Publications by authors named "Martin Filipits"

106 Publications

Detection of EGFR Activating and Resistance Mutations by Droplet Digital PCR in Sputum of EGFR-Mutated NSCLC Patients.

Clin Med Insights Oncol 2021 17;15:1179554921993072. Epub 2021 Feb 17.

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

Background: Proof of the T790M resistance mutation is mandatory if patients with -mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of mutations.

Methods: Twenty-eight patients with advanced -mutated NSCLC were included during stable and/or progressive disease. The initial activating mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR).

Results: Activating mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80.

Conclusions: We demonstrated that mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.
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http://dx.doi.org/10.1177/1179554921993072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894584PMC
February 2021

The Allele Frequency of EGFR Mutations Predicts Survival in Advanced EGFR T790M-Positive Non-small Cell Lung Cancer Patients Treated with Osimertinib.

Target Oncol 2021 Jan 3;16(1):77-84. Epub 2020 Dec 3.

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.

Background: The allele frequency of epidermal growth factor receptor (EGFR) mutations could be a potential molecular biomarker for the outcome of osimertinib therapy.

Objective: The purpose of our study was to assess the clinical relevance of the allele frequency of EGFR mutations in plasma-based circulating tumor DNA (ctDNA) before starting osimertinib therapy in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) who had progressed under treatment with EGFR tyrosine kinase inhibitors (TKIs).

Patients And Methods: We enrolled 141 patients with advanced EGFR T790M-positive NSCLC who underwent second-line osimertinib treatment. Plasma ctDNA was tested for EGFR-activating mutations (EGFR deletions in exon 19, L858R, L861Q, S768I) and T790M by means of droplet digital polymerase chain reaction (ddPCR).

Results: The allele frequency of EGFR-activating mutations in plasma ctDNA before osimertinib initiation ranged from 0 to 81,543 copies/ml and was independently associated with progression-free survival (PFS) and overall survival (OS) after adjusting for known clinicopathological risk factors (PFS: adjusted hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.15-1.39, P < 0.0001; OS: adjusted HR 1.32, 95% CI 1.18-1.47, P < 0.0001). The allele frequency of T790M in plasma ctDNA before starting osimertinib therapy ranged from 0 to 38,092 copies/ml. Multivariate analyses showed that a higher T790M allele frequency was associated with a trend towards a shorter PFS (adjusted HR 1.19, 95% CI 0.99-1.42, P = 0.05) and a significantly shorter OS (adjusted HR 1.25, 95% CI 1.02-1.53, P = 0.03) of the patients.

Conclusion: A higher allele frequency of EGFR mutations, particularly EGFR-activating mutations, in plasma ctDNA is a poor prognostic marker. Further studies on the clinical utility of liquid biopsy are needed.
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http://dx.doi.org/10.1007/s11523-020-00781-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810636PMC
January 2021

Evaluation of an Assay for MGMT Gene Promoter Methylation in Glioblastoma Samples.

Anticancer Res 2020 Nov;40(11):6229-6236

Department of Pathology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, U.S.A.

Background/aim: To compare the GeneXpert® O6-methylguanine DNA methyltransferase (MGMT) methylation prototype (GX MGMT) assay with pyrosequencing in glioblastomas.

Materials And Methods: The MGMT methylation status was retrospectively assessed in formalin-fixed paraffin embedded (FFPE) tumor blocks from 262 glioblastoma patients obtained from three independent cohorts using either a standard of care pyrosequencing laboratory developed test or the GX MGMT assay.

Results: The concordance rate was 92.1% (58/63) for Oregon Health and Science University (OSHU) samples, 91.7% (88/96) for Medical University of Vienna (MUV) samples, and 82.5% (85/103) for Kepler University Hospital (KUH) samples. Patients with MGMT promoter hypermethylation assessed by pyrosequencing or the GX MGMT test had a significantly longer overall survival compared to patients without hypermethylation (HR=0.43, 95%CI=0.26-0.72, p=0.001 and HR=0.51, 95%CI=0.31-0.84, p=0.008, respectively).

