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1.  I-SPY 2: optimising cancer drug development in the 21st century 
ESMO Open  2016;1(5):e000113.
PMCID: PMC5115814  PMID: 27900209
Breast Cancer; I-SPY2
2.  Prognostic value of HMGB1 in early breast cancer patients under neoadjuvant chemotherapy 
Cancer Medicine  2016;5(9):2350-2358.
The response to neoadjuvant chemotherapy in breast cancer patients is usually assessed by pCR and RCB score. However, the prognostic value of these parameters is still in discussion. We showed recently that an epirubicin/docetaxel therapy is associated with an increase in the cell death marker high‐mobility group box 1 protein (HMGB1) in the circulation. Here, we investigate whether this increase correlates with the long‐term outcome. Thirty‐six early breast cancer patients under neoadjuvant epirubicin/docetaxel combination chemotherapy were included in this study. To determine the immediate effect of this treatment on HMGB1, we collected blood samples before and 24–96 h after the initial dose. This time course was then compared to the 5‐year follow‐up of the patients. HMGB1 levels varied before chemotherapy between 4.1 and 11.3 ng/mL and reacted differently in response to therapy. Some patients showed an increase while others did not show any changes. Therefore, we subdivided the patient collective into two groups: patients with an at least 1.1 ng/mL increase in HMGB1 and patients with smaller changes. The disease‐free survival was longer in the HMGB1 increase group (56.2 months vs. 46.6 months), but this difference did not reach significance. The overall survival (OS) was significantly better in patients with an increase in HMGB1 (log rank P = 0.021). These data suggest that an immediate increase in HMGB1 levels correlates with improved outcome in early breast cancer patients receiving neoadjuvant chemotherapy, and may be a valuable complementary biomarker for early estimation of prognosis.
PMCID: PMC5055166  PMID: 27457217
Breast cancer; chemotherapy; high‐mobility group box 1 protein; immunogenic cell death; prognostic marker
3.  The European Society for Medical Oncology Magnitude of Clinical Benefit Scale in daily practice: a single institution, real-life experience at the Medical University of Vienna 
ESMO Open  2016;1(4):e000066.
The European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) has been designed to stratify the therapeutic benefit of a certain drug registered for the treatment of cancer. However, though internally validated, this tool has not yet been evaluated for its feasibility in the daily practice of a major center of medical oncology.
The practicability of the MCBS for advanced oncological diseases at the Clinical Division of Oncology, Medical University of Vienna, which constitutes one of the largest oncological centres in Europe, was analysed in a three-step approach. First, retrospectively collected data were analysed to gain an overview of treatments in regular use. Second, data were scored by using the MCBS. Third, the ensuing results were evaluated within corresponding programme directorships to assess feasibility in a real-life clinical context.
In the majority of tumour entities, the MCBS results reported earlier are consistent with daily clinical practice. Thus, in metastatic breast cancer or advanced lung cancer, there was a high level of clinical benefit for first-line treatment standards, and these results reflected well real-life experience. However, analyses based on the first version of the MCBS are limited if it comes to salvage treatment in tumour entities in which optimal sequencing of potential treatment options is of major importance, as in metastatic colorectal or renal cell cancer. In contrast to this, it is remarkable that certain novel therapies such as nivolumab assessed for heavily pretreated advanced renal cancer reached the highest level of clinical benefit due to prolongation in survival and a favourable toxicity profile. The MCBS clearly underlines the potential benefit of these compounds.
The MCBS is an excellent tool for daily clinical practice of a tertiary referral centre. It supports treatment decisions based on the clinical benefit to be expected from a novel approach such as immunotherapy in as yet untested indications.
PMCID: PMC5070236  PMID: 27843624
ESMO-MCBS; quality control; clinical benefit; metastatic disease
4.  Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases 
Oncoimmunology  2015;5(1):e1057388.
