Publications by authors named "Konstantin J Dedes"

61 Publications

Setting a diagnostic benchmark for tumor BRCA testing: Detection of BRCA1 and BRCA2 large genomic rearrangements in FFPE tissue - A pilot study.

Exp Mol Pathol 2021 Oct 9:104705. Epub 2021 Oct 9.

Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland; Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.

PARP inhibitors are used for treatment of tumors lacking function of the double-strand DNA break repair proteins BRCA1 or BRCA2 and are already approved for several cancer types. Thus, it is clinically crucial to determine germline as well as somatic BRCA1/2 mutations in those patients. The amplicon-based Oncomine BRCA1 and BRCA2 Assay is a test routinely used in diagnostics with FFPE specimens. The assay is validated for the detection of mutations, however, data on its performance in detecting large genomic rearrangements in FFPE tissue, is scarce. We cross-validated Oncomine BRCA1 and BRCA2 Assay in blood samples and/or FFPE tissue with multiplex ligation-dependent probe amplification (MLPA) for exon deletions and with OncoScan and an in-house hybridization-based target capture assay (MelArray) with a customized pipeline for the detection of loss of heterozygosity (LOH) and heterozygous versus complete gene loss. The Oncomine BRCA1 and BRCA2 Assay could detect both exon deletion and mono- and bi-allelic losses of the BRCA1/2 genes. We show that the therapeutically relevant large genomic rearrangements are reliably detected with the amplicon-based Oncomine BRCA1 and BRCA2 Assay in FFPE tumor tissue. Based on our data, we suggest tumor BRCA testing as standard diagnostic prescreening prior to germline BRCA testing.
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http://dx.doi.org/10.1016/j.yexmp.2021.104705DOI Listing
October 2021

Prepectoral implant-based breast reconstruction with TiLOOP® Bra Pocket - a single-centre retrospective study.

J Plast Reconstr Aesthet Surg 2021 Sep 17. Epub 2021 Sep 17.

Breast Cancer Center, Department of Gynecology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. Electronic address:

Background: Prepectoral implant-based reconstruction using synthetic meshes is feasible with good outcomes. We present our data using TiLOOP® Bra Pocket, a novel ready-to-use mesh pocket which acts as an internal bra and prevents the implant from dislocating or twisting.

Materials And Methods: A single-centre retrospective cohort study was performed to assess short-term complication rates and cosmetic outcomes in patients with prepectoral implant-based reconstruction using the TiLOOP® Bra Pocket. The primary endpoint was complication rates during the first 6 months. The secondary endpoint was the cosmetic outcome after 6 to 12 months, which was judged by two breast surgeons using the Harvard score.

Results: A total of 63 breasts (43 patients) were reconstructed using the TiLOOP® Bra Pocket between 2018 and 2020, 57 were immediate reconstructions. The overall complication rate was 30,2% (n = 19/63). Major complications occurred in seven breasts (n = 7/63; 11,1%) and minor complications occurred in 12 breasts (12/63; 19,0%). The unplanned revision rate was 12,7%. The cosmetic outcome was good (Harvard score: mean 3, range 1-4; SD 0,75). Seventeen cosmetic complications were observed (17/63; 27,0%) and six cosmetic revision surgeries were performed (6/63; 9,5%).

Conclusion: The use of the TiLOOP® Bra Pocket is convenient and standardized because the pocket is preformed and does not require to be sewn first. Cosmetic outcome is good; however, the surgical morbidity needs to be addressed in future reconstructions. Careful patient selection and preparation techniques are vital in order to achieve acceptable complication rates and satisfying cosmetic results.
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http://dx.doi.org/10.1016/j.bjps.2021.08.027DOI Listing
September 2021

Tailored axillary surgery in patients with clinically node-positive breast cancer: Pre-planned feasibility substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

Breast 2021 Sep 8;60:98-110. Epub 2021 Sep 8.

Breast Center Bern, Lindenhof Group, Bern, Switzerland.

Aim: We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS.

Methods: International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load.

Results: A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3-7) nodes, two (IQR 1-4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10-17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%.

Conclusions: TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND.
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http://dx.doi.org/10.1016/j.breast.2021.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463904PMC
September 2021

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.

Br J Cancer 2021 Aug 25;125(3):380-389. Epub 2021 May 25.

Breast Center, Universitätsspital Zürich, Zurich, Switzerland.

Background: The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses.

Methods: In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0-N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT.

Results: Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17-0.88) P = 0.0091.

Conclusion: TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect.

Trial Registration: ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).
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http://dx.doi.org/10.1038/s41416-021-01440-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329051PMC
August 2021

Ectopic axillary breast cancer in a male patient.

Clin Case Rep 2020 Nov 18;8(11):2324-2325. Epub 2020 Sep 18.

Breast Cancer Center Comprehensive Cancer Center Zürich University Hospital of Zurich Zurich Switzerland.

Ectopic breast tissue can persist in the axilla due to lack of involution of mammary glands along the mammary lines. It is rare in men, and the malignant transformation to breast cancer has occasionally been described. Differential diagnosis of any axillary tumor should include breast cancer arising at ectopic sites.
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http://dx.doi.org/10.1002/ccr3.3336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669415PMC
November 2020

[Rare Forms of Mastitis].

Praxis (Bern 1994) 2020 ;109(13):1055-1062

Universitätsspital Zürich.

