and the 1-year OS rate 71.2%. The ORR was 42.3%, including 4 complete and 7 partial remissions. TNBC patients reached an ORR of 71.4%. Anthracycline-pretreated patients showed an ORR of 43.8%, confirming bendamustine's lack of cross-resistance to anthracycline agents. BP represents a favorable option with moderate toxicity in pretreated metastatic breast cancer and offers a possibility for application in anthracycline-pretreated and TNBC patients.
doi:10.1159/000335199
PMCID: PMC3290015  PMID: 22419900
Bendamustine; Paclitaxel; Breast cancer, metastatic; Efficacy; Combination therapy; First-line chemotherapy
16.  Can We Keep the ‘PROMISE’? AGO Breast Commission: Commentary on Recent Evidence Regarding LHRH Analogues for the Preservation of Ovarian Function 
Breast Care  2011;6(6):467-470.
Recently reported data from the German ZORO trial and the Italian PROMISE-GIM6 trial have come to different conclusions. The AGO Breast Commission does not recommend the general use of luteinizing hormone-releasing hormone (LHRH) analogues for the preservation of ovarian function. Instead, we distinguish between patients with hormone receptor-negative and hormone receptor-positive disease. This article reviews the AGO recommendations in light of the ZORO and PROMISE-GIM6 data. In conclusion, separate recommendations are needed for the prevention of ovarian failure and for fertility preservation because the trials did not investigate fertility rate as a primary outcome measure. The results from not yet published trials such as OPTION and POEM may shed new light on the role of LHRH analogues.
doi:10.1159/000335477
PMCID: PMC3290029  PMID: 22419902
LHRH; Ovarian function preservation; Fertility preservation; Chemotherapy; Breast cancer
17.  Neutrophil Gelatinase-Associated Lipocalin (NGAL) Predicts Response to Neoadjuvant Chemotherapy and Clinical Outcome in Primary Human Breast Cancer 
PLoS ONE  2012;7(10):e45826.
In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.
doi:10.1371/journal.pone.0045826
PMCID: PMC3467272  PMID: 23056218
18.  Prediction of Response to Neoadjuvant Chemotherapy: New Biomarker Approaches and Concepts 
Breast Care  2011;6(4):265-272.
Summary
About 10-25% of breast cancer patients achieve a pathologically confirmed complete response after neoadjuvant chemotherapy. Tissue samples of pretreatment core biopsies are a valuable resource for translational research aiming towards predictive biomarkers for selecting patients who are likely to benefit from neoadjuvant therapy. The German Breast Group (GBG) and the AGO-B Group (AGO = Working Group Gynecological Oncology) have extensive experience in conducting neoadjuvant clinical trials. Technologies as immunohistochemistry on tissue microarrays and standardized reverse transcription-polymerase chain reaction (RT-PCR) approaches on formalin-fixed paraffin-embedded samples allow high-throughput investigation of protein and mRNA biomarkers. With these approaches, we could demonstrate that molecular tumor subtypes and immunological infiltrates are valuable and independent predictors of therapy response. New biomarkers such as poly(ADPribose) polymerase (PARP) might be useful for the prediction of response to conventional and new targeted therapies. This review summarizes current research projects focusing on biomarker discovery in the neoadjuvant setting.
doi:10.1159/000331696
PMCID: PMC3225210  PMID: 22135624
Neoadjuvant; Chemotherapy; Breast cancer Lymphocytes; PARP
19.  Re-Challenging Taxanes in Recurrent Breast Cancer in Patients Treated with (Neo-)Adjuvant Taxane-Based Therapy 
Breast Care  2011;6(4):279-283.