Conclusion: Standardized, simplified, and on-demand testing of MGMT promoter methylation by the GX MGMT assay is feasible.
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http://dx.doi.org/10.21873/anticanres.14643DOI Listing
November 2020

Retrospective analysis of the prevalence of specialised palliative care services for patients with metastatic breast cancer.

ESMO Open 2020 09;5(5):e000905

Department of Internal Medicine 2, UH Krems, Krems, Austria. Electronic address:

Background: Patients with metastatic breast cancer (MBC) have a considerable symptom burden and may require extensive care for a long period of time. Palliative care (PC) has the potential to improve their quality of care and reduce their use of medical services. However, the role of specialised PC (SPC) in patients with MBC remains unclear.

Patients And Methods: We performed a retrospective analysis of the medical records of patients diagnosed with breast cancer (BC) from 2008 to 2018 at an university-based referral centre to examine the extent of early and late integration of SPC services for patients with MBC. A descriptive analysis of the patients was also established.

Results: In all, 932 patients were diagnosed with BC from 2008 to 2018; 225 of these patients had or developed metastases related to their BC. In addition, 132 patients received SPC (58.7%) and 93 patients did not receive SPC (41.3%). The median probability of overall survival (OS) for patients who did not receive SPC services was 3.6 years (95% CI 2.0 to 5.1) and 1.8 years (95% CI 1.3 to 2.3) (p<0.0001) for patients who did receive SPC. In multivariate analysis, referral to SPC services was independently associated with OS (HR 1.60, 95% CI 1.16 to 2.22, p=0.004).

Conclusion: Patients who received SPC lived significantly shorter amounts of time than patients not referred for SPC services at our hospital. We concluded that the referral to SPC services was often too late and should be implemented earlier in the course of the disease. We suggest that patients with MBC should participate in a consultation by a SPC team ≤60 days after the start of systemic palliative anticancer therapy in addition to endocrine treatment. Larger prospective studies are needed to evaluate the benefit of the early integration of SPC services for patients with MBC.
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http://dx.doi.org/10.1136/esmoopen-2020-000905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511635PMC
September 2020

Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns.

Cancers (Basel) 2020 Jun 19;12(6). Epub 2020 Jun 19.

Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.

Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres ( = 0.086), and changes in expression of miR449a ( = 0.157), HDAC4 ( = 0.146) and HDAC9 ( = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN.
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http://dx.doi.org/10.3390/cancers12061625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352723PMC
June 2020

Prognostic Value of EndoPredict in Women with Hormone Receptor-Positive, HER2-Negative Invasive Lobular Breast Cancer.

Clin Cancer Res 2020 Sep 19;26(17):4682-4687. Epub 2020 Jun 19.

Medical University of Vienna, Department of Surgery and Comprehensive Cancer Centre, Vienna, Austria.

Purpose: Invasive lobular carcinoma (ILC) accounts for approximately 5%-15% of all invasive breast cancer cases. Most of the correlations between multigene assays and patient outcome were derived from studies based on patients with invasive ductal carcinoma (IDC) or without distinction between the subtypes. Here, we investigate the prognostic value of EndoPredict (EPclin) in a large cohort of ILCs pooled from three phase III randomized trials (ABCSG-6, ABCSG-8, TransATAC).

Experimental Design: The primary objective of this analysis was to determine the prognostic value of EPclin for distant recurrence (DR) in years 0-10 in postmenopausal women with ILC. The primary outcome was DR.

Results: 470 women (17.9%) presented with ILC, 1,944 (73.9%) with IDC, and 216 (8.2%) with other histologic types. EPclin was highly prognostic in women with ILC [HR = 3.32 (2.54-4.34)] and provided more prognostic value than the Clinical Treatment Score [CTS; HR = 2.17 (1.73-2.72)]. 63.4% of women were categorized into the low EPclin risk group and they had a 10-year DR of 4.8% (2.7-8.4) compared with 36.6% of women in the high-risk group with a 10-year DR risk of 26.6% (20.0-35.0). EPclin also provided highly prognostic information in women with node-negative disease [HR = 2.56 (1.63-4.02)] and node-positive disease [HR = 3.70 (2.49-5.50)].