The immune microenvironment of the brain differs from that of other organs and the role of tumor-infiltrating lymphocytes (TILs) in brain metastases (BM), one of the most common and devastating complication of cancer, is unclear. We investigated TIL subsets and their prognostic impact in 116 BM specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1. The Immunoscore was calculated as published previously. Overall, we found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density (p > 0.05). TIL density was not associated with corticosteroid administration (p > 0.05). A significant difference in infiltration density according to TIL subtype was present (p < 0.001; Chi Square); high infiltration was most frequently observed for CD3+ TILs (95/116; 81.9%) and least frequently for PD1+ TILs (18/116; 15.5%; p < 0.001). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). The density of CD8+ TILs correlated positively with the extent of peritumoral edema seen on pre-operative magnetic resonance imaging (p = 0.031). The density of CD3+ (15 vs. 6 mo; p = 0.015), CD8+ (15 vs. 11 mo; p = 0.030) and CD45RO+ TILs (18 vs. 8 mo; p = 0.006) showed a positive correlation with favorable median OS times. Immunoscore showed significant correlation with survival prognosis (27 vs. 10 mo; p < 0.001). The prognostic impact of Immunoscore was independent from established prognostic parameters at multivariable analysis (HR 0.612, p < 0.001). In conclusion, our data indicate that dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and survival prognosis, thus identifying the immune system as potential biomarker for cancer patients with CNS affection. Further studies are needed to substantiate our findings.
PMCID: PMC4760339  PMID: 26942067
brain metastases; immunoscore; overall survival; prognosis; tumor infiltrating lymphocytes
5.  Recent developments and translational aspects in targeted therapy for metastatic breast cancer 
ESMO Open  2016;1(3):e000036.
Biologically distinct subtypes of metastatic breast cancer (MBC) have been defined by multiple efforts in recent years, showing broad heterogeneity at the molecular level of disease. Throughout this endeavour, oncogenic drivers within MBC were identified as potential therapeutic targets. With recent results from clinical trials targeting these well-known cancer-promoting pathways, this review is trying to elucidate as well as summarise current new therapeutic aspects in MBC and shed light on translational aspects within this entity.
PMCID: PMC5070263  PMID: 27843605
Metastatic Breast Cancer; Breast Cancer; Breast; Targeted Therapy; Translational Cancer Research
6.  Descriptive statistical analysis of a real life cohort of 2419 patients with brain metastases of solid cancers 
ESMO Open  2016;1(2):e000024.
We provide a descriptive statistical analysis of baseline characteristics and the clinical course of a large real-life cohort of brain metastases (BM) patients.
We performed a retrospective chart review for patients treated for BM of solid cancers at the Medical University of Vienna between 1990 and 2011.
We identified a total of 2419 BM patients (50.5% male, 49.5% female, median age 59 years). The primary tumour was lung cancer in 43.2%, breast cancer in 15.7%, melanoma in 16.4%, renal cell carcinoma in 9.1%, colorectal cancer in 9.3% and unknown in 1.4% of cases. Rare tumour types associated with BM included genitourinary cancers (4.1%), sarcomas (0.7%). gastro-oesophageal cancer (0.6%) and head and neck cancers (0.2%). 48.7% of patients presented with a singular BM, 27.7% with 2–3 and 23.5% with >3 BM. Time from primary tumour to BM diagnosis was shortest in lung cancer (median 11 months; range 1–162) and longest in breast cancer (median 44 months; 1–443; p<0.001). Multiple BM were most frequent in breast cancer (30.6%) and least frequent in colorectal cancer (8.5%; p<0.001). Patients with breast cancer had the longest median overall survival times (8 months), followed by patients with lung cancer (7 months), renal cell carcinoma (7 months), melanoma (5 months) and colorectal cancer (4 months; p<0.001; log rank test). Recursive partitioning analysis and graded prognostic assessment scores showed significant correlation with overall survival (both p<0.001, log rank test). Evaluation of the disease status in the past 2 months prior to patient death showed intracranial progression in 35.9%, extracranial progression in 27.5% and combined extracranial and intracranial progression in 36.6% of patients.
Our data highlight the heterogeneity in presentation and clinical course of BM patients in the everyday clinical setting and may be useful for rational planning of clinical studies.
PMCID: PMC5070252  PMID: 27843591
brain metastases; prognosis; disease status in end of life period; descriptive analysis
7.  Phase II study on the efficacy and safety of Lapatinib administered beyond disease progression and combined with vinorelbine in HER-2/neu– positive advanced breast cancer: results of the CECOG LaVie trial 
BMC Cancer  2016;16:121.
