Publications by authors named "Zsuzsanna Bago-Horvath"

63 Publications

Intra-Tumour Heterogeneity Is One of the Main Sources of Inter-Observer Variation in Scoring Stromal Tumour Infiltrating Lymphocytes in Triple Negative Breast Cancer.

Cancers (Basel) 2021 Aug 31;13(17). Epub 2021 Aug 31.

Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland.

Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring. Twenty-three breast pathologists scored sTILs in digitized slides of 49 TNBC biopsies using the scoring aid. Subsequently, fields of view (FOV) from each case were selected by one pathologist and scored by the group using the tool. Inter-observer agreement was good for absolute sTILs (ICC 0.634, 95% CI 0.539-0.735, < 0.001) but was poor to fair using binary cutpoints. sTILs heterogeneity was the main contributor to disagreement. When pathologists scored the same FOV from each case, inter-observer agreement was excellent for absolute sTILs (ICC 0.798, 95% CI 0.727-0.864, < 0.001) and good for the 20% (ICC 0.657, 95% CI 0.561-0.756, < 0.001) and 40% (ICC 0.644, 95% CI 0.546-0.745, < 0.001) cutpoints. However, there was a wide range of scores for many cases. Reproducibility scoring sTILs is good when the scoring aid is used. Heterogeneity is the main contributor to variance and will need to be overcome for analytic validity to be achieved.
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http://dx.doi.org/10.3390/cancers13174410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431498PMC
August 2021

The OncoMasTR Test Predicts Distant Recurrence in Estrogen Receptor-Positive, HER2-Negative Early-Stage Breast Cancer: A Validation Study in ABCSG Trial 8.

Clin Cancer Res 2021 Aug 11. Epub 2021 Aug 11.

St. Anna Breast Center, Hirslanden Klinik St. Anna, Lucerne, Switzerland.

Purpose: To validate the clinical performance of the OncoMasTR Risk Score in the biomarker cohort of Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8.

Experimental Design: We evaluated the OncoMasTR test in 1,200 formalin-fixed, paraffin-embedded (FFPE) surgical specimens from postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer with 0 to 3 involved lymph nodes in the prospective, randomized ABCSG Trial 8. Time to distant recurrence (DR) was analyzed by Cox models.

Results: The OncoMasTR Risk Score categorized 850 of 1,087 (78.2%) evaluable patients as "low risk". At 10 years, the DR rate for patients in the low-risk group was 5.8% versus 21.1% for patients in the high-risk group ( < 0.0001, absolute risk reduction 15.3%). The OncoMasTR Risk Score was highly prognostic for prediction of DR in years 0 to 10 in all patients [HR 1.91, 95% confidence interval (CI) 1.62-2.26, < 0.0001; C-index 0.73], in patients that were node negative (HR 1.79, 95% CI, 1.43-2.24, < 0.0001; C-index 0.72), and in patients with 1 to 3 involved lymph nodes (HR 1.93, 95% CI, 1.44-2.58, < 0.0001; C-index 0.71). The OncoMasTR Risk Score provided significant additional prognostic information beyond clinical parameters, Ki67, Nottingham Prognostic Index, and Clinical Treatment Score.

Conclusions: OncoMasTR Risk Score is highly prognostic for DR in postmenopausal women with ER-positive, HER2-negative primary breast cancer with 0 to 3 involved lymph nodes. In combination with prior validation studies, this fully independent validation in ABCSG Trial 8 provides level 1B evidence for the prognostic capability of the OncoMasTR Risk Score.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1023DOI Listing
August 2021

Correlation Between Preoperative Radiological and Postoperative Pathological Tumor Size in Patients With HER2 Breast Cancer After Neoadjuvant Chemotherapy Plus Trastuzumab and Pertuzumab.

Clin Breast Cancer 2021 Jun 10. Epub 2021 Jun 10.

Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, Austria. Electronic address:

Background: Neoadjuvant chemotherapy (NAC) in combination with anti-HER2 treatment is standard of care in patients with early HER2 positive breast cancer. Preoperative radiological evaluation is mandatory for defining the extent of surgery. In this study, we evaluated the correlation between preoperative radiological and postoperative pathological tumor size in early HER2 positive patients after neoadjuvant chemotherapy in combination with trastuzumab and pertuzumab. In a patient population with HER2 positive breast cancer, who received neoadjuvant chemotherapy and anti-HER2 treatment, the correlation between preoperative radiological and postoperative pathological tumor size was performed. Concordance of radiological and pathological tumor size was found in 55.7%, leading to more extensive breast surgery as required in 7 cases and to the underestimation of 6 neoplastic lesions before surgery, respectively.

Patients And Methods: Seventy early HER2 positive breast cancer patients were included and retrospectively analysed. All preoperative radiological assessments as well as the tumor board decision on surgical extent and pathological evaluation were completed at the Medical University of Vienna. Preoperative radiological assessment of tumor size and lymph node status were compared with final histopathological findings. The correlation between different radiological modalities regarding tumor size was investigated.

Results: Concordance of radiological and pathological tumor size was found in 55.7 % (50% by sonography and 66.7% by MRI, respectively) of patients with a nonsignificant correlation of r = 0.31 (P = .08). Of the 39 patients with pathologic complete remission (pCR), 16 were also classified as radiological complete response (rCR) while 23 of those showed a radiological stable disease or partial response. In 6 patients, radiological assessment showed a CR but invasive cancer with a tumor size range from 7 to 36 mm was found in histopathological examination. Neither menopausal status (P= .69) nor BMI (P = .60) and age (P = .50) had an impact on the correlation between radiological and histopathological tumor size. Regarding lymph node status, a statistically significant association and clinically relevant correlation between radiological and histopathological evaluation was found (r = 0.66, P < .001).

Conclusion: Concordance between radiology and histopathology was low regarding tumor size after NAC in combination with trastuzumab and pertuzumab, but significant regarding lymph node status.
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http://dx.doi.org/10.1016/j.clbc.2021.05.017DOI Listing
June 2021

Androgen Receptor is Expressed in Breast Cancer Brain Metastases.

