Michael Gnant

Medical University of Vienna, Wien, Vienna, Austria

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Publications (261)1766.41 Total impact

  • Guenther G Steger · Michael Gnant · Rupert Bartsch
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    ABSTRACT: Introduction Breast cancer is a heterogeneous disease comprising different biological subtypes. In two thirds of tumours, expression of steroid-receptors is present, allowing for targeted treatment with endocrine therapy. In metastatic breast cancer, sequential administration of different non-cross resistant drugs offers a chance to delay cytotoxic chemotherapy. Activity of endocrine therapy, however, decreases with time as indicated by a shorter progression-free survival interval with every further treatment line, suggesting onset of resistance. Current research therefore focuses on prevention or delay of resistance by combining endocrine therapy with other targeted treatment approaches such as small-molecule pathway-inhibitors. Indeed, combining the steroidal aromatase-inhibitor exemestane with the mTor-inhibitor everolimus doubles activity of endocrine therapy in a pretreated population albeit at the price of increased toxicity. Data from several clinical trials suggest that inhibitors of the cycline-dependent kinases (CDK) 4 and 6 are able to delay or reverse resistance to endocrine therapy as well, while tolerability may be superior. Areas Covered This review provides a summary of clinical data on CDK 4/6 inhibitors, summarizes the biological rational for their use and provides an outlook to future developments in this field. A systematic literature search was performed in order to identify publications concerning the use of CDK 4/6 inhibitors in breast cancer. The search included original research articles, abstracts from major conferences and reviews published from 2005 to 2015 and was limited to English-language publications. Expert opinion Based upon available data regarding activity and tolerability, it is believed that CDK 4/6 inhibitors will evolve to become a valuable addition to the therapeutic options in metastatic breast cancer.
    No preview · Article · Dec 2015 · Expert Opinion on Pharmacotherapy
  • Nadia Harbeck · Michael Gnant · Christoph Thomssen

    No preview · Article · Dec 2015 · Breast Care
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    ABSTRACT: Randomized trials have studied bisphosphonates in the adjuvant setting of early breast cancer to investigate their ability to prevent treatment-induced bone loss. Trial results have also suggested their potential to prevent disease recurrence and metastases. These trials are summarized in this review. A recent patient-level meta-analysis by the Early Breast Cancer Trials Collaborative Group (EBCTCG) finds convincing evidence that adjuvant antiresorptive treatments provide persistent benefits to breast cancer patients in low-estrogen situations and should be considered an important part of the treatment algorithm. Expected final online publication date for the Annual Review of Medicine Volume 67 is January 14, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    No preview · Article · Aug 2015 · Annual review of medicine
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    ABSTRACT: Background: The four intrinsic subtypes of breast cancer, defined by differential expression of 50 genes (PAM50), have been shown to be predictive of risk of recurrence and benefit of hormonal therapy and chemotherapy. Here we describe the development of Prosigna™, a PAM50-based subtype classifier and risk model on the NanoString nCounter Dx Analysis System intended for decentralized testing in clinical laboratories. Methods: 514 formalin-fixed, paraffin-embedded (FFPE) breast cancer patient samples were used to train prototypical centroids for each of the intrinsic subtypes of breast cancer on the NanoString platform. Hierarchical cluster analysis of gene expression data was used to identify the prototypical centroids defined in previous PAM50 algorithm training exercises. 304 FFPE patient samples from a well annotated clinical cohort in the absence of adjuvant systemic therapy were then used to train a subtype-based risk model (i.e. Prosigna ROR score). 232 samples from a tamoxifen-treated patient cohort were used to verify the prognostic accuracy of the algorithm prior to initiating clinical validation studies. Results: The gene expression profiles of each of the four Prosigna subtype centroids were consistent with those previously published using the PCR-based PAM50 method. Similar to previously published classifiers, tumor samples classified as Luminal A by Prosigna had the best prognosis compared to samples classified as one of the three higher-risk tumor subtypes. The Prosigna Risk of Recurrence (ROR) score model was verified to be significantly associated with prognosis as a continuous variable and to add significant information over both commonly available IHC markers and Adjuvant! Online. Conclusions: The results from the training and verification data sets show that the FDA-cleared and CE marked Prosigna test provides an accurate estimate of the risk of distant recurrence in hormone receptor positive breast cancer and is also capable of identifying a tumor's intrinsic subtype that is consistent with the previously published PCR-based PAM50 assay. Subsequent analytical and clinical validation studies confirm the clinical accuracy and technical precision of the Prosigna PAM50 assay in a decentralized setting.
    Full-text · Article · Aug 2015 · BMC Medical Genomics
  • Rupert Bartsch · Michael Gnant · Guenther G Steger