Rare Forms of Mastitis Inflammatory breast diseases caused by bacterial infections represent the main cause for mastitis in breastfeeding and non-breastfeeding women. The clinical appearance and a standardized evaluation can indicate rare inflammatory breast diseases. An underlying comorbidity or the evidence of rare pathogens could be suggestive. However, core needle biopsy is the main step in diagnostics. Malignancy, e.g. an inflammatory breast cancer must consistently be excluded. This mini review outlines a few rare inflammatory breast diseases, their initial presentation, and how to diagnose them accurately.
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http://dx.doi.org/10.1024/1661-8157/a003509DOI Listing
October 2020

Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.

BMJ 2020 08 19;370:m2836. Epub 2020 Aug 19.

Breast Centre, University Hospital Zurich, Zurich, Switzerland.

Objective: To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.

Design: Prospective, open label, randomised controlled clinical trial.

Setting: 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.

Participants: 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).

Interventions: Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).

Main Outcome Measures: Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.

Results: Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 11/1158) but 14 fewer deaths (42/1140 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).

Conclusion: For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.

Trial Registration: ISRCTN34086741, NCT00983684.
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http://dx.doi.org/10.1136/bmj.m2836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500441PMC
August 2020

Anesthesia and Circulating Tumor Cells in Primary Breast Cancer Patients: A Randomized Controlled Trial.

Anesthesiology 2020 09;133(3):548-558

From the Institute of Anesthesiology, University Hospital of Zurich and University of Zurich, Zurich, Switzerland (F.H., M.S., B.B.-S.) the Epidemiology, Biostatistics and Prevention Institute, Department of Public and Global Health (F.H.) the Epidemiology, Biostatistics and Prevention Institute, Department of Epidemiology (J.B., M.A.P.) the Institute of Physiology and Zurich Center for Integrative Human Physiology (B.R.Z., M.S., B.B.-S.) the Cytometry Facility (C.D., C.E.), University of Zurich, Zurich, Switzerland the Department of Gynecology, University Hospital of Zurich, Zurich, Switzerland (K.J.D., D.F.) the Institute of Anesthesiology, Hirslanden Clinic Zurich, Zurich, Switzerland (U.R., M.S.) the Faculty of Medicine, University of Basel, Basel, Switzerland (M.S.) the Department of Surgery (C.T.) the Clinical Trial Unit (B.P.), Breast Center Zurich, Zurich, Switzerland the Department of Anesthesiology, University of Illinois College of Medicine at Chicago, Chicago, Illinois (B.B.-S.).

Background: The effect of anesthetic drugs on cancer outcomes remains unclear. This trial aimed to assess postoperative circulating tumor cell counts-an independent prognostic factor for breast cancer-to determine how anesthesia may indirectly affect prognosis. It was hypothesized that patients receiving sevoflurane would have higher postoperative tumor cell counts.

Methods: The parallel, randomized controlled trial was conducted in two centers in Switzerland. Patients aged 18 to 85 yr without metastases and scheduled for primary breast cancer surgery were eligible. The patients were randomly assigned to either sevoflurane or propofol anesthesia. The patients and outcome assessors were blinded. The primary outcome was circulating tumor cell counts over time, assessed at three time points postoperatively (0, 48, and 72 h) by the CellSearch assay. Secondary outcomes included maximal circulating tumor cells value, positivity (cutoff: at least 1 and at least 5 tumor cells/7.5 ml blood), and the association between natural killer cell activity and tumor cell counts. This trial was registered with ClinicalTrials.gov (NCT02005770).

Results: Between March 2014 and April 2018, 210 participants were enrolled, assigned to sevoflurane (n = 107) or propofol (n = 103) anesthesia, and eventually included in the analysis. Anesthesia type did not affect circulating tumor cell counts over time (median circulating tumor cell count [interquartile range]; for propofol: 1 [0 to 4] at 0 h, 1 [0 to 2] at 48 h, and 0 [0 to 1] at 72 h; and for sevoflurane: 1 [0 to 4] at 0 h, 0 [0 to 2] at 48 h, and 1 [0 to 2] at 72 h; rate ratio, 1.27 [95% CI, 0.95 to 1.71]; P = 0.103) or positivity. In one secondary analysis, administrating sevoflurane led to a significant increase in maximal tumor cell counts postoperatively. There was no association between natural killer cell activity and circulating tumor cell counts.

Conclusions: In this randomized controlled trial investigating the effect of anesthesia on an independent prognostic factor for breast cancer, there was no difference between sevoflurane and propofol with respect to circulating tumor cell counts over time.
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http://dx.doi.org/10.1097/ALN.0000000000003409DOI Listing
September 2020

Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer.

JAMA Oncol 2020 07 9;6(7):e200249. Epub 2020 Jul 9.

Breast Center, Universitätsspital Zürich, Zurich, Switzerland.

Importance: Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed.

Objective: To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control.

Design, Setting, And Participants: In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019.

Interventions: The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound.

Main Outcomes And Measures: A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes.

Results: Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80).

Conclusions And Relevance: These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival.

Trial Registration: ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684.
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http://dx.doi.org/10.1001/jamaoncol.2020.0249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348682PMC
July 2020

Loss of MDC1 in Endometrial Carcinoma Is Associated With Loss of MRN Complex and MMR Deficiency.