Appl Immunohistochem Mol Morphol 2021 Jun 14. Epub 2021 Jun 14.

Department of Medicine I, Division of Oncology Departments of Neurosurgery Pathology Surgery Radiooncology, Medical University of Vienna, Vienna, Austria.

Background: Androgen receptor (AR) expression is a potential therapeutic target in breast cancer (BC) as it is frequently expressed in the luminal A and B subtypes and in approximately one third of basal-like cancers. As AR-positive BC displays a distinct biological behavior, we aimed to analyze AR expression in the particular context of BC brain metastases (BM).

Materials And Methods: Patients with newly diagnosed BC BM treated with neurosurgical resection were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, biological tumor subtypes and overall survival were obtained by retrospective chart review. Formalin-fixed and paraffin-embedded specimen containing BM tissue were retrieved from the Neuro-Biobank. Immunohistochemical staining of AR was performed and AR expression in the tumor-cell nucleus was evaluated.

Results: Fifty-seven BM samples from 57 individual patients with BC were available for this analysis. AR expression of ≥1% tumor cells was evident in 20/57 (35.1%) BM specimens; the median AR-expression rate was 10% (range: 1% to 60%). AR expression was observed in 11/21 (52.4%) BM of the luminal/human epidermal growth factor receptor 2 (HER2)-negative subtype, 3/13 (23.1%) of the luminal/HER2-positive subtype, 2/7 (28.6%) of the HER2-positive subtype and 4/16 (25.0%) of the triple-negative subtype (P=0.247). Median survival from diagnosis of BM was 10 months (range: 0 to 104 mo) in the entire cohort. No significant association of overall survival and AR expression ≥1% was observed (15 vs. 13 mo; P>0.05).

Conclusion: AR is expressed in more than one third of BC BM with the highest rates among the luminal/HER2-negative BC subtype and may therefore be a potential prognostic and predictive biomarker in this particular BC population.
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http://dx.doi.org/10.1097/PAI.0000000000000952DOI Listing
June 2021

Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab.

Ther Adv Med Oncol 2021 22;13:17588359211009002. Epub 2021 Apr 22.

Division of Oncology, Department of Medicine 1, Medical University of Vienna, Austria.

Background: Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown.

Methods: Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into 'TP', 'other-HER2-targeted therapy' and 'no-HER2-targeted therapy' according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM).

Results: A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 17 3 months,  < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%.

Conclusion: First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.
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http://dx.doi.org/10.1177/17588359211009002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072867PMC
April 2021

Breast Tumor Characterization Using [F]FDG-PET/CT Imaging Combined with Data Preprocessing and Radiomics.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Division of Molecular and Gender Imaging, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria.

: This study investigated the performance of ensemble learning holomic models for the detection of breast cancer, receptor status, proliferation rate, and molecular subtypes from [F]FDG-PET/CT images with and without incorporating data pre-processing algorithms. Additionally, machine learning (ML) models were compared with conventional data analysis using standard uptake value lesion classification. : A cohort of 170 patients with 173 breast cancer tumors (132 malignant, 38 benign) was examined with [F]FDG-PET/CT. Breast tumors were segmented and radiomic features were extracted following the imaging biomarker standardization initiative (IBSI) guidelines combined with optimized feature extraction. Ensemble learning including five supervised ML algorithms was utilized in a 100-fold Monte Carlo (MC) cross-validation scheme. Data pre-processing methods were incorporated prior to machine learning, including outlier and borderline noisy sample detection, feature selection, and class imbalance correction. Feature importance in each model was assessed by calculating feature occurrence by the R-squared method across MC folds. : Cross validation demonstrated high performance of the cancer detection model (80% sensitivity, 78% specificity, 80% accuracy, 0.81 area under the curve (AUC)), and of the triple negative tumor identification model (85% sensitivity, 78% specificity, 82% accuracy, 0.82 AUC). The individual receptor status and luminal A/B subtype models yielded low performance (0.46-0.68 AUC). SUV model yielded 0.76 AUC in cancer detection and 0.70 AUC in predicting triple negative subtype. : Predictive models based on [F]FDG-PET/CT images in combination with advanced data pre-processing steps aid in breast cancer diagnosis and in ML-based prediction of the aggressive triple negative breast cancer subtype.
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http://dx.doi.org/10.3390/cancers13061249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000810PMC
March 2021

Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34.

Br J Cancer 2021 May 24;124(11):1795-1802. Epub 2021 Mar 24.

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.

Background: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences.

Methods: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint.

Results: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation.

Conclusion: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.
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http://dx.doi.org/10.1038/s41416-021-01284-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144560PMC
May 2021

Non-Invasive Assessment of Hypoxia and Neovascularization with MRI for Identification of Aggressive Breast Cancer.

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

Department of Neurosurgery, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.

The aim of this study was to investigate the potential of magnetic resonance imaging (MRI) for a non-invasive synergistic assessment of tumor microenvironment (TME) hypoxia and induced neovascularization for the identification of aggressive breast cancer. Fifty-three female patients with breast cancer underwent multiparametric breast MRI including quantitative blood-oxygen-level-dependent (qBOLD) imaging for hypoxia and vascular architecture mapping for neovascularization. Quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), mitochondrial oxygen tension (mitoPO2), microvessel radius (VSI), microvessel density (MVD), and microvessel type indicator (MTI) were calculated. Histopathology was the standard of reference. Histopathological markers (vascular endothelial growth factor receptor 1 (FLT1), podoplanin, hypoxia-inducible factor 1-alpha (HIF-1alpha), carbonic anhydrase 9 (CA IX), vascular endothelial growth factor C (VEGF-C)) were used to confirm imaging biomarker findings. Univariate and multivariate regression analyses were performed to differentiate less aggressive luminal from aggressive non-luminal (HER2-positive, triple negative) malignancies and assess the interplay between hypoxia and neoangiogenesis markers. Aggressive non-luminal cancers ( = 40) presented with significantly higher MRO2 (i.e., oxygen consumption), lower mitoPO2 values (i.e., hypoxia), lower MTI, and higher MVD than less aggressive cancers ( = 13). Data suggest that a model derived from OEF, mitoPO2, and MVD can predict tumor proliferation rate. This novel MRI approach, which can be easily implemented in routine breast MRI exams, aids in the non-invasive identification of aggressive breast cancer.
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http://dx.doi.org/10.3390/cancers12082024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464174PMC
July 2020

Predictive Value of Molecular Subtypes in Premenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the ABCSG Trial 5.