Vinorelbine constitutes effective chemotherapy for metastatic breast cancer (MBC) and acts synergistically with trastuzumab in HER-2/neu positive disease. The present study was set out to evaluate the efficacy and safety of vinorelbine when combined with lapatinib, an anti-HER2 tyrosine-kinase inhibitor, as late-line regimen administered beyond previous disease progression on prior lapatinib in patients with HER-2/neu- positive MBC.
The CECOG LaVie study was designed as open-labeled, single-arm, multicenter phase II trial. Patients had to be pretreated with lapatinib plus chemotherapy, and received lapatinib at a daily dose of 1250 mg in combination with vinorelbine 20 mg/m2 i.v. on days 1 and 8 of a three-week cycle until disease progression, intolerable toxicity or withdrawal of consent. Progression-free survival (PFS) was defined as primary study endpoint; secondary endpoints included overall survival (OS), response rate according to RECIST 1.1, and safety. The study was terminated early due to poor accrual.
A total number of nine patients were included; lapatinib administered beyond disease progression combined with vinorelbine resulted in a median PFS of 7.7 months (95 % CI 0.56-14.91) and a median OS of 23.4 months (95 % CI 16.61–30.13), respectively. Partial remission was seen in one of nine patients, three patients had stable disease of > six months, whereas the remaining five patients had primary disease progression. In two patients, modification of vinorelbine dose due to toxicity became necessary; no dose modification was needed for lapatinib. The majority of reported adverse events (AE) were grade 1 and 2 in severity with diarrhea being the most commonly observed AE
In this heavily pretreated patient population, combination of vinorelbine plus lapatinib showed encouraging activity and was characterized by an acceptable safety profile. Despite the low patient number, lapatinib plus vinorelbine may constitute a potential treatment option in heavily pretreated patients with HER-2/neu-positive MBC previously exposed to lapatinib.
Trial registration
EudraCT number 2009-016826-15, (15. 10.2009)
PMCID: PMC4758093  PMID: 26887956
Metastatic Breast Cancer; HER-2/neu; Lapatinib; Vinorelbine; Chemotherapy
8.  Taxanes Plus Trastuzumab Compared To Oral Vinorelbine Plus Trastuzumab in HER2-Overexpressing Metastatic Breast Cancer 
Breast Care  2014;9(5):344-348.
This retrospective analysis was planned as a direct comparison of taxanes plus trastuzumab to the less toxic combination of oral vinorelbine (OV) plus trastuzumab as a first-line therapy for metastatic HER2-positive breast cancer.
Patients and Methods
Patients (n = 76) receiving either taxanes (group A) or OV (group B) in combination with trastuzumab were identified from a breast cancer database. Progression-free survival (PFS) was defined as the primary study endpoint; secondary endpoints were overall survival (OS), response rate (RR), incidence of brain metastases, and brain metastases-free survival (BMFS).
36 patients received taxanes and 40 patients OV in combination with trastuzumab. At a median follow-up of 47.5 months, median PFS was 7 months (group A) and 9 months in group B (log-rank; non-significant), respective numbers for OS were 49 and 59 months (p = 0.033). The incidence of brain metastases did not differ significantly between the 2 treatment groups, whereas BMFS was significantly longer in patients receiving OV.
OV plus trastuzumab yielded similar results in terms of PFS and RR and was superior in terms of OS and BMFS. These results add to the growing body of evidence that vinorelbine is a viable alternative to taxanes in HER2-positive metastatic breast cancer.
PMCID: PMC4322687  PMID: 25759615
Brain metastases; Metastatic breast cancer; HER2-positive breast cancer; Oral vinorelbine; Taxanes; Trastuzumab
9.  Optimal Sequencing of Anti-HER2 Therapy 
Breast Care  2014;9(2):138-140.
PMCID: PMC4038308  PMID: 24944559
10.  Alleviation of Brain Edema and Restoration of Functional Independence by Bevacizumab in Brain-Metastatic Breast Cancer: A Case Report 
Breast Care  2014;9(2):134-136.