    No preview · Article · Aug 2015 · The Lancet Oncology
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    ABSTRACT: Neoadjuvant chemotherapy (NACT) is an accepted treatment approach in early-stage breast cancer. In contrast, the potential role of postneoadjuvant chemotherapy after taxane-containing NACT remains unclear. The aim of this study was to evaluate postneoadjuvant chemotherapy and further prognostic factors that predict outcome in women without pathologic complete remission (pCR). A total of 377 patients with breast cancer who received preoperative chemotherapy were included in this retrospective study. Patients without standard NACT (6 cycles of epirubicin with docetaxel) or primary metastatic breast cancer and locally advanced, inoperable cancer were excluded from further analysis (n = 186). This resulted in a study population of 191 women (30 [15.7%] with pCR; 161 [84.3%] without pCR). Major outcome parameters were event-free survival (EFS) and overall survival (OS). The following parameters were tested for their prognostic role: postneoadjuvant chemotherapy, patient age, breast cancer subtype (luminal/HER2-negative tumors, HER2-positive tumors, and triple-negative tumors), histological grade, pCR, residual lymph node invasion, and residual invasive tumor size. At a median follow-up of 54 months, 51 disease relapses (26.7%) and 21 deaths (11%) were observed. In a comparison of patients with pCR with those without, no significant differences in EFS or OS were observed. Postneoadjuvant chemotherapy was significantly associated with shorter OS in patients without pCR. In this population, which included a high percentage of patients with luminal cancers, pCR did not predict for improved OS. Postneoadjuvant chemotherapy showed no discernible benefit even in subgroups with aggressive tumor biology or significant remaining tumor burden. The use of such treatment should therefore be discouraged outside of clinical trials. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Clinical Breast Cancer
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    ABSTRACT: Breast International Group (BIG) 2-98 is a randomised phase III trial that tested the effect of adding docetaxel, either in sequence to or in combination with anthracycline-based adjuvant chemotherapy, in women with node-positive breast cancer (BC). Here, we present the 10-year final trial safety and efficacy analyses. We also report an exploratory analysis on the predictive value of Ki67 for docetaxel efficacy, in the BIG 2-98 and using a pooled analysis of three other randomised trials. 2887 patients were randomly assigned in a 2×2 trial design to one of four treatments. The primary objective was to evaluate the overall efficacy of docetaxel on disease free survival (DFS). Secondary objectives included comparisons of sequential docetaxel versus sequential control arm, safety and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry. After a median follow-up of 10.1years, the addition of docetaxel did not significantly improve DFS or OS (hazard ratio (HR)=0.91, 95% confidence interval (CI)=0.81-1.04; P=0.16 and HR=0.88, 95% CI=0.76-1.03; P=0.11, respectively). Sequential docetaxel did not improve DFS compared to the sequential control arm (HR=0.86, 95% CI=0.72-1.03; P=0.10). In oestrogen receptor (ER)-positive tumours with Ki67⩾14%, the addition of docetaxel resulted in 5.4% improvement in 10-year OS (P=0.03, test for interaction=0.1). In a multivariate model, there was a trend for improved DFS and OS in ER-positive patients with high Ki67 and treated with docetaxel (HR=0.79, 95% CI=0.63-1.01; P=0.05 and HR=0.76, 95% CI=0.57-1.01; P=0.06, respectively). A pooled analysis of four randomised trials showed a benefit of taxanes in highly proliferative ER-positive disease but not in low proliferating tumours (interaction test P=0.01). The DFS benefit previously demonstrated with sequential docetaxel is no longer observed at 10years. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly proliferative ER-positive BC. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · European journal of cancer (Oxford, England: 1990)
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    ABSTRACT: We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344–3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.
    Full-text · Article · Jun 2015 · EBioMedicine
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    ABSTRACT: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. Amgen. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · May 2015 · The Lancet
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    Michael Gnant · Christoph Thomssen · Nadia Harbeck
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    ABSTRACT: The 2015 St. Gallen Consensus Conference on early breast cancer took place in Vienna, Austria, for the first time. After 3 days of high-level presentations by international panel members of clinical trials having been reported recently in the field, the traditional Saturday voting tried to translate the assembled knowledge into clinical treatment recommendations intended to guide clinical practice of breast cancer care for the 'average' patient. This report summarizes the results of the 2015 international panel voting procedures with respect to locoregional and endocrine treatment, chemotherapy, targeted therapy, as well as adjuvant bisphosphonate use. This report is not aimed to replace the official St. Gallen consensus publication - some recommendations may even be altered in the final paper - but should serve as a preliminary rapid report of this important meeting.
    Full-text · Article · May 2015 · Breast Care
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    ABSTRACT: Brain metastases (BM) are frequently diagnosed in metastatic Her2-positive breast cancer. Local treatment remains the standard of care but lapatinib plus capecitabine was recently established as systemic therapy option. Due to a disruption of the blood-brain/tumour-barrier at metastatic sites, even large molecules may penetrate into the central nervous system (CNS). Here, we report on the activity of T-DM1 in Her2-positive breast cancer BM. T-DM1 was administered at a dose of 3.6 mg once every 3 weeks as primary systemic therapy for BM or upon documented CNS progression after initial local treatment. Thus, this study allowed for the appraisal of T-DM1 activity in BM. Restaging was conducted every 12 weeks with MRI or whenever symptoms of disease progression occurred. Ten patients were included; in two asymptomatic subjects, T-DM1 was administered as primary therapy, while eight had progressive BM. All patients had received prior treatment with trastuzumab, six had already received lapatinib, and three pertuzumab as well. Three patients had partial remission of BM, and two patient had stable disease lasting for ≥6 months; two further patients had stable disease for <6 months while three progressed despite treatment. At 8.5 months median follow-up, intracranial PFS was 5 months, and median OS from initiation of T-DM1 was not reached. Local treatment of BM remains the standard of care; lapatinib plus capecitabine is currently the best established systemic therapy option. Still, T-DM1 apparently offers relevant clinical activity in BM and further investigation is warranted.
    No preview · Article · May 2015 · Cancer Research