Anticancer Res 2019 Dec;39(12):6547-6553

Department of Gynecologic Oncology, University Hospital of Zurich, Zurich, Switzerland

Aim: To evaluate the frequency of loss of mediator of DNA damage checkpoint protein 1 (MDC1) protein expression in endometrial cancer (EC) and to determine whether loss of MDC1 is associated with certain clinicopathological parameters.

Materials And Methods: MDC1 expression was examined in 426 samples of EC. The nuclear immunoreactivity of the protein was defined as: negative, weak, moderate and strong.

Results: Loss of MDC1 expression (defined as negative nuclear staining) was found in 8.9% (38/426) of ECs and was significantly associated with the loss of MRE11 homolog, double-strand break repair nuclease, RAD50 double-strand break repair protein and nibrin complex components. In addition, loss of expression of MDC1 showed a significant correlation with any mismatch repair deficiency, with endometrioid histological subtype and low tumour grading.

Conclusion: Based on these findings, we suggest that MDC1 loss frequently occurs in ECs with microsatellite instability. Due to deficient homologous recombination DNA repair, MDC1-negative ECs might show an increased sensitivity to poly(ADP-ribose) polymerase-inhibitory therapy.
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http://dx.doi.org/10.21873/anticanres.13870DOI Listing
December 2019

Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort.

Swiss Med Wkly 2019 Aug 18;149:w20092. Epub 2019 Aug 18.

Institute of Medical Genetics (IMG), University of Zurich, Schlieren-Zurich, Switzerland.

Background: Since the advent of high-throughput sequencing technologies, organised germline screening, independent of the personal and family cancer history, has been frequently proposed. Since ethnic and geographic populations significantly differ in their mutation spectra and prevalence, one critical prerequisite would be the knowledge of the expected carrier frequencies.

Objective: For the first time, in a retrospective non-cancer related cohort from a single Swiss genetic centre, we systematically assessed the prevalence of secondary findings in 19 genes (BRCA1/2 plus 17 non-BRCA genes) previously designated by the US National Comprehensive Cancer Network (NCCN) for hereditary breast and ovarian cancer (HBOC) germline testing.

Design: A total of 400 individuals without a cancer diagnosis undergoing whole-exome sequencing (WES) analysis for neurodevelopmental disorders (NDDs) from 2015 to 2017 at IMG Zurich were included after quality assessment. Among these, 180 were unaffected parental couples, 27 unaffected parental singles and 13 NDD index patients (mean age 43 years). The majority of the cohort was of Caucasian ethnicity (n = 336, 84.0%) and of Northwest European ancestry (n = 202, 50.5%), for 70 of whom (42.5%) an autochthonous Swiss descent was assumed. For WES filtering of rare, potentially actionable secondary variants in HBOC genes, an overall minor allele frequency (MAF) below 0.65% was used as cut-off. Each rare variant was manually evaluated according to the recommended ACGM-AMP standards, with some adaptations including “hypomorphic” as an additional distinct pathogenicity class.

Results: Overall, 526 rare secondary variants (339 different variants) were encountered, with the BRCA1/2 genes accounting for 27.2% of the total variant yield. If stratified for variant pathogenicity, for BRCA1/2, three pathogenic variants were found in three females of Italian ancestry (carrier frequency of 0.8%). In the non-BRCA genes, five carriers of (likely) pathogenic variants (1.3%) were identified, with two Swiss individuals harbouring the same CHEK2 Arg160Gly variant known to be recurrent among Caucasians. Hence, the overall carrier rate added up to 2.0%. Additionally, seven various hypomorphic HBOC predisposing alleles were detected in 22 individuals (5.5%).

Conclusion: We provide the first evidence of a high prevalence of HBOC-related cancer susceptibility in the heterogeneous Swiss general population and relevant subpopulations, particularly in individuals of Italian descent. These pioneering data may substantiate population-based HBOC screening in Switzerland.
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http://dx.doi.org/10.4414/smw.2019.20092DOI Listing
August 2019

Breast Cancer Assessment With Pulse-Echo Speed of Sound Ultrasound From Intrinsic Tissue Reflections: Proof-of-Concept.

Invest Radiol 2019 07;54(7):419-427

Computer-Assisted Applications in Medicine, ETH Zurich.

Purpose: The aim of this study was to differentiate malignant and benign solid breast lesions with a novel ultrasound (US) technique, which measures speed of sound (SoS) using standard US transducers and intrinsic tissue reflections and scattering (speckles) as internal reference.

Materials And Methods: This prospective, institutional review board-approved, Health Insurance Portability and Accountability Act-compliant prospective comparison study was performed with prior written informed consent from 20 women. Ten women with histological proven breast cancer and 10 with fibroadenoma were measured. A conventional US system with a linear probe was used for SoS-US (SonixTouch; Ultrasonix, Richmond, British Columbia, Canada). Tissue speckle reflections served as a timing reference for the US signals transmitted through the breasts. Relative phase inconsistencies were detected using plane wave measurements from different angular directions, and SoS images with 0.5-mm resolution were generated using a spatial domain reconstruction algorithm. The SoS of tumors were compared with the breast density of a larger cohort of 106 healthy women.

Results: Breast lesions show focal increments ΔSoS (meters per second) with respect to the tissue background. Peak ΔSoS values were evaluated. Breast carcinoma showed significantly higher ΔSoS than fibroadenomas ([INCREMENT]SoS > 41.64 m/s: sensitivity, 90%; specificity, 80%; area under curve, 0.910) and healthy breast tissue of different densities (area under curve, 0.938; sensitivity, 90%; specificity, 96.5%). The lesion localization in SoS-US images was consistent with B-mode imaging and repeated SoS-US measurements were reproducible.