Brain metastases (BM) are an increasing challenge in modern oncology, as treatment options especially after exhaustion of local treatment approaches are very limited.
Patient and Methods
A long-term surviving patient with brain-only metastatic breast cancer, who presented at our department with massive corticosteroid-refractory brain edema with serious neurological symptoms after exhaustion of all local therapy options, was started on bevacizumab.
Initiation of bevacizumab monotherapy led to rapid decrease of contrast-enhancing lesions and alleviation of brain edema, and allowed tapering and termination of corticosteroid administration. Neurological and neurocognitive function was restored and marked improvement in quality of life was observed.
Our case highlights that bevacizumab may represent a feasible and effective salvage treatment option in selected patients with BM.
PMCID: PMC4038309  PMID: 24944558
Breast cancer; Brain metastases; Neurocognitive functioning; Bevacizumab; Symptom control; Brain edema
11.  Invasion patterns in brain metastases of solid cancers 
Neuro-Oncology  2013;15(12):1664-1672.
Brain metastases are generally considered to be well demarcated from the surrounding brain parenchyma, although infiltrative growth patterns have been observed. We systemically investigated infiltration patterns and expression of adhesion molecules in a large and well-defined series of autopsy cases of brain metastases.
Ninety-seven autopsy specimens from 57 brain metastasis patients (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 2 colorectal cancer, 1 kidney cancer, and 13 other) were evaluated for patterns of invasion into surrounding brain parenchyma. Expression of integrins αv; cytoplasmic β3, αvβ3, αvβ5, αvβ6, and αvβ8; and of E and N cadherin were evaluated using immunohistochemistry.
Three main invasion patterns were seen: well-demarcated growth (29/57, 51%), vascular co-option (10/57, 18%), and diffuse infiltration (18/57, 32%). There was no statistically significant association of invasion pattern with primary tumor type, although vascular co-option was most common in melanoma brain metastases (4/10). Invasion patterns of different brain metastases of the same patient were highly concordant (P < .001, chi-square test). Distance of infiltration from the main tumor mass ranged from 12.5 µm to 450 µm (median 56.2 µm) and was not significantly different between the vascular co-option and the diffuse infiltration groups. Levels of αvβ6 were significantly higher in the well-demarcated group than in the vascular co-option and the diffuse infiltration groups (P = .033, Kruskal-Wallis test). Expression of αvβ5 in tumor cells was higher in brain metastasis lesions previously treated with stereotactic radiosurgery (P = .034, chi-square test).
Distinct invasion patterns of brain metastases into the brain parenchyma are not specific for primary tumor types, seem to be influenced by expression of αv integrin complexes, and may help to guide clinical decision-making.
PMCID: PMC3829586  PMID: 24084410
adhesion molecules; brain metastases; cadherin; integrin; invasion
12.  Indocyanine Green Video Angiography Predicts Outcome of Extravasation Injuries 
PLoS ONE  2014;9(8):e103649.
Extravasation of cytotoxic drugs is a serious complication of systemic cancer treatment. Still, a reliable method for early assessment of tissue damage and outcome prediction is missing. Here, we demonstrate that the evaluation of blood flow by indocyanine green (ICG) angiography in the extravasation area predicts for the need of surgical intervention.
Twenty-nine patients were evaluated by ICG angiography after extravasation of vesicant or highly irritant cytotoxic drugs administered by peripheral i.v. infusion. Tissue perfusion as assessed by this standardized method was correlated with clinical outcome.
The perfusion index at the site of extravasation differed significantly between patients with reversible tissue damage and thus healing under conservative management (N = 22) versus those who needed surgical intervention due to the development of necrosis (N = 7; P = 0.0001). Furthermore, in patients benefiting from conservative management, the perfusion index was significantly higher in the central extravasation area denoting hyperemia, when compared with the peripheral area (P = 0.0001).
In this patient cohort, ICG angiography as indicator of local perfusion within the extravasation area was of prognostic value for tissue damage. ICG angiography could thus be used for the early identification of patients at risk for irreversible tissue damage after extravasation of cytotoxic drugs.
PMCID: PMC4140719  PMID: 25144707
13.  Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients 
Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena.
We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).
ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells.
The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This finding supports the application of trastuzumab at any stage of the disease.