Conclusions: EPclin provided highly significant prognostic value and significant risk stratification for women with ILC. Ten-year DR risk in the EPclin low-risk groups were similar between ILC and IDC. Our results show that EPclin is informative in women with ILC and suggest that it is equally valid in both histologic subtypes.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0260DOI Listing
September 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 Nov 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

IDO1 Paneth cells promote immune escape of colorectal cancer.

Commun Biol 2020 May 22;3(1):252. Epub 2020 May 22.

Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria.

Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1) Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1 Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1 Paneth cells as a target for immunotherapy.
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http://dx.doi.org/10.1038/s42003-020-0989-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244549PMC
May 2020

mutation tracking predicts survival in advanced -mutated non-small cell lung cancer patients treated with osimertinib.

Transl Lung Cancer Res 2020 Apr;9(2):239-245

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

Background: Osimertinib has become standard therapy of advanced epidermal growth factor receptor ()-mutated non-small cell lung cancer (NSCLC) patients and T790M-mediated resistance. We investigated the clinical utility of mutation tracking in plasma-based circulating tumor DNA (ctDNA) after start of osimertinib therapy in metastatic, -mutant NSCLC patients who had progressed on prior therapy with EGFR tyrosine kinase inhibitors (TKIs).

Methods: We enrolled 141 patients with advanced -mutated NSCLC who underwent second-line osimertinib treatment for T790M-positive disease. After initiation of osimertinib, we obtained plasma samples from 108 patients. Plasma ctDNA was tested for mutations by means of droplet digital PCR and was termed positive if any mutation was detected.

Results: Plasma ctDNA was detected in 58 of 108 (54%) patients after osimertinib initiation and was associated with poor progression-free survival (PFS) [hazard ratio (HR) 4.26, 95% confidence interval (CI): 2.55-7.10, P<0.0001] and overall survival (OS) (HR 3.23, 95% CI: 1.80-5.78, P<0.0001). In multivariable analysis, ctDNA status remained significantly associated with PFS and OS (HR 4.87, 95% CI: 2.81-8.44, P<0.0001; HR 3.49, 95% CI: 1.88-6.50, P<0.0001). Patients with persistence of activating EGFR mutations within eight weeks had shorter durations of PFS (HR 6.17, 95% CI: 3.03-12.56, P<0.0001) and OS (HR 4.83, 95% CI: 2.25-10.36, P<0.0001) than patients with total clearance of the activating EGFR mutation. Persistence of activating EGFR mutations in plasma ctDNA remained an independent predictor of poor PFS and OS in multivariable analyses.

Conclusions: Patients with persistence of activating mutations in plasma ctDNA within eight weeks after osimertinib initiation have worse prognosis and may require the addition of chemotherapy or other treatments in order to achieve better outcome.
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http://dx.doi.org/10.21037/tlcr.2020.03.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225165PMC
April 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

Beyond tissue biopsy: a diagnostic framework to address tumor heterogeneity in lung cancer.

Curr Opin Oncol 2020 01;32(1):68-77

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

Purpose Of Review: The objective of this review is to discuss the strength and limitations of tissue and liquid biopsy and functional imaging to capture spatial and temporal tumor heterogeneity either alone or as part of a diagnostic framework in non-small cell lung cancer (NSCLC).

Recent Findings: NSCLC displays genetic and phenotypic heterogeneity - a detailed knowledge of which is crucial to personalize treatment. Tissue biopsy often lacks spatial and temporal resolution. Thus, NSCLC needs to be characterized by complementary diagnostic methods to resolve heterogeneity. Liquid biopsy offers detection of tumor biomarkers and for example, the classification and monitoring of EGFR mutations in NSCLC. It allows repeated sampling, and therefore, appears promising to address temporal aspects of tumor heterogeneity. Functional imaging methods and emerging image analytic tools, such as radiomics capture temporal and spatial heterogeneity. Further standardization of radiomics is required to allow introduction into clinical routine.