Conclusions: Using SoS-US, based on conventional US and tissue speckles as timing reference, breast carcinoma showed significantly higher SoS values than fibroadenoma and healthy breast tissue of different densities. The SoS presents a promising technique for differentiating solid breast lesions.
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http://dx.doi.org/10.1097/RLI.0000000000000553DOI Listing
July 2019

A cost-effectiveness analysis of consolidative local therapy in oligometastatic non-squamous non-small cell lung cancer (NSCLC).

Radiother Oncol 2018 11 10;129(2):257-263. Epub 2018 Aug 10.

Swiss Group for Clinical Cancer Research Coordinating Centre, Bern, Switzerland; Institute of Pharmaceutical Medicine, University of Basel, Switzerland.

Background: Novel systemic therapies have improved the prognosis of metastatic non-small cell lung cancer (NSCLC), but costs of some of these drugs are a matter of ongoing debate. More recently, local therapies (LT) such as radiotherapy and surgery have been suggested as additional treatment in oligometastatic NSCLC demonstrating an improved progression-free survival (PFS) in a phase II trial compared to maintenance chemotherapy (MC) alone. The aim of this analysis was to assess the cost-effectiveness of local therapies in oligometastatic NSCLC.

Methods: We constructed a Markov model comparing the cost-effectiveness of LT versus MC for oligometastatic NSCLC from the Swiss healthcare payer's perspective. Treatment specifications and PFS were based on the phase II trial (NCT01725165). Overall survival (OS) was inferred from a recent phase III trial. Utilities were taken from published data. Primary outcome was the incremental cost-effectiveness-ratio (ICER, costs in Swiss Francs (CHF) per quality-adjusted life-year (QALY) gained).

Results: PFS in the model was 3.8 months for MC and 11.4 months for LT (compared to 3.9 months and 11.9 months in the trial). OS in the model was 15.5 months in both arms. LT was cost-effective with a gain of 0.24 QALYs at an additional cost of CHF 9641, resulting in an ICER of CHF 40,972/QALY gained. Probabilistic sensitivity analyses demonstrated that LT was dominant or cost-effective at a willingness-to-pay threshold of CHF 100,000 per QALY in 61.7% of the simulations.

Conclusions: LT may be cost-effective for selected patients with oligometastatic NSCLC responding to first-line systemic therapy.
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http://dx.doi.org/10.1016/j.radonc.2018.07.017DOI Listing
November 2018

Feasibility of F-FDG Dose Reductions in Breast Cancer PET/MRI.

J Nucl Med 2018 12 7;59(12):1817-1822. Epub 2018 Jun 7.

Department of Nuclear Medicine, University Hospital of Zurich, Zurich, Switzerland.

The goal of this study was to determine the level of clinically acceptable F-FDG dose reduction in time-of-flight PET/MRI in patients with breast cancer. Twenty-six consecutive women with histologically proven breast cancer were analyzed (median age, 51 y; range, 34-83 y). Simulated dose-reduced PET images were generated by unlisting the list-mode data on PET/MRI. The acquired 20-min PET frame was reconstructed in 5 ways: a reconstruction of the first 2 min with 3 iterations and 28 subsets for reference, and reconstructions simulating 100%, 20%, 10%, and 5% of the original dose. General image quality and artifacts, image sharpness, image noise, and lesion detectability were analyzed using a 4-point scale. Qualitative parameters were compared using the nonparametric Friedman test for multiple samples and the Wilcoxon signed-rank test for paired samples. Different groups of independent samples were compared using the Mann-Whitney test. Overall, 355 lesions (71 lesions with 5 different reconstructions each) were evaluated. The 20-min reconstruction with 100% injected dose showed the best results in all categories. For general image quality and artifacts, image sharpness, and noise, the reconstructions with a simulated dose of 20% and 10% were significantly better than the 2-min reconstructions ( ≤ 0.001). Furthermore, 20%, 10%, and 5% reconstructions did not yield results different from those of the 2-min reconstruction for detectability of the primary lesion. For 10% of the injected dose, a calculated mean dose of 22.6 ± 5.5 MBq (range, 17.9-36.9 MBq) would have been applied, resulting in an estimated whole-body radiation burden of 0.5 ± 0.1 mSv (range, 0.4-0.7 mSv). Ten percent of the standard dose of F-FDG (reduction of ≤90%) results in clinically acceptable PET image quality in time-of-flight PET/MRI. The calculated radiation exposure would be comparable to the effective dose of a single digital mammogram. A reduction of radiation burden to this level might justify partial-body examinations with PET/MRI for dedicated indications.
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http://dx.doi.org/10.2967/jnumed.118.209007DOI Listing
December 2018

Tissue Factor Expression Does Not Predict Mortality in Breast Cancer Patients.

Anticancer Res 2017 06;37(6):3259-3264

Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

Background: Tissue factor (TF), the trigger of coagulation, not only initiates thrombus formation, but also elicits tumor growth and invasion in breast cancer. However, the characterization of TF expression in breast cancer tissue and its prognostic value remain unclear.

Materials And Methods: Three hundred and three primary breast cancer specimens from the local tumor tissue database were immunostained for TF expression and evaluated semiquantitatively. Tumor characteristics (size, grade, nodal status, and ER expression) as well as patient's survival were assessed.