PMCID: PMC4029549  PMID: 24330813
ADCC; ADCP; HER2/neu; Breast cancer; Trastuzumab
14.  Influence of the American ODAC Statement on Austrian Bevacizumab Prescribing Practice for Metastatic Breast Cancer 
The Oncologist  2012;17(7):e13-e17.
The influence of the discrepancy between the Oncologic Drugs Advisory Committee (ODAC) and European Medicines Agency positions on bevacizumab prescribing practice for metastatic breast cancer in Austria during January 2006 to June 2011 was investigated. The Austrian bevacizumab prescribing practice was found to be significantly influenced by the ODAC statement issued in July 2010.
Results of trial E2100 led to the accelerated approval of bevacizumab as first-line therapy for patients with metastatic breast cancer (MBC) in the U.S. in February 2008. Based on results from subsequent trials, the U.S. Food and Drug Administration Oncologic Drugs Advisory Committee (ODAC) issued a statement proposing to withdraw the license for bevacizumab in July 2010, whereas bevacizumab approval for MBC was not withdrawn in Europe.
In this nationwide survey, we investigated the influence of the discrepancy between the ODAC and European Medicines Agency (EMA) positions on the prescription practice of bevacizumab for MBC in Austria during the period January 2006 to June 2011.
The absolute number of bevacizumab administrations for MBC patients per month in all Austrian hospitals within the mentioned time frame was retrieved from a comprehensive national database. Bevacizumab prescription numbers for other malignancies were retrieved in order to rule out that a change in bevacizumab prescribing practice might reflect general changes in Austrian health care policy.
A steady increase in bevacizumab use was seen from January 2006 to June 2010 (42 versus 1,357 administrations per month) for MBC. Thereafter, a significant decline in bevacizumab prescriptions for MBC became evident, with numbers dropping to 842 in March 2011 and 662 in June 2011. Bevacizumab prescriptions showed only minor variations in control cohorts.
The Austrian bevacizumab prescribing practice in MBC patients was significantly influenced by the ODAC statement issued in July 2010, whereas the EMA position was accepted to a lesser degree.
PMCID: PMC3399659  PMID: 22744818
Bevacizumab; Breast cancer; EMA; FDA; Oncologic Drugs Advisory Committee; Prescription Practice
15.  Challenges in managing breast cancer during pregnancy 
Journal of Thoracic Disease  2013;5(Suppl 1):S62-S67.
Pregnancy-associated breast cancer (PABC) is defined as breast cancer occurring anytime during gestation, lactation or within one year after delivery. The optimal management of pregnant women with breast cancer is challenging and not well established; the main concern is the effect of the drugs on the developing fetus and long-term complications after in utero exposure to anti-cancer drugs. Surgical resection is the mainstay of treatment for early breast cancer diagnosed during pregnancy. Modified radical mastectomy is standard of care in first trimester, whereas breast-conserving surgery (lumpectomy with lymph node dissection) can be performed preferably in the second and third trimester. Of note, breast-conserving surgery is not contraindicated per se during the first trimester, but owing to the potential impact of delaying radiotherapy. Radiation therapy is not favored during pregnancy. Moreover, tamoxifen is contraindicated during pregnancy; the agent has been associated with birth defects in up to 20% of exposures. Chemotherapy is generally contraindicated during the first trimester because of the possible damage to organogenesis. Anthracyclines-based regimens are the most widely used is breast cancer treatment and were been shown to be associated with favourable safety profile when administered during pregnancy. As for taxanes, more limited data is available. The use of trastuzumab is contraindicated during pregnancy, given the apparent risk of oligo- and/or anhydramnios as well as the unknown long-term sequelae on the fetus. It is obvious that, diagnosis of breast cancer during pregnancy adds complexity to cancer treatment recommendations. In all cases, a multidisciplinary therapeutic approach among obstetricians, gynaecologists, surgical oncologists, radiation oncologists, medical oncologists, pediatricians and hematologists is clearly warranted.
PMCID: PMC3695539  PMID: 23819029
Breast cancer; pregnancy; controversies; chemotherapy
16.  Trends and Novel Approaches in Neoadjuvant Treatment of Breast Cancer 
Breast Care  2011;6(6):427-433.