Summary: To augment the potential of precision therapy, improved diagnostic characterization of tumors is pivotal. We suggest a comprehensive diagnostic framework combining tissue and liquid biopsy and functional imaging to address the known aspects of spatial and temporal tumor heterogeneity on the example of NSCLC. We envision how this framework might be implemented in clinical practice.
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http://dx.doi.org/10.1097/CCO.0000000000000598DOI Listing
January 2020

From crizotinib to lorlatinib: continuous improvement in precision treatment of ALK-positive non-small cell lung cancer.

ESMO Open 2019 8;4(5):e000548. Epub 2019 Sep 8.

Internal Medicine I, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1136/esmoopen-2019-000548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735665PMC
September 2019

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

Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus chemotherapy or endocrine therapy alone.

Breast Cancer Res Treat 2019 Jul 30;176(2):377-386. Epub 2019 Apr 30.

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

Purpose: EndoPredict (EPclin) is a prognostic test validated to inform decisions on adjuvant chemotherapy to endocrine therapy alone for patients with oestrogen receptor-positive, HER2-negative breast cancer. Here, we determine the performance of EPclin for estimating 10-year distant recurrence-free interval (DRFI) rates for those who received adjuvant endocrine therapy (ET) alone compared to those with chemotherapy plus endocrine therapy (ET + C).

Methods: A total of 3746 women were included in this joint analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET + C (GEICAM 2003-02/9906). The primary objective was to evaluate the ability of EPclin to provide an estimate of the 10-year DR rate as a continuous function of EPclin separately for ET alone and ET + C. Cox proportional hazard models were used for these analyses.

Results: EPclin was highly prognostic for DR in women who received ET alone (HR 2.79 (2.49-3.13), P < 0.0001) as well as in those who received ET + C (HR 2.27 (1.99-2.59), P < 0.0001). Women who received ET + C had significantly smaller increases in 10-year DR rates with the increasing EPclin score than those receiving ET alone (EPclin = 5; 12% ET + C vs. 20% ET alone). We observed a significant positive interaction between EPclin and treatment groups (P- = 0.022).

Conclusions: In this comparative non-randomised analysis, the rate of increase in DR with EPclin score was significantly reduced in women who received ET + C versus ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease.
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http://dx.doi.org/10.1007/s10549-019-05226-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555778PMC
July 2019

EGFR Mutations in Cell-free Plasma DNA from Patients with Advanced Lung Adenocarcinoma: Improved Detection by Droplet Digital PCR.

Target Oncol 2019 04;14(2):197-203

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.

Background: Analysis of cell-free DNA from blood could provide an alternative method for identifying genomic changes in the tumors of patients with advanced lung adenocarcinoma.

Objective: We compared the performance of droplet digital PCR (ddPCR) and Cobas EGFR Mutation Test v2 (Cobas) for detecting EGFR mutations in cell-free plasma DNA.

Patients And Methods: Plasma samples from patients with advanced EGFR-mutated lung adenocarcinoma were analyzed for EGFR T790M, exon 19 deletions, and L858R mutations by both ddPCR and Cobas.

Results: T790M testing was performed in 354 plasma samples collected from 129 patients. The concordance rate between ddPCR and Cobas for T790M, sensitivity, and specificity were 86, 100, and 85%, respectively. Exon 19 deletions were analyzed in 196 plasma samples obtained from 71 of the 129 patients using both platforms. The concordance rate between ddPCR and Cobas for exon 19 deletions, sensitivity, and specificity were 90, 92, and 89%, respectively. L858R mutations were studied in 124 plasma samples obtained from 44 of the 129 patients using both assays. The concordance rate between ddPCR and Cobas for L858R, sensitivity, and specificity were 90, 91, and 89%, respectively. In patients who progressed under treatment with an EGFR TKI (n = 50), the T790M positivity rate was 66% using ddPCR, but only 24% using Cobas.