Summary
Background: Docetaxel and paclitaxel are among the most active substances for the treatment of breast cancer. As both drugs are used today in adjuvant regimens, efficacy data from pivotal trials in the metastatic setting in taxane-naive populations cannot reliably be used as references. Patients and Methods: The Taxane Re-Challenge Cohort Study identified participants from 6 prospective (neo-)adjuvant taxane-based studies with recurrent disease and collected data on their subsequent treatment. Out of 381 recurrent patients, 106 (27.8%) were re-challenged with a taxane-based treatment as first- or later-line therapy for recurrent disease. Results: Taxanes were used as first-line therapy in 74 patients and showed a response rate of 48.6% (including complete responses in 27.0%). The response rate was dependent on the disease-free interval (<1 year: 34.8%; 1-2 years: 42.9%; >2 years: 63.3%; p = 0.04) and visceral metastasis (present: 62.5%; not present 32.4%; p = 0.01). Patients without visceral metastasis and with a disease-free interval of >2 years achieved the longest overall survival. Hormone and HER2 receptor status were not predictive; however, triple-negative tumors responded in 50.0%. The overall response rate of later-line taxane-based treatment was 28.2%. Conclusion: Re-challenging taxanes appears to be effective and therefore represents a reasonable option in this population.
doi:10.1159/000330946
PMCID: PMC3225212  PMID: 22164126
Docetaxel; Paclitaxel; Adjuvant; Recurrent breast cancer
20.  Opinions on the ASCO 2011 Annual Meeting 
Breast Care  2011;6(4):315-319.
doi:10.1159/000331171
PMCID: PMC3225217  PMID: 22164128
21.  Evaluating the impact of Relative Total Dose Intensity (RTDI) on patients' short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer- a pooled analysis 
BMC Cancer  2011;11:131.
Background
Chemotherapy dose delay and/or reduction lower relative total dose intensity (RTDI) and may affect short- and long-term outcome of metastatic breast cancer (MBC) patients.
Methods
Based on 933 individual patients' data of from 3 randomized MBC trials using an anthracycline and taxane we examined the impact of RTDI on efficacy and determined the lowest optimal RTDI for MBC patients.
Results
Median time to disease progression (TTDP) and overall survival (OS) of all patients were 39 and 98 weeks. Overall higher RTDI was correlated with a shorter TTDP (log-rank p = 0.0525 for 85% RTDI cut-off). Proportional hazards assumption was violated, there was an early drop in the TTDP-curve for the high RTDI group. It was explained by the fact that patients with primary disease progression (PDP) do have a high RTDI per definition. Excluding those 114 patients with PDP the negative correlation between RTDI and TTDP vanished. However, non-PDP patients with RTDI-cut-off levels <85% showed a shorter OS than patients with higher RTDI levels (p = 0.0086).
Conclusions
Optimizing RTDI above 85% appears to improve long-term outcome of MBC patients receiving first-line chemotherapy. Lowering RTDI had no negative influence on short term outcome like OR and TTDP.
doi:10.1186/1471-2407-11-131
PMCID: PMC3083375  PMID: 21486442
22.  Identification of biology-based breast cancer types with distinct predictive and prognostic features: role of steroid hormone and HER2 receptor expression in patients treated with neoadjuvant anthracycline/taxane-based chemotherapy 
Introduction
Reliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable breast cancer to test for associations with pathological complete response (pCR) and disease-free survival (DFS). Particularly, we evaluated if interactions between hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression might lead to a different clinical behavior of HR+/HER2+ co-expressing and HR+/HER2- tumors and whether subgroups of triple negative tumors might be identified by the help of Ki67 labeling index, cytokeratin 5/6 (CK5/6), as well as cyclooxygenase-2 (COX-2), and Y-box binding protein 1 (YB-1) expression.
Methods
Expression analysis was performed using immunohistochemistry and silver-enhanced in situ hybridization on tissue microarrays (TMAs) of pretherapeutic core biopsies.
Results
pCR rates were significantly different between the biology-based tumor types (P = 0.044) with HR+/HER2+ and HR-/HER2- tumors having higher pCR rates than HR+/HER2- tumors. Ki67 labeling index, confirmed as significant predictor of pCR in the whole cohort (P = 0.001), identified HR-/HER- (triple negative) carcinomas with a higher chance for a pCR (P = 0.006). Biology-based tumor type (P = 0.046 for HR+/HER2+ vs. HR+/HER2-), Ki67 labeling index (P = 0.028), and treatment arm (P = 0.036) were independent predictors of pCR in a multivariate model. DFS was different in the biology-based tumor types (P < 0.0001) with HR+/HER2- and HR+/HER2+ tumors having the best prognosis and HR-/HER2+ tumors showing the worst outcome. Biology-based tumor type was an independent prognostic factor for DFS in multivariate analysis (P < 0.001).