Breast cancer is the most prevalent malignant disease in women worldwide. Traditionally, surgical tumour resection was the primary step within the treatment algorithm of early stage disease; systemic therapy in order to reduce the rate of systemic recurrences followed. National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-18 found that pre- and postoperative administration of chemotherapy was equally effective. This study therefore established neoadjuvant chemotherapy as a valid treatment option, as the breast conservation rate is increased. Modern neoadjuvant regimens encompassing anthracyclines and taxanes yield pathological complete response (pCR) rates of around 20%, with higher efficacy observed in triple-negative tumours. The antibody trastuzumab is the first targeted agent established in neoadjuvant regimens for the treatment of Her2-positive breast cancer, as it raised pCR rates up to 50%. Novel approaches are aiming to increase the efficacy of neoadjuvant therapy. Inclusion of capecitabine might further increase pCR rates in selected patients, although data are not unanimous throughout the respective clinical trials. In patients harbouring BRCA-1 germline mutations, platinum derivatives are apparently promising. Novel Her2-targeted agents such as lapatinib and pertuzumab are currently under investigation in several clinical trials, while the role of bevacizumab, a monoclonal antibody inhibiting angiogenesis, awaits future clarification.
PMCID: PMC3290012  PMID: 22419895
Breast cancer; Chemotherapy; Neoadjuvant therapy; Targeted therapy
17.  Opinions on the ASCO 2011 Annual Meeting 
Breast Care  2011;6(4):315-319.
PMCID: PMC3225217  PMID: 22164128
18.  Breast Cancer: Rank Ligand Inhibition 
Breast Care  2010;5(5):320-325.
Breast cancer and bone health are closely linked. Early menopause induced by gonadotropin-releasing hormone analogues or chemotherapy as well as aromatase inhibitors reduce oestrogen levels, thereby causing cancer treatment-induced bone loss (CTIBL). Furthermore, bone metastases are commonly found in advanced disease. Current treatment options for bone lesions comprise systemic anti-tumour therapy, irradiation, surgery and bisphosphonates. The main mechanism of osteolysis, osteoclast activation, is induced by the RANK ligand and suppressed by osteoprotegerin (OPG). A human antibody targeting the RANK ligand, denosumab, had superior activity compared to OPG and was therefore further developed in the clinical setting. This article reviews clinical data on denosumab. Data were obtained by searching the Medline database and abstracts from the ASCO annual meeting, ASCO breast meeting, ECCO, ESMO, and the San Antonio Breast Cancer Symposium. Clinical trials have demonstrated that denosumab reduces markers of bone turnover, and suggest equal efficacy to bisphosphonates in reducing the rate of skeletal-related events. While overall fewer side effects were observed, a numerically increased rate of osteonecrosis of the jaw was reported. Denosumab was well tolerated, and clinical activity was similar to bisphosphonates in metastatic disease. Trials of denosumab in the prevention of CTIBL are ongoing.
PMCID: PMC3132956  PMID: 21779214
Bisphosphonates; Bone metastases; Denosumab; Osteoporosis; Cancer treatment-induced bone loss
19.  Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion 
Introduction: Denosumab, a fully human monoclonal antibody, targets the receptor activator of nuclear factor-kappaB (RANK) ligand, a protein essential for osteoclast differentiation, activity and survival. Loss of osteoclasts from the bone surface reduces bone turnover and bone loss in malignant and benign diseases. In breast cancer, bone metastases are frequently observed; cancer treatment-induced bone loss (CTIBL) may result as a consequence of endocrine treatment or chemotherapy. Furthermore, preclinical studies suggest a direct role of the RANK/RANK-ligand pathway in breast tumorigenesis. This paper reviews preclinical and clinical data on denosumab in breast cancer.
Materials and methods: Studies were identified through the Medline database. Key search terms included: AMG-162, bisphosphonates, denosumab, RANK-ligand and zoledronic acid. Information available in abstract form only was retrieved from major oncology meetings, such as the American Society of Clinical Oncology (ASCO) annual meeting, ASCO breast meeting, European Cancer Organization, European Society of Medical Oncology and the San Antonio Breast Cancer Symposium.