Clin Cancer Res 2020 11 16;26(21):5682-5688. Epub 2020 Jun 16.

Institute of Cancer Research, Department of Medicine I, Breast Health Center and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy.

Experimental Design: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors.

Results: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: = 0.84 for RFS; = 0.69 for OS).

Conclusions: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0673DOI Listing
November 2020

The EndoPredict score predicts response to neoadjuvant chemotherapy and neoendocrine therapy in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients from the ABCSG-34 trial.

Eur J Cancer 2020 07 2;134:99-106. Epub 2020 Jun 2.

Institute of Cancer Research, Department of Medicine I, Breast Health Center and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: Neoadjuvant chemotherapy (NaCT) and neoadjuvant endocrine therapy (NET) can reduce pre-operative tumour burden in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer. This prospective translational study assessed the ability of a 12-gene molecular score (MS; EndoPredict®) to predict response to NaCT or NET within the ABCSG-34 trial.

Patients And Methods: Hormone receptor (HR)-positive, HER2-negative samples from patients in the ABCSG-34 randomized phase II trial were selected and EndoPredict testing was performed to generate a 12-gene MS. ABCSG-34 patients were assigned to receive either NaCT or NET based on menopausal status, HR expression, grade and Ki67. Response was measured by residual cancer burden (RCB).

Results: Patients selected for NaCT generally had high-risk disease by 12-gene MS (125/134), while slightly more patients treated with NET had low-risk disease (44/83). Low-risk NaCT-treated and high-risk NET-treated tumours responded poorly (NPV 100% [95% CI 66.4%-100%] and NPV 92.3% [95% CI 79.1%-98.4%], respectively]. The 12-gene MS significantly predicted treatment response for NaCT (AUC 0.736 [95% CI 0.63-0.84]) and NET (AUC 0.726 [95% CI 0.60-0.85]).

Conclusions: The 12-gene MS predicted RCB after treatment with neoadjuvant therapies for patients with HR-positive, HER2-negative early-stage breast cancer. Tumours with low MS were unlikely to benefit from NaCT, whereas a high MS predicted resistance to NET. This additional biologic information can aid personalized treatment selection in daily practice and builds a strong rationale to use EndoPredict in biomarker-driven studies in the neoadjuvant setting.
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http://dx.doi.org/10.1016/j.ejca.2020.04.020DOI Listing
July 2020

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.

NPJ Breast Cancer 2020 12;6:16. Epub 2020 May 12.

30Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.
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http://dx.doi.org/10.1038/s41523-020-0154-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217824PMC
May 2020

Factors influencing agreement of breast cancer luminal molecular subtype by Ki67 labeling index between core needle biopsy and surgical resection specimens.

Virchows Arch 2020 Oct 7;477(4):545-555. Epub 2020 May 7.

Department of Pathology and Comprehensive Cancer Center, Medical University of Vienna, 18-20 Waehringer Guertel, A-1090, Vienna, Austria.

Reliable determination of Ki67 labeling index (Ki67-LI) on core needle biopsy (CNB) is essential for determining breast cancer molecular subtype for therapy planning. However, studies on agreement between molecular subtype and Ki67-LI between CNB and surgical resection (SR) specimens are conflicting. The present study analyzed the influence of clinicopathological and sampling-associated factors on agreement. Molecular subtype was determined visually by Ki67-LI in 484 pairs of CNB and SR specimens of invasive estrogen receptor (ER)-positive, human epidermal growth factor (HER2)-negative breast cancer. Luminal B disease was defined by Ki67-LI > 20% in SR. Correlation of molecular subtype agreement with age, menopausal status, CNB method, Breast Imaging Reporting and Data System imaging category, time between biopsies, type of surgery, and pathological tumor parameters was analyzed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. CNB had a sensitivity of 77.95% and a specificity of 80.97% for identifying luminal B tumors in CNB, compared with the final molecular subtype determination after surgery. The correlation of Ki67-LI between CNB and SR was moderate (ROC-AUC 0.8333). Specificity and sensitivity for CNB to correctly define molecular subtype of tumors according to SR were significantly associated with tumor grade, immunohistochemical progesterone receptor (PR) and p53 expression (p < 0.05). Agreement of molecular subtype did not significantly impact RFS and OS (p = 0.22 for both). The identified factors likely mirror intratumoral heterogeneity that might compromise obtaining a representative CNB. Our results challenge the robustness of a single CNB-driven measurement of Ki67-LI to identify luminal B breast cancer of low (G1) or intermediate (G2) grade.
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http://dx.doi.org/10.1007/s00428-020-02818-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508960PMC
October 2020

Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomised, neoadjuvant phase II study (ABCSG 34).

Eur J Cancer 2020 06 20;132:43-52. Epub 2020 Apr 20.

Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients.

Patients And Methods: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life.

Findings: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone.

Interpretation: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.ejca.2020.03.018DOI Listing
June 2020

Feed‑back loops integrating RELA, SOX18 and FAK mediate the break‑down of the lymph‑endothelial barrier that is triggered by 12(S)‑HETE.

Int J Oncol 2020 04 13;56(4):1034-1044. Epub 2020 Feb 13.

Department of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria.