Results: Expression of TF was detected in 99% of specimens with higher expression in invasive lobular than ductal carcinoma (p=0.008). TF expression correlated with ER expression (p<0.0001) and inversely with tumor grade (p=0.006). Survival analysis did not reveal any prognostic impact of TF expression (p=0.966).

Conclusion: This study - by analyzing TF expression in the largest cohort of breast cancer patients so far - does not support a prognostic impact of TF expression.
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http://dx.doi.org/10.21873/anticanres.11689DOI Listing
June 2017

Adjuvant treatment recommendations for patients with ER-positive/HER2-negative early breast cancer by Swiss tumor boards using the 21-gene recurrence score (SAKK 26/10).

BMC Cancer 2017 04 13;17(1):265. Epub 2017 Apr 13.

Luzerner Kantonsspital, Lucerne, Switzerland.

Background: To evaluate the effect of Recurrence Score® results (RS; Oncotype DX® multigene assay ODX) on treatment recommendations by Swiss multidisciplinary tumor boards (TB).

Methods: SAKK 26/10 is a multicenter, prospective cohort study of early breast cancer patients: Eligibility: R0-resection, ≥10% ER+ malignant cells, HER2-, pN0/pN1a. Patients were stratified into low-risk (LR) and non-low-risk (NLR) groups based on involved nodes (0 vs 1-3) and five additional predefined risk factors. Recommendations were classified as hormonal therapy (HT) or chemotherapy plus HT (CT + HT). Investigators were blinded to the statistical analysis plan. A 5%/10% rate of recommendation change in LR/NLR groups, respectively, was assumed independently of RS (null hypotheses).

Results: Two hundred twenty two evaluable patients from 18 centers had TB recommendations before and after consideration of the RS result. A recommendation change occurred in 45 patients (23/154 (15%, 95% CI 10-22%) in the LR group and 22/68 (32%, 95% CI 22-45%) in the NLR group). In both groups the null hypothesis could be rejected (both p < 0.001). Specifically, in the LR group, only 5/113 (4%, 95% CI 1-10%) with HT had a recommendation change to CT + HT after consideration of the RS, while 18/41 (44%, 95% CI 28-60%) of patients initially recommended CT + HT were subsequently recommended only HT. In the NLR group, 3/19 (16%, 95% CI 3-40%) patients were changed from HT to CT + HT, while 19/48 (40%, 95% CI 26-55%) were changed from CT + HT to HT.

Conclusion: There was a significant impact of using the RS in the LR and the NLR group but only 4% of LR patients initially considered for HT had a recommendation change (RC); therefore these patients could forgo ODX testing. A RC was more likely for NLR patients considered for HT. Patients considered for HT + CT have the highest likelihood of a RC based on RS.
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http://dx.doi.org/10.1186/s12885-017-3261-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390385PMC
April 2017

First ultrasound diagnosis of BI-RADS 3 lesions in young patients: Can 6-months follow-up be sufficient to assess stability?

Eur J Radiol 2017 Apr 16;89:226-233. Epub 2017 Feb 16.

Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Switzerland. Electronic address:

Objectives: To evaluate the outcome of repeated short-term follow-up with ultrasound in no high-risk young patients with a BI-RADS3 lesion at first examination.

Methods: In this IRB-approved study 492 women, aged 18-34 years (mean±standard deviation, 28±4.5years) with first breast ultrasound examination in 2012-2014 were retrospectively evaluated. Inclusion criteria were: at least one BI-RADS3 lesion and (a) biopsy/surgical excision or (b) follow-up of at least 18 months (including a 6-month follow-up). BI-RADS category assigned during follow-up and pathologic findings in cases undergoing biopsy/surgical excision were collected. At the 6- and 18-month follow-up the recommended biopsy rates (RBR) and the corresponding positive predictive value (PPV) were calculated.

Results: In 97 patients, 151 BI-RADS3 lesions were identified. Biopsy/surgical excision was initially performed in 25/151 (16.5%) lesions. After 6-month, category was downgraded to BI-RADS1/2 in 23/126 (15.3%) and upgraded to BI-RADS4 in 9/126 lesions (7.1%). Pathological diagnosis of these lesions was fibroadenoma in 5 and benign phyllodes tumor in 4 cases (RBR 7%, PPV 44.4%). After 18-month one lesion was classified BI-RADS4 and pathological diagnosis was fibroadenoma (RBR 1.1%, PPV 0%).

Conclusions: Our preliminary data show that follow-up imaging performed after 18 months from a first BI-RADS3 diagnosis does not affect clinical treatment and 6-month follow-up may be sufficient to assess the stability of probably benign lesions.
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http://dx.doi.org/10.1016/j.ejrad.2017.02.012DOI Listing
April 2017

Uterine Tumors Resembling Ovarian Sex Cord Tumors - Treatment, recurrence, pregnancy and brief review.

Gynecol Oncol Rep 2017 Feb 11;19:53-56. Epub 2017 Jan 11.

Department of Gynecology, Zurich University Hospital, CH-8091 Zurich, Switzerland.

Background: Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCT) are rare tumors of low malignancy. In the past, these tumors were mainly treated by hysterectomy. More recently, some authors have proposed conservative surgical management for women wishing to preserve fertility. This article is the first to report on organ-preserving treatment in the case of recurrence or disease persistence.