Results: Denosumab was consistently well tolerated throughout clinical trials, although the observed incidence of osteonecrosis of the jaw was comparable to that with bisphosphonates. Efficacy as determined by a reduction of skeletal-related events was at least equal to zoledronic acid, and superior in one phase III study conducted in patients with metastatic breast cancer. Clinical trials investigating the role of denosumab for the prevention of CTIBL and breast cancer recurrences are currently ongoing.
Conclusion: In conclusion, denosumab appears to be an effective and safe treatment option in patients with bone metastases from breast cancer with the potential of also preventing CTIBL.
PMCID: PMC3169928  PMID: 21957430
bisphosphonates; bone metastases; cancer treatment-induced bone loss; denosumab; osteoporosis; receptor activator of nuclear factor-kappaB
20.  Single-agent pegylated liposomal doxorubicin (PLD) in the treatment of metastatic breast cancer: results of an Austrian observational trial 
BMC Cancer  2011;11:373.
In advanced breast cancer, multiple sequential lines of treatments are frequently applied. Pegylated liposomal doxorubicin (PLD) has a favourable toxicity profile and can be used in first or higher lines of therapy. PLD has demonstrated response activity even after prior anthracycline exposure.
129 consecutive patients with advanced breast cancer, of whom the majority had been massively pretreated, received PLD as monotherapy within licensed approval, for which efficacy and toxicities were documented.
In a routine therapy setting, PLD was administered in a slightly reduced dose (median, 40 mg/m2 per cycle). Response rate (complete and partial remission) was 26%, and stable disease was observed in 19% of patients. Progression-free (PFS) and overall survival (OS) were 5.8 months and 14.2 months, respectively. There was no difference in terms of response and PFS, no matter if patients had already received anthracycline treatment. Interestingly, PFS proved similar regardless whether PLD was administered as palliative therapy in first, second or third line. Furthermore, PFS and OS were similar in patients with response or stable disease, underscoring the view that disease stabilization is associated with a profound clinical benefit. The most common side effects reported were palmar-plantar erythrodysesthesia (17%), exanthema (14%) and mucositis (12%).
Efficacy and toxicity data in these "real life" patients permit the conclusion that PLD is a valuable option in the treatment of advanced breast cancer even in heavily pretreated patients.
PMCID: PMC3178544  PMID: 21864402
21.  Capecitabine and Vinorelbine as an All-Oral Chemotherapy in HER2-Negative Locally Advanced and Metastatic Breast Cancer 
Breast Care  2010;5(3):158-162.
The oral formulation of vinorelbine together with capecitabine allows for an all-oral combination chemotherapy which promises to raise quality of life of patients with advanced breast cancer.
Patients and Methods
Patients with HER2-negative, locally advanced, inoperable or metastatic breast cancer were included in this prospective observational trial (treatment schedule: capecitabine 500 mg/m2 twice daily, days 1-14; vinorelbine 60 mg/m2, days 1+8; repeated in 3-week cycles).
All 32 patients (median age 50 years) were evaluable for toxicity, and 30 patients for response. Twentyfour patients received therapy as first-line treatment, and 8 patients as beyond first-line treatment. Median time to progression was 8 months, and median overall survival was 32 months. Complete response was observed in 1 patient (3%), partial response in 10 patients (33%), and disease stabilization for more than 6 months (SD > 6) in 10 patients (33%). This results in an overall response rate (ORR) of 37% and a clinical benefit rate (ORR + SD > 6) of 70%. The only grade 3/4 toxicities were neutropenia (19%) and hand-foot syndrome (9%).
The all-oral combination of capecitabine/vinorelbine at this schedule appears to be an effective, well-tolerated regimen for treatment of advanced breast cancer, and offers a promising alternative to single-agent capecitabine and vinorelbine as well as intravenous polychemotherapy.
PMCID: PMC2931054  PMID: 21048830
Capecitabine; Vinorelbine; Combination therapy; Breast cancer, advanced
22.  The Role of Supportive Therapy in the Era of Modern Adjuvant Treatment – Current and Future Tools 
Breast Care  2009;4(3):167-176.