Conclusions: We observed a high concordance between ddPCR and Cobas in detecting EGFR mutations in plasma samples of patients with advanced EGFR-mutated lung adenocarcinoma, but ddPCR was more sensitive than Cobas.
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http://dx.doi.org/10.1007/s11523-019-00623-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453866PMC
April 2019

PIK3CA Mutational Status Is Associated with High Glycolytic Activity in ER+/HER2- Early Invasive Breast Cancer: a Molecular Imaging Study Using [F]FDG PET/CT.

Mol Imaging Biol 2019 10;21(5):991-1002

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

Purpose: In PIK3CA mutant breast cancer, downstream hyperactivation of the PI3K/AKT/mTOR pathway may be associated with increased glycolysis of cancer cells. The purpose of this study was to investigate the functional association of PIK3CA mutational status and tumor glycolysis in invasive ER+/HER2- early breast cancer.

Procedures: This institutional review board-approved retrospective study included a dataset of 67 ER+/HER2- early breast cancer patients. All patients underwent 2-deoxy-2-[F]fluoro-D-glucose positron emission tomography/X-ray computed tomography ([F]FDG PET/CT) and clinico-pathologic assessments as part of a prospective study. For this retrospective analysis, pyrosequencing was used to detect PIK3CA mutations of exons 4, 7, 9, and 20. Tumor glucose metabolism was assessed semi-quantitatively with [F]FDG PET/CT using maximum standardized uptake values (SUV). SUV values were corrected for the partial volume effect, and metabolic tumor volume was calculated using the volume of interest automated lesion growing function 2D tumor size, i.e., maximum tumor diameter was assessed on concurrent pre-treatment contrast-enhanced magnetic resonance imaging.

Results: PIK3CA mutations were present in 45 % of all tumors. Mutations were associated with a small tumor diameter (p < 0.01) and with low nuclear grade (p = 0.04). Glycolytic activity was positively associated with nuclear grade (p = 0.01), proliferation (p = 0.002), regional lymph node metastasis (p = 0.015), and metabolic tumor volume (p = 0.001) but not with tumor size/T-stage. In invasive ductal carcinomas, median SUV was increased in PIK3CA-mutated compared to wild-type tumors; however, this increase did not reach statistical significance (p = 0.05). Multivariate analysis of invasive ductal carcinomas revealed [F]FDG uptake to be independently associated with PIK3CA status (p = 0.002) and nuclear tumor grade (p = 0.046). Size, volume, and regional nodal status had no influence on glycolytic activity. PIK3CA mutational status did not influence glycolytic metabolism in lobular carcinomas. Glycolytic activity and PIK3CA mutational status had no significant influence on recurrence-free survival or disease-specific survival.

Conclusions: In ER+/HER2- invasive ductal carcinomas of the breast, glucose uptake is independently associated with PIK3CA mutations. Initial data suggest that [F]FDG uptake reflects complex genomic alterations and may have the potential to be used as candidate biomarker for monitoring therapeutic response and resistance mechanisms in emerging therapies that target the PI3K/AKT/mTOR pathway.
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http://dx.doi.org/10.1007/s11307-018-01308-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489296PMC
October 2019

Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib.

Target Oncol 2019 02;14(1):75-83

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.

Background: Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce.

Objective: To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib.

Patients And Methods: In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib.

Results: Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number.

Conclusion: EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.
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http://dx.doi.org/10.1007/s11523-018-0612-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403194PMC
February 2019

LACE-Bio: Validation of Predictive and/or Prognostic Immunohistochemistry/Histochemistry-based Biomarkers in Resected Non-small-cell Lung Cancer.

Clin Lung Cancer 2019 03 11;20(2):66-73.e6. Epub 2018 Oct 11.

Departments of Medical Oncology and Hematology (FAS) and Pathology (M-ST), University Health Network, Princess Margaret Cancer Centre, and the University of Toronto, Toronto, Ontario, Canada.