  • No preview · Article · May 2015 · Cancer Research

  • No preview · Article · May 2015 · Cancer Research

  • No preview · Article · May 2015 · Cancer Research
  • Michael Gnant

    No preview · Article · Mar 2015 · The Breast
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    ABSTRACT: ABSTRACT Aim: To determine the impact of educational materials (EMs) on the treatment compliance of postmenopausal women with hormone receptor-positive (HR(+)) early-stage breast cancer. Patients (n = 2757) were randomized to standard aromatase inhibitors (AI) alone (group A) or with EMs (group B) in a global, real-world setting. The 2-year results (n = 2242) showed EMs had no impact on compliance (82 vs 82%, group A vs B), compliance with initial AI (82 vs 81%) or persistence (90 vs 88%), confirming the 1-year interim analysis (n = 2567). Of the 2082 patients considered compliant at 1 year, 77% remained compliant at 2 years. Discontinuations (9%) were mainly attributed to AI-related side effects (68% of discontinuations). Exploratory analyses suggest a relationship between patient characteristics and compliance behaviors. EMs do not improve compliance in this patient population. Compliance and persistence are complex end points influenced by multiple variables. Side effects were the main reasons for discontinuations.
    Full-text · Article · Jan 2015 · Future Oncology
  • Michael Gnant · Guenther G Steger · Rupert Bartsch