Metastatic cancer cells cross endothelial barriers and travel through the blood or lymphatic fluid to pre‑metastatic niches, leading to their colonisation. 'S' stereoisomer 12S‑hydroxy‑5Z,8Z,10E,14Z‑eicosatetraenoic acid [12(S)‑HETE] is secreted by a variety of cancer cell types and has been indicated to open up these barriers. In the present study, another aspect of the endothelial unlocking mechanism was elucidated. This was achieved by investigating 12(S)‑HETE‑treated lymph endothelial cells (LECs) with regard to their expression and mutual interaction with v‑rel avian reticuloendotheliosis viral oncogene homolog A (RELA), intercellular adhesion molecule 1, SRY‑box transcription factor 18 (SOX18), prospero homeobox 1 (PROX1) and focal adhesion kinase (FAK). These key players of LEC retraction, which is a prerequisite for cancer cell transit into vasculature, were analysed using western blot analysis, reverse transcription‑quantitative PCR and transfection with small interfering (si)RNA. The silencing of a combination of these signalling and executing molecules using siRNA, or pharmacological inhibition with defactinib and Bay11‑7082, extended the mono‑culture experiments to co‑culture settings using HCT116 colon cancer cell spheroids that were placed on top of LEC monolayers to measure their retraction using the validated 'circular chemorepellent‑induced defect' assay. 12(S)‑HETE was indicated to induce the upregulation of the RELA/SOX18 feedback loop causing the subsequent phosphorylation of FAK, which fed back to RELA/SOX18. Therefore, 12(S)‑HETE was demonstrated to be associated with circuits involving RELA, SOX18 and FAK, which transduced signals causing the retraction of LECs. The FAK‑inhibitor defactinib and the NF‑κB inhibitor Bay11‑7082 attenuated LEC retraction additively, which was similar to the suppression of FAK and PROX1 (the target of SOX18) by the transfection of respective siRNAs. FAK is an effector molecule at the distal end of a pro‑metastatic signalling cascade. Therefore, targeting the endothelial‑specific activity of FAK through the pathway demonstrated herein may provide a potential therapeutic method to combat cancer dissemination via vascular routes.
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http://dx.doi.org/10.3892/ijo.2020.4985DOI Listing
April 2020

Prediction of Distant Recurrence Using EndoPredict Among Women with ER, HER2 Node-Positive and Node-Negative Breast Cancer Treated with Endocrine Therapy Only.

Clin Cancer Res 2019 07 7;25(13):3865-3872. Epub 2019 May 7.

Department of Surgery, Medical University Vienna, Vienna, Austria.

Purpose: Prognostic molecular assays may aid in treatment decisions for women with estrogen receptor (ER)-positive, HER2-negative breast cancer. The prognostic value of a 12-gene expression assay (EndoPredict) was reevaluated in the combined ABCSG-6/8 cohorts with longer clinical follow-up.

Experimental Design: EndoPredict (EP; molecular score, EPclin score) was evaluated in women with ER-positive, HER2-negative node-positive and node-negative breast cancer who received 5 years of endocrine therapy only (median follow-up, 9.6 years; = 1,702). Distant recurrence-free rate (DRFR; 95% confidence interval) was assessed 10 and 15 years after diagnosis.

Results: Overall, 62.6% of patients had low-risk EPclin scores with significantly improved DRFR relative to high-risk patients (HR, 4.77; 95% CI, 3.37-6.67; < 0.0001). Ten-year DRFR (0-10 years) was improved among patients with low-risk versus high-risk EPclin scores in the full cohort [95.5% (94.1%-97.0%) vs. 80.3% (76.9%-83.9%)] as well as for patients with node-negative disease [95.5% (94.0%-97.1%) vs. 87.0% (82.6%-91.7%)] or with 1 to 3 positive nodes [95.6% (92.2%-99.1%) vs. 80.9% (75.9%-86.1%)]. The molecular and EPclin scores were significant predictors of DRFR after adjusting for clinical variables, regardless of nodal status. Similar results were observed for late recurrence (5-15 years; HR, 4.52; 95% CI, 2.65-7.72; < 0.0001). The EPclin score significantly added prognostic information to a late metastasis nomogram (CTS5 score; < 0.001).

Conclusions: This study demonstrates that EPclin can identify patients at low risk for early or late recurrence who may safely forgo adjuvant chemotherapy or extended endocrine therapy, respectively, regardless of nodal status.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0376DOI Listing
July 2019

Automatic segmentation and classification of breast lesions through identification of informative multiparametric PET/MRI features.

Eur Radiol Exp 2019 04 27;3(1):18. Epub 2019 Apr 27.

Computational Imaging Research Laboratory, Department of Biomedical Imaging and Image-guided Therapy, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: Multiparametric positron emission tomography/magnetic resonance imaging (mpPET/MRI) shows clinical potential for detection and classification of breast lesions. Yet, the contribution of features for computer-aided segmentation and diagnosis (CAD) need to be better understood. We proposed a data-driven machine learning approach for a CAD system combining dynamic contrast-enhanced (DCE)-MRI, diffusion-weighted imaging (DWI), and F-fluorodeoxyglucose (F-FDG)-PET.

Methods: The CAD incorporated a random forest (RF) classifier combined with mpPET/MRI intensity-based features for lesion segmentation and shape features, kinetic and spatio-temporal texture features, for lesion classification. The CAD pipeline detected and segmented suspicious regions and classified lesions as benign or malignant. The inherent feature selection method of RF and alternatively the minimum-redundancy-maximum-relevance feature ranking method were used.

Results: In 34 patients, we report a detection rate of 10/12 (83.3%) and 22/22 (100%) for benign and malignant lesions, respectively, a Dice similarity coefficient of 0.665 for segmentation, and a classification performance with an area under the curve at receiver operating characteristics analysis of 0.978, a sensitivity of 0.946, and a specificity of 0.936. Segmentation but not classification performance of DCE-MRI improved with information from DWI and FDG-PET. Feature ranking revealed that kinetic and spatio-temporal texture features had the highest contribution for lesion classification. F-FDG-PET and morphologic features were less predictive.

Conclusion: Our CAD enables the assessment of the relevance of mpPET/MRI features on segmentation and classification accuracy. It may aid as a novel computational tool for exploring different modalities/features and their contributions for the detection and classification of breast lesions.
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http://dx.doi.org/10.1186/s41747-019-0096-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486931PMC
April 2019

Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1.