Recent advances in adjuvant treatment of breast cancer have improved progression-free and overall survival. Optimal management of treatment-induced side effects has therefore gained further importance. This review cannot provide a comprehensive overview of treatment-related toxicity and its management, but focuses on important new developments in the field of supportive therapy. Erythropoietins, while highly effective in treating chemotherapy-induced anaemia, may have detrimental effects on outcome, and should only be used with the aim to reduce the number of whole blood transfusions. Granulocyte colony-stimulating factors were a prerequisite for development of dose-dense regimens, and are also necessary in many anthracycline/taxane combination regimens. A potential tumour-stimulating effect was not proven in solid cancers. For side effects of conventional chemotherapy, such as mucositis, nausea, or diarrhoea, regularly updated guidelines may improve symptom control. Overall, modern supportive treatment tools will further reduce treatment-related mortality and help increase quality of life.
PMCID: PMC2931004  PMID: 20847876
Adjuvant treatment; Breast cancer; Growth factors; Side effects; Supportive care
23.  Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer 
BMC Cancer  2009;9:367.
In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression). Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy.
Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP) on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS) were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression) were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. p values < 0.05 were considered to indicate statistical significance.
Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26), and 8 months (95% CI 6.25-9.74) on first-line, respectively (n.s.). In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter.
Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.
PMCID: PMC2770076  PMID: 19835621
24.  Expression of thymidine phosphorylase in peripheral blood cells of breast cancer patients is not increased by paclitaxel 
A synergistic cytotoxic effect has been hypothesized for taxanes and capecitabine, a prodrug of 5-fluorouracil. Based on preclinical studies, this synergism has been attributed to an up-regulation of the enzyme thymidine phosphorylase (TP). Beside tumour tissue, TP is highly expressed in white blood cells, possibly causing increased hematotoxicity, when taxanes are combined with capecitabine. So far, this hypothesis has not been investigated in humans.
A total of 128 consecutive blood samples were collected from eight patients with advanced breast cancer receiving paclitaxel weekly at a dose of 80 mg/m2. To assess the expression of TP in blood cells, samples were collected prior to first therapy, at the end of infusion, and up to 15 days thereafter. This procedure was repeated during the sixth application of paclitaxel. After isolation of the peripheral mononuclear blood cells, the expression of TP was assessed by ELISA. In parallel, paclitaxel level in plasma was evaluated at three selected time points as pharmacokinetic control parameter.
Paclitaxel concentrations at the end of infusion did not change significantly from week 1 to week 6. The expression of TP in peripheral mononuclear blood cells decreased significantly after infusion below pretherapeutic values (p = 0.023; n = 8). After the nadir on day 3, the expression of TP increased moderately returning to baseline levels within one week. The overall picture in week 6 was similar to week 1. Using a trend analysis, neither a short-term nor a long-term induction of TP was observed.
TP in peripheral mononuclear blood cells was hardly regulated under therapy with paclitaxel. Therefore, no increased haematotoxicity due to TP upregulation is expected from the combination of taxanes and capecitabine.
PMCID: PMC1939983  PMID: 17640356
25.  Trastuzumab in the management of early and advanced stage breast cancer 
Biologics : Targets & Therapy  2007;1(1):19-31.
Trastuzumab is a monoclonal humanized antibody that has revolutionized the treatment of patients with Her2-positive breast cancer. Already well established in advanced stage disease, the substance was recently introduced in the adjuvant setting, reducing disease recurrences by more than 50% and mortality by approximately one third. Trastuzumab is a rationally designed substance which binds to cancer cells expressing the targeted antigen, and, by different mechanisms, causes tumor cell degradation. However, only one third of patients have an initial response to trastuzumab therapy, and the majority of initial responders demonstrate disease progression within 1 year of treatment initiation. It is therefore necessary to gain further insight into mechanisms of resistance, and develop ways to overcome those. In this article, the role of trastuzumab in early and advanced stage breast cancer is reviewed. We discuss current understandings of the specific tumor biology of Her2-positive breast cancer, and review the mechanism of action of trastuzumab. Further, we try to highlight possible mechanisms of resistance.
PMCID: PMC2721347  PMID: 19707345
Her2-positive breast cancer; monoclonal antibodies; trastuzumab

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