Cases: We report on three patients with UTROSCT, two of them young, not having completed family planning. One even gave birth to a healthy child after fertility-preserving treatment of a persistent UTROSCT. To our knowledge, this is the first pregnancy reported after surgical treatment of a persistent UTROSCT so far.

Conclusion: A fertility-sparing approach should always be considered in young women with UTROSCT who wish to preserve their fertility, also in cases of recurrence or disease persistence.
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http://dx.doi.org/10.1016/j.gore.2017.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5238603PMC
February 2017

A Micro CT Study in Patients with Breast Microcalcifications Using a Mathematical Algorithm to Assess 3D Structure.

PLoS One 2017 20;12(1):e0169349. Epub 2017 Jan 20.

Department of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Purpose: The aim of this study was to evaluate the relevance of the three-dimensional (3D) structure of breast microcalcifications (MC) as a predictor of malignancy using highly resolved micro-computed tomography (micro-CT) datasets of biopsy samples.

Material And Methods: The study included 28 women with suspicious MC in their mammogram undergoing vacuum-assisted biopsy. Directly after the intervention, the specimens were scanned in a micro-CT with an isometric spatial resolution of 9 μm. Datasets were analysed regarding the number, volume and morphology of suspicious non-monomorphic MC (fl-fine linear, fp-fine pleomorphic, ch-coarse heterogeneous) and the structure model index (SMI). Histological evaluation was performed according to the B-classification: normal tissue or benign (group A: B1, B2), unclear malignant potential or suspicious of malignancy (group B: B3, B4) and malignant lesions (group C: B5).

Results: In all groups, suspicious non-monomorphic MC were found: group A exhibited fp MC in 38.5% of samples, no fl/ch; group B: fl 14.3%, fp 28.6%, ch 14.3%; group C always had at least one type of suspicious non-monomorphic MC (fl (57.1%) or fp (57.1%)) in each sample. The different histologic groups showed a similar mean SMI (benign: 2.97 ± 0.31, malignant: 3.02 ± 0.10, unclear: 2.90 ± 0.28). Between the three groups, no significant differences were found regarding number, volume or SMI value of MC.

Conclusion: 3D structure based on the SMI of MC analysed with highest spatial resolution is not significantly associated with the B-classification of breast lesions. Thus, magnification views of MC may be omitted in the analysis of MC detected in mammograms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169349PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5249054PMC
August 2017

Tracking the origin of simultaneous endometrial and ovarian cancer by next-generation sequencing - a case report.

BMC Cancer 2017 01 19;17(1):66. Epub 2017 Jan 19.

Institute of Pathology, University Hospital Zurich, Zurich, Switzerland.

Background: Endometrioid adenocarcinoma of the uterus and ovarian endometrioid carcinoma share many morphological and molecular features. Differentiation between simultaneous primary carcinomas and ovarian metastases of an endometrial cancer may be very challenging but is essential for prognostic and therapeutic considerations.

Case Presentation: In the present case study of a 33 year-old patient we used targeted amplicon next-generation re-sequencing for clarifying the origin of synchronous endometrioid cancer of the corpus uteri and the left ovary. The patient developed a metachronous lung metastasis of an endometrioid adenocarcinoma four years after hyster- and adnexectomy, vaginal brachytherapy and treatment with the synthetic steroid tibolone. Removal of the metastasis and megestrol treatment for seven years led to a complete remission. A total of 409 genes from the Ampliseq Comprehensive Cancer Panel (Ion Torrent, Thermo Fisher) were analysed by next generation sequencing and mutations in 10 genes, including ARID1A, CTNNB1, PIK3CA and PTEN were identified and confirmed by Sanger sequencing. Primary endometrial as well as ovarian cancer showed an identical mutational profile, suggesting the presence of an ovarian metastasis of the endometrial cancer, rather than a simultaneous endometrial and ovarian cancer. The metachronous lung metastasis showed a different mutational profile compared to the primary cancer. Immunohistochemical staining of the corresponding proteins suggested that the tumour development was driven by alterations in the protein function rather than by changes of the protein abundance in the cell.

Conclusions: Our results have demonstrated next generation sequencing as a valuable tool in the differentiation of synchronous primary tumours and metastases, which has an important impact on the clinical decision making process. Similar to breast cancer, targeted therapies based on mutational tumour profiling will become increasingly important in endometrial and ovarian cancer. In summary, our results support the usage of next generation sequencing as a supplementary diagnostic tool, assisting in personalized precision medicine.
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http://dx.doi.org/10.1186/s12885-017-3054-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247816PMC
January 2017

Lack of MRE11-RAD50-NBS1 (MRN) complex detection occurs frequently in low-grade epithelial ovarian cancer.

BMC Cancer 2017 01 10;17(1):44. Epub 2017 Jan 10.

Department of Gynecology, University Hospital Zurich, CH- 8091, Zurich, Switzerland.

Background: BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA breaks. The relevance of other homologous recombination repair proteins, e.g. MRE11, RAD50, NBS1 (MRN complex) in ovarian carcinomas is unclear. The objective of this study was to investigate the prevalence of lack of MRE11, RAD50, NBS1 protein detection in epithelial ovarian cancer (EOC).

Methods: A tissue microarray (TMA) with 134 EOC was immunohistochemically evaluated for MRE11, RAD50 and NBS1. Data was analysed for associations with clinicopathological parameters, histological subtype, patient overall survival and mismatch repair (MMR) protein status. Sensitivity towards the PARP inhibitor BMN673 was tested in two ovarian cancer cell lines (TOV-21 and OVTOKO) using colony formation assays.