Cell Rep 2019 02;26(9):2394-2406.e5

Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria. Electronic address:

Cytomegalovirus (CMV) has a high prevalence worldwide, is often fatal for immunocompromised patients, and causes bone marrow suppression. Deficiency of signal transducer and activator of transcription 1 (STAT1) results in severely impaired antiviral immunity. We have used cell-type restricted deletion of Stat1 to determine the importance of myeloid cell activity for the defense against murine CMV (MCMV). We show that myeloid STAT1 limits MCMV burden and infection-associated pathology in the spleen but does not affect ultimate clearance of infection. Unexpectedly, we found an essential role of myeloid STAT1 in the induction of extramedullary hematopoiesis (EMH). The EMH-promoting function of STAT1 was not restricted to MCMV infection but was also observed during CpG oligodeoxynucleotide-induced sterile inflammation. Collectively, we provide genetic evidence that signaling through STAT1 in myeloid cells is required to restrict MCMV at early time points post-infection and to induce compensatory hematopoiesis in the spleen.
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http://dx.doi.org/10.1016/j.celrep.2019.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447072PMC
February 2019

Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping as a quantitative imaging biomarker for prediction of immunohistochemical receptor status, proliferation rate, and molecular subtypes of breast cancer.

J Magn Reson Imaging 2019 09 27;50(3):836-846. Epub 2019 Feb 27.

Department of Radiology, Breast Imaging Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping is one of the most useful additional MRI parameters to improve diagnostic accuracy and is now often used in a multiparameric imaging setting for breast tumor detection and characterization.

Purpose: To evaluate whether different ADC metrics can also be used for prediction of receptor status, proliferation rate, and molecular subtype in invasive breast cancer.

Study Type: Retrospective.

Subjects: In all, 107 patients with invasive breast cancer met the inclusion criteria (mean age 57 years, range 32-87) and underwent multiparametric breast MRI.

Field Strength/sequence: 3 T, readout-segmented echo planar imaging (rsEPI) with IR fat suppression, dynamic contrast-enhanced (DCE) T -weighted imaging, T -weighted turbo-spin echo (TSE) with fatsat.

Assessment: Two readers independently drew a region of interest on ADC maps on the whole tumor (WTu), and on its darkest part (DpTu). Minimum, mean, and maximum ADC values of both WTu and DpTu were compared for receptor status, proliferation rate, and molecular subtypes.

Statistical Tests: Wilcoxon rank sum, Mann-Whitney U-tests for associations between radiologic features and histopathology; histogram and q-q plots, Shapiro-Wilk's test to assess normality, concordance correlation coefficient for precision and accuracy; receiver operating characteristics curve analysis.

Results: Estrogen receptor (ER) and progesterone receptor (PR) status had significantly different ADC values for both readers. Maximum WTu (P = 0.0004 and 0.0005) and mean WTu (P = 0.0101 and 0.0136) were significantly lower for ER-positive tumors, while PR-positive tumors had significantly lower maximum WTu values (P = 0.0089 and 0.0047). Maximum WTu ADC was the only metric that was significantly different for molecular subtypes for both readers (P = 0.0100 and 0.0132) and enabled differentiation of luminal tumors from nonluminal (P = 0.0068 and 0.0069) with an area under the curve of 0.685 for both readers.

Data Conclusion: Maximum WTu ADC values may be used to differentiate luminal from other molecular subtypes of breast cancer.

Level Of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:836-846.
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http://dx.doi.org/10.1002/jmri.26697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767396PMC
September 2019

Continued Endocrine Therapy Is Associated with Improved Survival in Patients with Breast Cancer Brain Metastases.

Clin Cancer Res 2019 05 15;25(9):2737-2744. Epub 2019 Jan 15.

Comprehensive Cancer Center, Vienna, Austria.

Purpose: Brain metastases (BMs) are a rare but devastating condition in estrogen receptor (ER)-positive metastatic breast cancer (MBC). Although endocrine therapy (ET) is the mainstay of treatment in this disease subtype, only case reports have been published concerning the activity of ET in BMs henceforth. Therefore, we aimed to systematically investigate the impact of ET after diagnosis of BM on outcome and clinical course of disease in patients with ER-positive MBC.

Experimental Design: Patient characteristics, detailed information about BMs including diagnosis-specific graded prognostic assessment class (DS-GPA), and clinical outcome were obtained by retrospective chart review for all patients treated for ER-positive breast cancer BMs between 1990 and 2017 at an academic care center. Overall survival (OS) was measured as the interval from diagnosis of BM until death or last date of follow-up.

Results: Overall, 198 patients [female: 195/198 (98.5%); male: 3/198 (1.5%)] with ER-positive breast cancer BMs were available for this analysis. Eighty-eight of 198 patients (44.4%) received ET after diagnosis of BM including aromatase inhibitors (AIs; letrozole, anastrozole, exemestane), tamoxifen, and fulvestrant. Median OS was significantly longer in patients receiving ET after diagnosis of BM compared with patients who did not (15 vs. 4 months, < 0.001; log-rank test). No significant difference in terms of OS was observed between patients receiving AIs, tamoxifen, or fulvestrant. In patients with concomitant leptomeningeal carcinomatosis (LC), ET prolonged median OS significantly as well (7 vs. 3 months, = 0.012; log-rank test). In a multivariate analysis including DS-GPA and ET, only treatment with ET after diagnosis of BM (HR, 0.69; 95% confidence interval, 0.48-0.99; = 0.046) was associated with prognosis (Cox regression model).

Conclusions: Continuing ET after BM diagnosis was associated with a significantly prolonged OS in this large single-center cohort. No substantial differences between substances were observed. These findings should be validated in a prospective cohort.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1968DOI Listing
May 2019

Development of a Non-invasive Assessment of Hypoxia and Neovascularization with Magnetic Resonance Imaging in Benign and Malignant Breast Tumors: Initial Results.

Mol Imaging Biol 2019 08;21(4):758-770

Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Purpose: To develop a novel magnetic resonance imaging (MRI) approach for the noninvasive assessment of hypoxia and neovascularization in breast tumors.