    No preview · Article · Dec 2014 · The Lancet Oncology
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    ABSTRACT: OT1-1-01; http://www.abstracts2view.com/sabcs14/view.php?nu=SABCS13L_108
    Full-text · Conference Paper · Dec 2014
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    ABSTRACT: Background: Estrogen-receptor (ER) positive breast cancer co-expresses androgen receptor (AR) in 75% to 95% of cases. The Austrian Breast & Colorectal Cancer Study Group (ABCSG) trial 12 compared anastrozole plus goserelin with tamoxifen plus goserelin in premenopausal patients with hormone receptor positive early breast cancer. In addition, patients were randomized to receive zoledronic acid or not. The aim of this analysis was to investigate the effect of AR expression on outcome in dependency of the treatment arm. Patients and methods: AR expression was analyzed by immunohistochemistry using a mouse monoclonal antibody (Novocastra) in formalin-fixed paraffin-embedded specimens from 194 early breast cancer patients treated within the ABCSG 12 trial at our institution. As there is no generally accepted cut-off level defining AR positivity, we used two definitions for this analysis: A) positive staining of ≥ 10% of tumor cells B) an immune reactive score (IRS; intensity of staining X percentage of stained cells) ≥ 3 according to the Remmele score used for ER/PR evaluation. Results: A total of 194 patients were included in this analysis. In tissue samples collected before 2001 AR staining was very weak, interpreted as a loss of antigenicity due to archival time and conditions. Therefore, 40 patients with tissue samples achieved earlier than 2001 were excluded from further analysis. Seventy-nine percent (122 of 154) and 63% (97 of 154) of tumors were AR positive by definition A and B, respectively. All except one of the AR positive tumors according to definition B, were also positive according to definition A. Disease free survival (DFS) and overall survival (OS) data: N (%) DFS OS Definition A (≥ 10%) AR positive 122 (79) HR 0.61 (0.21-1.72) P=0.3428 HR 0.17 (0.03-0.99) P=0.025 AR negative 32 (21) Definition B (IRS ≥ 3) AR positive 97 (63) HR 0.88 (0.33-2.35) P=0.7994 HR 0.39 (0.07-2.34) P=0.2846 AR negative 57 (37) DFS and OS did not differ between both endocrine treatment arms in a Cox regression model tested for interaction between AR expression and endocrine treatment. Conclusion: In this pilot study patients with AR positive disease had a numerically better DFS and OS compared to AR negative patients, but only prolongation of OS in patients with ≥ 10% AR positive tumor cells was statistically significant. AR expression did not influence outcome between tamoxifen and anastrozole treated patients, but based on the small number of events, this results have to be interpreted with caution. This data will be confirmed in a larger proportion of patients treated within the ABCSG-12 trial.
    No preview · Conference Paper · Dec 2014
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    ABSTRACT: 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. 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. 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. 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. 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.
    Full-text · Article · Nov 2014 · PharmacoEconomics

Publication Stats

9k Citations
1,766.41 Total Impact Points

Institutions

  • 2002-2015
    • Medical University of Vienna
      • Comprehensive Cancer Center Vienna
      Wien, Vienna, Austria
  • 2013
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2012
    • University of Toronto
      Toronto, Ontario, Canada
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2005-2011
    • Vienna General Hospital
      Wien, Vienna, Austria
  • 1990-2011
    • University of Vienna
      • • Department of Surgery
      • • Clinic for Internal Medicine I
      Wien, Vienna, Austria
  • 2007
    • Paracelsus Medical University Salzburg
      Salzburg, Salzburg, Austria
    • Hanusch Krankenhaus
      Wien, Vienna, Austria
  • 1999
    • Technische Universität München
      München, Bavaria, Germany
    • National Cancer Institute (USA)
      • Surgery Branch
      Bethesda, MD, United States
    • National Institutes of Health
      • Section on Human Iron Metabolism
      베서스다, Maryland, United States