Results: Lack of MRN complex protein detection was seen in 41% (55/134) of EOC and was more frequent in low-grade (57.6%; 19/33) than in high-grade EOC (18.8%; 36/101; n = 134; p = 0.04). There was an association with the ovarian carcinoma subtype (60.3%; 35/58 lack of detection in type I versus 26.3%; 20/76 in type II; n = 134; p < 0.001) as well as undetectable DNA mismatch repair proteins MLH1 and MSH2 (89.3%; 25/28; n = 131; p < 0.001). MRE11 knockdown led to moderately increased sensitivity towards the PARP inhibitor BMN673 in one ovarian carcinoma cell line in vitro.

Conclusions: Frequent lack of MRE11, RAD50, NBS1 protein detection in type I human ovarian carcinomas is observed in EOC and our data suggests further investigation regarding sensitivity to PARP-inhibition in tumours lacking MRE11 expression.
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http://dx.doi.org/10.1186/s12885-016-3026-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223425PMC
January 2017

Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer.

Oncotarget 2017 Jan;8(4):6057-6066

The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.

Purpose: To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition.

Experimental Design: The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry.

Results: A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 -9.4 (SD +/- 0.29) vs -8.1 (SD +/- 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases.

Conclusions: A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by γH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs.
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http://dx.doi.org/10.18632/oncotarget.14011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351612PMC
January 2017

Acrokeratosis paraneoplastica in serous ovarian carcinoma: case report.

BMC Cancer 2015 Jul 8;15:507. Epub 2015 Jul 8.

Department of Gynaecology, University Hospital Zurich, Frauenklinikstrasse, 8091, Zurich, Switzerland.

Background: Acrokeratosis paraneoplastica is a rare paraneoplastic phenomenon associated with upper aerodigestive tract carcinomas, usually manifesting as psoriasiform keratosis over the acral sites. It is primarily seen in white males above the age of 40 years. Here we report a case of paraneoplastic acrokeratosis in a woman with serous ovarian cancer. To the best of our knowledge, no similar case has been reported previously.

Case Presentation: We report the case of a 60-year-old woman diagnosed with a serous ovarian cancer and complaining of a thickening and peeling of the skin on her feet. Clinical and histological examination, as well as the course of disease, confirmed the diagnosis of a paraneoplastic plantar keratosis. Under systemic chemotherapy with carboplatin and paclitaxel the lesion resolved gradually in concordance with tumour marker CA 125.

Conclusions: We present the reported case of paraneoplastic acrokeratosis associated with advanced high-grade ovarian cancer.
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http://dx.doi.org/10.1186/s12885-015-1527-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495707PMC
July 2015

Prolonged complete remission of metastatic HER2-positive breast cancer after continuous trastuzumab treatment: a case report and review of the literature.

Target Oncol 2015 Jun 17;10(2):297-301. Epub 2014 Dec 17.

Division of Gynecology, University Hospital of Zurich, Frauenklinistrasse, CH-8091, Zurich, Switzerland,

Metastatic breast cancer is considered an incurable disease. Targeted treatments against the human epidermal growth factor receptor 2 (HER2), however, significantly improve survival in patients with metastatic HER2-positive breast cancer. Some patients may respond with prolonged complete remission. Evidence on safety of long-term trastuzumab and risk of relapse after trastuzumab cessation is limited. We present a case of an 81-year-old patient with HER2-amplified metastatic breast cancer (MBC) in the liver. Following taxane-based chemotherapy in combination with trastuzumab after local treatment resulted in a complete radiological remission after 21 months of trastuzumab maintenance therapy. The patient remains in complete remission 6 years later and continues to receive trastuzumab as maintenance therapy. Prolonged remission in cases with complete response under trastuzumab-based regimens for metastatic HER2-positive breast cancer can be observed in some patients. Reviewing the few available cases published in the literature, these patients share some common characteristics: hormone receptor negative disease and metastases to the liver. There is no evidence that trastuzumab maintenance treatment can be safely interrupted after a certain time period.
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http://dx.doi.org/10.1007/s11523-014-0350-9DOI Listing
June 2015

Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition.

Oncotarget 2014 Jul;5(14):5295-303

Department of Gynecology, University Hospital of Zurich, Zürich, Switzerland.

ARID1A mutations are observed in various tumors, including ovarian clear cell (OCCC) and endometrioid carcinomas, endometrial, and breast carcinomas. They commonly result in loss of ARID1A-protein expression and frequently co-occur with PI3K/AKT-pathway activating mechanisms. The aim of this study was to test the hypothesis as to whether PI3K/AKT-pathway activation is a critical mechanism in ARID1A-mutated tumors and if consequently ARID1A-deficient tumors show increased sensitivity to treatment with PI3K- and AKT-inhibitors. Upon ARID1A knockdown, MCF7 breast cancer cells and primary MRC5 cells exhibited a significantly increased sensitivity towards the AKT-inhibitors MK-2206 and perifosine, as well as the PI3K-inhibitor buparlisib. Knockdown of ARID1A in MCF7 led to an increase of pAKT-Ser473. AKT-inhibition with MK-2206 led to increased apoptosis and to a decrease of pS6K in ARID1A-depleted MCF7 cells but not in the controls. In five OCCC cell lines ARID1A-deficiency correlated with increased pAKT-Ser473 levels and with sensitivity towards treatment with the AKT-inhibitor MK-2206. In conclusion, ARID1A-deficient cancer cells demonstrate an increased sensitivity to treatment with small molecule inhibitors of the PI3K/AKT-pathway. These findings suggest a specific requirement of the PI3K/AKT pathway in ARID1A-deficient tumors and reveal a synthetic lethal interaction between loss of ARID1A expression and inhibition of the PI3K/AKT pathway.
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http://dx.doi.org/10.18632/oncotarget.2092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170604PMC
July 2014

Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro.