Procedures: In this IRB-approved prospective study, 20 patients with suspicious breast lesions (BI-RADS 4/5) underwent multiparametric breast MRI including quantitative BOLD (qBOLD) and vascular architecture mapping (VAM). Custom-made in-house MatLab software was used for qBOLD and VAM data postprocessing and calculation of quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO), and mitochondrial oxygen tension (mitoPO) to measure tissue hypoxia and neovascularization including vascular architecture including microvessel radius (VSI), density (MVD), and type (MTI). Histopathology was used as standard of reference. Appropriate statistics were performed to assess and compare correlations between MRI biomarkers for hypoxia and neovascularization.

Results: qBOLD and VAM data with good quality were obtained from all patients with 13 invasive ductal carcinoma (IDC) and 7 benign breast tumors with a lesion diameter of at least 10 mm in all spatial directions. MRI biomarker maps of oxygen metabolism and neovascularization demonstrated intratumoral spatial heterogeneity with a broad range of biomarker values. Bulk tumor neovasculature consisted of draining venous microvasculature with slow flowing blood. High OEF and low mitoPO were associated with low MVD and vice versa. The heterogeneous pattern of MRO values showed spatial congruence with VSI. IDCs showed significantly higher MRO (P = 0.007), lower mitoPO (P = 0.021), higher MVD (P = 0.005), and lower (i.e., more pathologic) MTI (P = 0.001) compared with benign breast tumors. These results indicate that IDCs consume more oxygen and are more hypoxic and neovascularized than benign tumors.

Conclusions: We developed a novel MRI approach for the noninvasive assessment of hypoxia and neovascularization in benign and malignant breast tumors that can be easily integrated in a diagnostic MRI protocol and provides insight into intratumoral heterogeneity.
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http://dx.doi.org/10.1007/s11307-018-1298-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480075PMC
August 2019

Impact of Machine Learning With Multiparametric Magnetic Resonance Imaging of the Breast for Early Prediction of Response to Neoadjuvant Chemotherapy and Survival Outcomes in Breast Cancer Patients.

Invest Radiol 2019 02;54(2):110-117

Department of Radiology, Breast Imaging Service, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: The aim of this study was to assess the potential of machine learning with multiparametric magnetic resonance imaging (mpMRI) for the early prediction of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) and of survival outcomes in breast cancer patients.

Materials And Methods: This institutional review board-approved prospective study included 38 women (median age, 46.5 years; range, 25-70 years) with breast cancer who were scheduled for NAC and underwent mpMRI of the breast at 3 T with dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), and T2-weighted imaging before and after 2 cycles of NAC. For each lesion, 23 features were extracted: qualitative T2-weighted and DCE-MRI features according to BI-RADS (Breast Imaging Reporting and Data System), quantitative pharmacokinetic DCE features (mean plasma flow, volume distribution, mean transit time), and DWI apparent diffusion coefficient (ADC) values. To apply machine learning to mpMRI, 8 classifiers including linear support vector machine, linear discriminant analysis, logistic regression, random forests, stochastic gradient descent, decision tree, adaptive boosting, and extreme gradient boosting (XGBoost) were used to rank the features. Histopathologic residual cancer burden (RCB) class (with RCB 0 being a pCR), recurrence-free survival (RFS), and disease-specific survival (DSS) were used as the standards of reference. Classification accuracy with area under the receiving operating characteristic curve (AUC) was assessed using all the extracted qualitative and quantitative features for pCR as defined by RCB class, RFS, and DSS using recursive feature elimination. To overcome overfitting, 4-fold cross-validation was used.

Results: Machine learning with mpMRI achieved stable performance as shown by mean classification accuracies for the prediction of RCB class (AUC, 0.86) and DSS (AUC, 0.92) based on XGBoost and the prediction of RFS (AUC, 0.83) with logistic regression. The XGBoost classifier achieved the most stable performance with high accuracies compared with other classifiers. The most relevant features for the prediction of RCB class were as follows: changes in lesion size, complete pattern of shrinkage, and mean transit time on DCE-MRI; minimum ADC on DWI; and peritumoral edema on T2-weighted imaging. The most relevant features for prediction of RFS were as follows: volume distribution, mean plasma flow, and mean transit time; DCE-MRI lesion size; minimum, maximum, and mean ADC with DWI. The most relevant features for prediction of DSS were as follows: lesion size, volume distribution, and mean plasma flow on DCE-MRI, and maximum ADC with DWI.

Conclusions: Machine learning with mpMRI of the breast enables early prediction of pCR to NAC as well as survival outcomes in breast cancer patients with high accuracy and thus may provide valuable predictive information to guide treatment decisions.
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http://dx.doi.org/10.1097/RLI.0000000000000518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310100PMC
February 2019

SABCS 2017 pathology: from bench to bedside.

Memo 2018 15;11(3):217-219. Epub 2018 Aug 15.

Clinical Institute of Pathology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.

The 40th International San Antonio Breast Cancer Symposium offered a multifaceted platform for the presentation of several innovative therapeutic approaches. The results of these preclinical and clinical studies provided insight into the development of novel therapy concepts from the laboratory bench to the bedside of breast cancer patients. One main focus of last year's symposium was the search for synergisms and opportunities for collaboration between basic research scientists and investigators in drug development. Highlights of these topics included preclinical data on selective estrogen receptor covalent antagonists (SERCAs), the discovery of immune-modulating effects of demethylating agents as well as the exact characterization and risk assessment of mutations of previously unknown significance. Pathological advances aimed at the molecular understanding of intratumoral heterogeneity and the evolution of lobular breast cancer. Beyond preclinical discoveries at the molecular level, clinical studies provided evidence on the duration of adjuvant bisphosphonate treatment and the use of the EndoPredict multigenomic assay to predict response to neoadjuvant chemo- and endocrine therapy. The SUCCESS A study reported that the prolonged adjuvant administration of zoledronic acid for 5 years did not improve patient survival after chemotherapy. A translational analysis of the ABCSG 34 trial revealed that the EndoPredict multigenomic assay could identify patients who do not benefit from neoadjuvant endocrine or chemotherapy. These recent advances are likely to promote individualized breast cancer care.
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http://dx.doi.org/10.1007/s12254-018-0427-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132829PMC
August 2018

Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy.