Background: Complete resection of non-small-cell lung cancer (NSCLC) offers the potential for cure after surgery and adjuvant chemotherapy. Patients may not benefit and may experience severe toxicity. There are no validated molecular tools to allow better patient selection.

Materials And Methods: The LACE-Bio (LACE [Lung Adjuvant Cisplatin Evaluation]) project includes 4 trials (International Adjuvant Lung Cancer Trial [IALT], Adjuvant Navelbine International Trialist Association [ANITA], JBR10, and Cancer and Leukemia Group B (CALGB)-9633). Immunohistochemistry biomarkers shown in one trial to have a prognostic/predictive effect on overall survival were tested.

Results: The majority of the promising biomarkers could not be validated; the prognostic effect of tumor infiltrating lymphocytes and β-tubulin was confirmed. Potential causes include tissue fixation, storage, the use of tissue microarrays, and varying reagent/antibody batches.

Conclusions: Immunohistochemistry assays from single trials may be misleading and require validation before being used for patient selection. LACE-Bio-2 is evaluating potential genomic biomarkers that may allow more precise selection of patients with NSCLC for adjuvant chemotherapy in NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2018.10.001DOI Listing
March 2019

Adjuvant Therapy in Patients With Completely Resected Non-small-cell Lung Cancer: Current Status and Perspectives.

Clin Lung Cancer 2019 01 24;20(1):1-6. Epub 2018 Sep 24.

Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Patients with early-stage non-small-cell lung cancer undergo surgery with curative intent. Many of these patients relapse and, therefore, adjuvant therapies are important for improving survival of these patients. Adjuvant chemotherapy has been established and increases the 5-year survival rate. Here, we discuss systemic treatment strategies for further improving outcome of patients with completely resected non-small-cell lung cancer.
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http://dx.doi.org/10.1016/j.cllc.2018.09.016DOI Listing
January 2019

PD-1 and PD-L1 Protein Expression Predict Survival in Completely Resected Lung Adenocarcinoma.

Clin Lung Cancer 2018 11 22;19(6):e957-e963. Epub 2018 Aug 22.

Institute of Cancer Research, Medical University of Vienna, Vienna, Austria; Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: We assessed the prognostic value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in patients with completely resected lung adenocarcinoma.

Patients And Methods: PD-1 and PD-L1 expression was determined using immunohistochemistry in formalin-fixed paraffin-embedded surgical specimens and correlated with the clinicopathologic features and survival of 161 patients with lung adenocarcinoma.

Results: PD-1 expression on immune cells was observed in 71 of 159 evaluable tumor samples (45%) and was not significantly associated with the clinicopathologic features. Multivariate analyses identified PD-1 expression as an independent prognostic factor for recurrence (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.95; P = .03) and death (adjusted HR, 0.48; 95% CI, 0.27-0.86; P = 0.01). PD-L1 expression on tumor cells was seen in 59 of 161 cases (37%) and correlated with KRAS mutation status (P = .02) and type of surgery (P = .01). PD-L1 expression was not associated with recurrence-free survival in the patients (adjusted HR, 0.90; 95% CI, 0.55-1.48; P = .68) but correlated with longer overall survival (adjusted HR, 0.54; 95% CI, 0.30-0.97; P = .04).

Conclusion: PD-1 and PD-L1 expression was associated with favorable overall survival in patients with completely resected adenocarcinoma of the lung.
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http://dx.doi.org/10.1016/j.cllc.2018.08.014DOI Listing
November 2018

Association of p27 and Cyclin D1 Expression and Benefit from Adjuvant Trastuzumab Treatment in HER2-Positive Early Breast Cancer: A TransHERA Study.

Clin Cancer Res 2018 07 12;24(13):3079-3086. Epub 2018 Mar 12.

Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.