PLoS One 2014 13;9(6):e100041. Epub 2014 Jun 13.

Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland.

Aim Of The Study: To evaluate the frequency of MRE11/RAD50/NBS1 (MRN)-complex loss of protein expression in endometrial cancers (EC) and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose) polymerase (PARP)-inhibitory treatment.

Methods: MRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T) allele in MRE11 was sequenced in selected cases (n = 26). Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR) DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment.

Results: Loss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T) mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells.

Conclusion: Loss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100041PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057395PMC
December 2015

Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast.

J Pathol 2014 Apr 5;232(5):553-65. Epub 2014 Feb 5.

The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.

Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC-NSTs, and recurrent mutations affecting mitogen-activated protein kinase family genes and NBPF10. RNA-sequencing analysis identified 17 high-confidence fusion genes, eight of which were validated and two of which were in-frame. No recurrent fusions were identified in an independent series of MPCs and IC-NSTs. Forced expression of in-frame fusion genes (SLC2A1-FAF1 and BCAS4-AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out-of-frame rearrangements was found in one MPC and in 13% of HER2-positive breast cancers, identified through a re-analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild-type CDK12 in a CDK12-null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities.
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http://dx.doi.org/10.1002/path.4325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013428PMC
April 2014

ARID1A mutations and PI3K/AKT pathway alterations in endometriosis and endometriosis-associated ovarian carcinomas.

Int J Mol Sci 2013 Sep 12;14(9):18824-49. Epub 2013 Sep 12.

Division of Gynecology, University Hospital Zurich, Frauenklinikstrasse 10, Zurich CH-8091, Switzerland.

Endometriosis is a common gynecological disease affecting 6%-10% of women of reproductive age and is characterized by the presence of endometrial-like tissue in localizations outside of the uterine cavity as, e.g., endometriotic ovarian cysts. Mainly, two epithelial ovarian carcinoma subtypes, the ovarian clear cell carcinomas (OCCC) and the endometrioid ovarian carcinomas (EnOC), have been molecularly and epidemiologically linked to endometriosis. Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) have been found to occur in high frequency in OCCC and EnOC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWI/SNF chromatin remodeling complex and considered as a bona fide tumor suppressor. ARID1A mutations frequently co-occur with mutations, leading to an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, such as mutations in PIK3CA encoding the catalytic subunit, p110α, of PI3K. In combination with recent functional observations, these findings strongly suggest cooperating mechanisms between the two pathways. The occurrence of ARID1A mutations and alterations in the PI3K/AKT pathway in endometriosis and endometriosis-associated ovarian carcinomas, as well as the possible functional and clinical implications are discussed in this review.
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http://dx.doi.org/10.3390/ijms140918824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794809PMC
September 2013

Histone deacetylase inhibitors down-regulate G-protein-coupled estrogen receptor and the GPER-antagonist G-15 inhibits proliferation in endometriotic cells.

Fertil Steril 2013 Sep 10;100(3):770-6. Epub 2013 Jun 10.

Department of Gynecology, University Hospital Zurich, Zurich, Switzerland.

Objective: To investigate whether histone deacetylase inhibitors reduce the expression of the G-protein-coupled estrogen receptor (GPER) and whether the functional inhibition of GPER by the antagonist G-15 decreases the proliferation of endometriotic cells.

Design: In vitro study.

Setting: University hospital.

Patient(s): Immortalized epithelial endometriotic cells.

Intervention(s): Treatment with the histone deacetylase inhibitor romidepsin or suberoylanilide hydroxamic acid (SAHA), or with the GPER antagonist G-15.

Main Outcome Measure(s): Western blot analysis and quantitative real-time polymerase chain reaction (PCR) were used to monitor the expression of GPER in response to drug treatment. Effects of GPER stimulation and inhibition on cell proliferation were investigated by the 93-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (Sigma) (MTT) assay.

Result(s): Our results demonstrate that romidepsin and SAHA reduce GPER expression in a concentration-dependent manner. This reduction correlated with the accumulation of acetylated histones. No decreased expression of the estrogen receptor (ER)-α and ERβ was found under comparable experimental conditions. Pretreatment of endometriotic cells with the GPER agonist G-1 stimulated cell proliferation accompanied by rapid Akt phosphorylation. G-15 reversed this stimulation and inhibited cell proliferation, which was accompanied by Akt dephosphorylation.

Conclusion(s): G-protein-coupled estrogen receptor is proposed as a potential therapeutic target in endometriosis. The down-regulation of GPER and/or the impairment of its function may reduce the estrogen responsiveness in endometriosis, and therefore might be considered a possible treatment option of endometriosis.
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http://dx.doi.org/10.1016/j.fertnstert.2013.05.008DOI Listing
September 2013
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