Blood 2018 08 14;132(7):694-706. Epub 2018 Jun 14.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.
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http://dx.doi.org/10.1182/blood-2017-10-810739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115916PMC
August 2018

Diffusion-Weighted Imaging With Apparent Diffusion Coefficient Mapping for Breast Cancer Detection as a Stand-Alone Parameter: Comparison With Dynamic Contrast-Enhanced and Multiparametric Magnetic Resonance Imaging.

Invest Radiol 2018 10;53(10):587-595

Department of Biomedical Imaging and Image-Guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.

Purpose: The aims of this study were to compare dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) with apparent diffusion coefficient mapping as a stand-alone parameter without any other supportive sequence for breast cancer detection and to assess its combination as multiparametric MRI (mpMRI) of the breast.

Materials And Methods: In this institutional review board-approved single-center study, prospectively acquired data of 106 patients who underwent breast MRI from 12/2010 to 09/2014 for an imaging abnormality (Breast Imaging Reporting and Data System 0, 4/5) were retrospectively analyzed. Four readers independently assessed DWI and DCE as well as combined as mpMRI. Breast Imaging Reporting and Data System categories, lesion size, and mean apparent diffusion coefficient values were recorded. Histopathology was used as the gold standard. Appropriate statistical tests were used to compare diagnostic values.

Results: There were 69 malignant and 41 benign tumors in 106 patients. Four patients presented with bilateral lesions. Dynamic contrast-enhanced MRI was the most sensitive test for breast cancer detection, with an average sensitivity of 100%. Diffusion-weighted imaging alone was less sensitive (82%; P < 0.001) but more specific than DCE-MRI (86.8% vs 76.6%; P = 0.002). Diagnostic accuracy was 83.7% for DWI and 90.6% for DCE-MRI. Multiparametric MRI achieved a sensitivity of 96.8%, not statistically different from DCE-MRI (P = 0.12) and with a similar specificity as DWI (83.8%; P = 0.195), maximizing diagnostic accuracy to 91.9%. There was almost perfect interreader agreement for DWI (κ = 0.864) and DCE-MRI (κ = 0.875) for differentiation of benign and malignant lesions.

Conclusion: Dynamic contrast-enhanced MRI is most sensitive for breast cancer detection and thus still indispensable. Multiparametric MRI using DCE-MRI and DWI maintains a high sensitivity, increases specificity, and maximizes diagnostic accuracy, often preventing unnecessary breast biopsies. Diffusion-weighted imaging should not be used as a stand-alone parameter because it detects significantly fewer cancers in comparison with DCE-MRI and mpMRI.
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http://dx.doi.org/10.1097/RLI.0000000000000465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123254PMC
October 2018

Intravasation of SW620 colon cancer cell spheroids through the blood endothelial barrier is inhibited by clinical drugs and flavonoids in vitro.

Food Chem Toxicol 2018 Jan 10;111:114-124. Epub 2017 Nov 10.

Clinical Institute of Pathology, Medical University of Vienna, Austria. Electronic address:

Mechanisms how colorectal cancer (CRC) cells penetrate blood micro-vessel endothelia and metastasise is poorly understood. To study blood endothelial cell (BEC) barrier breaching by CRC emboli, an in vitro assay measuring BEC-free areas underneath SW620 cell spheroids, so called "circular chemorepellent induced defects" (CCIDs, appearing in consequence of endothelial retraction), was adapted and supported by Western blotting, EIA-, EROD- and luciferase reporter assays. Inhibition of ALOX12 or NF-κB in SW620 cells or BECs, respectively, caused attenuation of CCIDs. The FDA approved drugs vinpocetine [inhibiting ALOX12-dependent 12(S)-HETE synthesis], ketotifen [inhibiting NF-κB], carbamazepine and fenofibrate [inhibiting 12(S)-HETE and NF-κB] significantly attenuated CCID formation at low μM concentrations. In the 5-FU-resistant SW620-R/BEC model guanfacine, nifedipine and proadifen inhibited CCIDs stronger than in the naïve SW620/BEC model. This indicated that in SW620-R cells formerly silent (yet unidentified) genes became expressed and targetable by these drugs in course of resistance acquisition. Fenofibrate, and the flavonoids hispidulin and apigenin, which are present in medicinal plants, spices, herbs and fruits, attenuated CCID formation in both, naïve- and resistant models. As FDA-approved drugs and food-flavonoids inhibited established and acquired intravasative pathways and attenuated BEC barrier-breaching in vitro, this warrants testing of these compounds in CRC models in vivo.
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http://dx.doi.org/10.1016/j.fct.2017.11.015DOI Listing
January 2018

Candidatus Dirofilaria hongkongensis as Causative Agent of Human Ocular Filariosis after Travel to India.

Emerg Infect Dis 2017 08;23(8):1428-1431

We report a human case of ocular Dirofilaria infection in a traveler returning to Austria from India. Analysis of mitochondrial sequences identified the worm as Candidatus Dirofilaria hongkongensis, a close relative of Dirofilaria repens, which was only recently described in Hong Kong and proposed as a new species.
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http://dx.doi.org/10.3201/eid2308.170423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547781PMC
August 2017

Expansion of BCR/ABL1 cells requires PAK2 but not PAK1.

Br J Haematol 2017 10 14;179(2):229-241. Epub 2017 Jul 14.

Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.

The p21-activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1 haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2- but not shPAK1-expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2-deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome-mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.
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http://dx.doi.org/10.1111/bjh.14833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655792PMC
October 2017

The effect of obesity on pathological complete response and survival in breast cancer patients receiving uncapped doses of neoadjuvant anthracycline-taxane-based chemotherapy.

Breast 2017 Jun 7;33:153-158. Epub 2017 Apr 7.

Department of Obstetrics and Gynecology, Division of Gynecology and Gynecologic Oncology, Breast Health Center, Medical University of Vienna, Vienna, Austria.