To assess the prognostic and predictive value of selected biomarkers involved in cell-cycle regulation or proliferation in patients with HER2-positive early breast cancer. Protein expression of TOP2A, Ki67, cyclin D1, and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 years; = 561) and observation ( = 301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables (predefined cutoffs). Interaction terms between biomarkers and treatment were assessed in multivariate Cox models adjusted for variables of clinical interest. A significant interaction was detected between p27 and treatment (adjusted = 0.0049). Trastuzumab effect was significant in the p27-low subgroup (≤70% p27-positive tumor cells; = 318). HR 0.44, 95% CI, 0.29-0.65 ( < 0.001). No trastuzumab effect was observed in the p27-high subgroup = 435; HR 0.97, 95% CI, 0.66-1.44, = 0.89), indicating that these patients derived little or no benefit from trastuzumab treatment. A prognostic effect of p27 on DFS was observed, with p27-high patients experiencing half the hazard of a DFS event compared with low ones (HR 0.49, 95% CI, 0.32-0.75). TOP2A, Ki67, and cyclin D1, as categorical variables were not predictive, whereas cyclin D1 as continuous variable was predictive of trastuzumab benefit. In TransHERA, patients with HER2-positive early breast cancer with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3473DOI Listing
July 2018

Cell-Free Plasma DNA-Guided Treatment With Osimertinib in Patients With Advanced EGFR-Mutated NSCLC.

J Thorac Oncol 2018 06 2;13(6):821-830. Epub 2018 Mar 2.

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical Center of Vienna, Vienna, Austria. Electronic address:

Introduction: Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non-small-cell lung cancer who have been pre-treated with EGFR-tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine.

Methods: From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated non-small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients.

Results: T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1-12.1). Median survival was not reached and the 1-year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number (<10 copies/mL) (hazard ratio for PFS = 1.72, 95% CI: 0.92-3.2, p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89-5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers.

Conclusion: Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.
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http://dx.doi.org/10.1016/j.jtho.2018.02.014DOI Listing
June 2018

Pooled Analysis of the Prognostic and Predictive Effects of TP53 Comutation Status Combined With KRAS or EGFR Mutation in Early-Stage Resected Non-Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy.

J Clin Oncol 2017 Jun 28;35(18):2018-2027. Epub 2017 Apr 28.

Frances A. Shepherd and Ming-Sound Tsao, Princess Margaret Cancer Centre; University of Toronto, Toronto; Lesley Seymour, Queen's University, Kingston, Ontario, Canada; Benjamin Lacas, Gwénaël Le Teuff, Jean-Pierre Pignon, Thierry Le Chevalier, and Jean-Charles Soria, Institut Gustave-Roussy; Benjamin Lacas, Gwénaël Le Teuff, Jean-Pierre Pignon, Thierry Le Chevalier, and Jean-Charles Soria, University Paris XI, Paris; Pierre Hainaut, International Agency for Research on Cancer, Lyon; Jean-Yves Douillard, R Gauducheau, St Herblain; Elizabeth Brambilla, Inserm U823, Institut Albert Bonniot, Département de Pathologie CHU, Albert Michallon University Joseph Fourrier, Grenoble, France; Pasi A. Jänne, Dana-Farber Cancer Institute, Boston, MA; Stephen Graziano, State University of New York Upstate Medical University, Syracuse, NY; Robert Kratzke, University of Minnesota Medical School, Minneapolis, MN; and Robert Pirker and Martin Filipits, Medical University of Vienna, Vienna, Austria.

Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non-small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.
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http://dx.doi.org/10.1200/JCO.2016.71.2893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075828PMC
June 2017

Telomerase activation in posterior fossa group A ependymomas is associated with dismal prognosis and chromosome 1q gain.

Neuro Oncol 2017 Sep;19(9):1183-1194

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, Austria; Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria; Neuromed Campus, Kepler University Hospital, Linz, Austria; Institute of Neurology, Medical University of Vienna, Austria; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neuropathology, University Hospital Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurosurgery, Medical University of Vienna, Austria; Department of Radiotherapy, Medical University of Vienna, Austria.