Conclusions
Our data demonstrate that a biology-based breast cancer classification using estrogen receptor (ER), progesterone receptor (PgR), and HER2 bears independent predictive and prognostic potential. The HR+/HER2+ co-expressing carcinomas emerged as a group of tumors with a good response rate to neoadjuvant chemotherapy and a favorable prognosis. HR+/HER2- tumors had a good prognosis irrespective of a pCR, whereas patients with HR-/HER- and HR-/HER+ tumors, especially if they had not achieved a pCR, had an unfavorable prognosis and are in need of additional treatment options.
Trial registration
ClinicalTrials.gov identifier: NCT00793377
doi:10.1186/bcr2363
PMCID: PMC2790846  PMID: 19758440
23.  Bendamustine in Metastatic Breast Cancer: An Old Drug in New Design  
Breast Care  2008;3(5):333-339.
The goal of treatment for patients with advanced breast cancer is to prolong survival, control symptoms, and reduce disease-related complications. Despite the introduction of many cytotoxic agents during the past decade, only modest improvement in survival in metastatic breast cancer has been achieved. In order to improve this situation, new cytotoxic drugs as well as molecule-targeted agents are now under investigation. Bendamustine is a bifunctional alkylating agent with cytotoxic activity against several types of solid tumors. In the search for new anthracycline-free combinations, taxanes and alkylating agents might be worth investigating, in order to reduce cardiac toxicity. In this article, we reviewed the latest information regarding antitumor activity, toxicity, pharmacokinetics, and clinical application of bendamustine as a cytotoxic agent in metastatic breast cancer.
doi:10.1159/000154105
PMCID: PMC2931105  PMID: 20824028
Bendamustine; First-line chemotherapy; Metastatic breast cancer
24.  Clinical feasibility of (neo)adjuvant taxane-based chemotherapy in older patients: analysis of >4,500 patients from four German randomized breast cancer trials 
Introduction
Despite the fact that people older than 65 years of age have the highest incidence of developing breast cancer, these patients are excluded from clinical trials in most cases. Furthermore, most physicians tend towards therapy regimens without the use of dose-dense, highly active taxane-based treatments because of a lack of data regarding toxicities of these compounds in older patients.
Methods
Pooled side-effect data were analyzed from four prospective, randomized clinical trials in which patients of different age groups (< 60 years, between 60 and 64 years, and > 64 years) with primary breast cancer received taxane-based chemotherapy.
Results
Dose delays, dose reductions, hospitalization, and therapy discontinuation increased with age. Hematologic toxicities and some nonhematologic toxicities were generally more common in older patients. Leucopenia increased from 55.3% in patients aged < 60 years to 65.5% in patients aged > 64 years (P < 0.001), and neutropenia increased from 46.9% to 57.4% (P < 0.001). There was no difference, however, in clinically more relevant febrile neutropenia between the different age groups. Thrombopenia shows a similar age-dependent increase, whereas there is no difference between the age groups concerning anemia. Hot flushes and elevated liver enzymes decreased with increasing age.
Conclusions
The present pooled analysis of a substantial cohort of older primary breast cancer patients demonstrates that taxane-containing (neo)adjuvant chemotherapy is feasible in older patients and that toxicity can be reduced by sequential therapy regimens.
doi:10.1186/bcr2144
PMCID: PMC2614510  PMID: 18796139
25.  New Therapeutic Options for Breast Cancer during Pregnancy 
Breast Care  2008;3(3):171-176.
Summary
National and international guidelines for pregnant breast cancer patients recommend to treat pregnant patients as closely as possible to the standards for non-pregnant patients. Therefore, new treatment options like sentinel lymph node biopsy or taxane-based chemotherapy have to be carefully checked for their possible implementation even for pregnant patients. These patients need to be treated in a breast cancer center where a multidisciplinary team is ready to support the patient and her family and to serve her with the best up-to-date treatment for mother and child.
doi:10.1159/000136002
PMCID: PMC2931113  PMID: 20824035
Breast cancer; Pregnancy; Chemotherapy; Radiation

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