Purpose: The effect of obesity in breast cancer patients undergoing neoadjuvant chemotherapy (NAC) remains controversial. The aim of this study was to determine the obesity-related effect on pathological complete response (pCR) and survival in women receiving full uncapped doses of NAC.

Methods: We retrospectively analyzed the data of all consecutive women who underwent anthracycline-taxane-based NAC for primary breast cancer between 2005 and 2015 at the Department of Obstetrics and Gynecology, Medical University of Vienna. Following the WHO criteria, women with a body mass index (BMI) ≥30 kg/m at baseline were considered obese, whereas those with a BMI <30 kg/m were considered non-obese. Those with dose reductions or dose capping were not eligible for study inclusion. Cox regression and logistic regression were performed. The Kaplan-Meier method was used to analyze disease-free, progression-free, and overall survival. The pCR served as the main outcome measure.

Results: Among 120 women who received neoadjuvant epirubicin plus cyclophosphamide and docetaxel, 28 (23.3%) were obese and 92 (76.7%) were non-obese. In the multivariate logistic regression model that adjusted for potentially confounding variables, obesity had an independent positive predictive effect on pCR (OR 4.29, 95% CI, 1.42-13.91; p = 0.011), which was significant in the postmenopausal subgroup (OR 4.72, 95% CI, 1.47-15.84; p = 0.01). When comparing non-obese with obese women, we found that obese women experienced longer progression-free survival (HR 0.10, 95% CI, 8.448 × 10-0.81; p = 0.025).

Conclusions: Obese women receiving full uncapped doses of anthracycline-taxane-based NAC have increased pCR and favorable progression-free survival. This could result from increased dose intensity with increased efficacy and toxicity.
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http://dx.doi.org/10.1016/j.breast.2017.04.001DOI Listing
June 2017

AHR/CYP1A1 interplay triggers lymphatic barrier breaching in breast cancer spheroids by inducing 12(S)-HETE synthesis.

Hum Mol Genet 2016 11;25(22):5006-5016

Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.

A causal link between overexpression of aryl hydrocarbon receptor (AHR) and its target cytochrome P450 1A1 (CYP1A1) and metastatic outgrowth of various cancer entities has been established. Nevertheless, the mechanism how AHR/CYP1A1 support metastasis formation is still little understood. In vitro we discovered a potential mechanism facilitating tumour dissemination based on the production of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Utilising a three-dimensional lymph endothelial cell (LEC) monolayer & MDA-MB231 breast cancer cell spheroid co-culture model in combination with knock-down approach allowed elucidation of the molecular/biochemical basis of AHR/CYP1A1-induced tumour breaching through the LEC barrier. Enzyme immunoassay evidenced the potential of recombinant CYP1A1 to synthesise 12(S)-HETE in vitro and qPCR and Western blotting measured gene and protein expression in specific experimental settings. In detail, AHR induced CYP1A1 expression and 12(S)-HETE secretion in tumour spheroids, which caused LEC junction retraction thereby forming large discontinuities allowing transmigration of the tumour. This was enforced by the activating AHR ligand 6-formylindolo (3,3-b)carbazole (FICZ), or inhibited by the AHR antagonist 3,3’-diindolylmethane (DIM) as well as by siRNA against AHR and CYP1A1. AHR and NF-κB were negatively cross talking and therefore, the inhibition of AHR (but not CYP1A1) induced RELA, RELB, NFKB1, NFKB2 and the NF-κB target MMP1, which itself promotes tumour intravasation by a mechanism that is different from 12(S)-HETE. Conversely, the inhibition of NFKB2 induced AHR, CYP1A1 and 12(S)-HETE synthesis. The approved clinical drugs guanfacine and vinpocetine, which inhibit CYP1A1 and NF-κB, respectively, significantly inhibited LEC barrier breaching in vitro indicating an option to reduce metastatic dissemination.
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http://dx.doi.org/10.1093/hmg/ddw329DOI Listing
November 2016

Pathological Complete Response to Neoadjuvant Trastuzumab Is Dependent on HER2/CEP17 Ratio in HER2-Amplified Early Breast Cancer.

Clin Cancer Res 2017 Jul 31;23(14):3676-3683. Epub 2017 Jan 31.

Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

To evaluate whether pathologic complete response (pCR) to neoadjuvant trastuzumab is dependent on the level of HER2 amplification. 114 HER2-overexpressing early breast cancer patients who had received neoadjuvant trastuzumab were included in this study. Absolute HER2 and chromosome 17 centromere (CEP17) were measured by hybridization analysis, and associations were examined between HER2/CEP17 ratio and tumor pCR status (commonly defined by ypT0 ypN0, ypT0/is ypN0, and ypT0/is). In trastuzumab-treated patients, ypT0 ypN0 was achieved in 69.0% of patients with high-level amplification (HER2/CEP17 ratio > 6), but only in 30.4% of tumors with low-level amplification (ratio ≤ 6; = 0.001). When pCR was defined by ypT0/is ypN0 or ypTis, 75.9% and 82.8% of tumors with high-level amplification had a complete response, whereas only 39.1%, and 38.3% with low-level amplification achieved pCR ( = 0.002 and < 0.001, respectively). Logistic regression revealed that tumors with high-level amplification had a significantly higher probability achieving ypT0 ypN0 (OR, 5.08; 95% confidence interval, 1.86-13.90; = 0.002) than tumors with low-level amplification, whereas no other clinicopathologic parameters were predictive of pCR. The association between high-level HER2 amplification and pCR was almost exclusively confined to hormone receptor (HR)-positive tumors (ypT0 ypN0: 62.5% vs. 24.0%, = 0.014; ypT0/is ypN0: 75.0% vs. 28.0%, = 0.005; and ypT0/is: 87.5% vs. 28.0%, < 0.001), and was largely absent in HR-negative tumors. An HER2/CEP17 ratio of >6 in the pretherapeutic tumor biopsy is associated with a significantly higher pCR rate, particularly in HER2/HR copositive tumors, and can be used as a biomarker to predict response before neoadjuvant trastuzumab is initiated. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2373DOI Listing
July 2017
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