Background: Ependymomas account for up to 10% of childhood CNS tumors and have a high rate of tumor recurrence despite gross total resection. Recently, classification into molecular ependymoma subgroups has been established, but the mechanisms underlying the aggressiveness of certain subtypes remain widely enigmatic. The aim of this study was to dissect the clinical and biological role of telomerase reactivation, a frequent mechanism of cancer cells to evade cellular senescence, in pediatric ependymoma.

Methods: We determined telomerase enzymatic activity, hTERT mRNA expression, promoter methylation, and the rs2853669 single nucleotide polymorphism located in the hTERT promoter in a well-characterized cohort of pediatric intracranial ependymomas.

Results: In posterior fossa ependymoma group A (PF-EPN-A) tumors, telomerase activity varied and was significantly associated with dismal overall survival, whereas telomerase reactivation was present in all supratentorial RelA fusion-positive (ST-EPN-RELA) ependymomas. In silico analysis of methylation patterns showed that only these two subgroups harbor hypermethylated hTERT promoters suggesting telomerase reactivation via epigenetic mechanisms. Furthermore, chromosome 1q gain, a well-known negative prognostic factor, was strongly associated with telomerase reactivation in PF-EPN-A. Additional in silico analyses of gene expression data confirmed this finding and further showed enrichment of the E-twenty-six factor, Myc, and E2F target genes in 1q gained ependymomas. Additionally, 1q gained tumors showed elevated expression of ETV3, an E-twenty-six factor gene located on chromosome 1q.

Conclusion: Taken together we describe a subgroup-specific impact of telomerase reactivation on disease progression in pediatric ependymoma and provide preliminary evidence for the involved molecular mechanisms.
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http://dx.doi.org/10.1093/neuonc/nox027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570194PMC
September 2017

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

Electronic State of Sodium trans-[Tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) in Tumor, Liver and Kidney Tissue of a SW480-bearing Mouse.

Sci Rep 2017 01 23;7:40966. Epub 2017 Jan 23.

Universität Wien, Fakultät für Chemie, Institut für Biophysikalische Chemie, Althanstraße 14, 1090 Wien, Austria.

Ruthenium complexes are promising candidates for anticancer agents, especially NKP-1339 (sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]), which is on the edge to clinical applications. The anticancer mechanism seems to be tightly linked to the redox chemistry but despite progress in human clinical trials the in vivo Ru oxidation state and the coordination of Ru remains unclear. The Ru-based anticancer drug NKP-1339 was studied applying XANES (Cl K- and Ru L-edges) in tumor, kidney and liver tissue of a SW480 bearing mouse. Based on coordination charge and 3D XANES plots containing a series of model compounds as well as pre-edge analysis of the ligand Cl K-edge it is suggested that NKP-1339 remains in its +III oxidation state after 24 hours and at least one of the four chlorido ligands remain covalently bound to the Ru ion showing a biotransformation from RuNCl to RuCl(N/O) (X = 1 or 2).
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http://dx.doi.org/10.1038/srep40966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256101PMC
January 2017

Gamma Knife Radiosurgery in Recurrent Glioblastoma.

Stereotact Funct Neurosurg 2016 8;94(4):265-272. Epub 2016 Oct 8.

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

Background: We evaluated Gamma Knife radiosurgery (GKRS) as a treatment option for patients with recurrent glioblastoma.

Patients And Methods: 42 patients with histopathologically diagnosed recurrent grade IV tumor were treated with GKRS. All patients had undergone standard multimodal first-line treatment. The average time from diagnosis to GKRS was 17.0 months. The median target volume was 5.1 cm3. The median margin dose was 10 Gy and the median central dose 20 Gy. In a subset of patients, O6-methylguanine methyltransferase (MGMT) promoter methylation analysis by pyrosequencing was performed.

Results: Most patients did not develop complications after GKRS. Time to radiological progression after initial GKRS was 4.4 months (95% CI: 3.1-5.7 months). Radiological progression mainly occurred beyond the GKRS-irradiated area. The median survival time after initial GKRS was 9.6 months (95% CI: 7.7-11.5 months). The median overall survival time from diagnosis was 25.6 months (95% CI: 21.8-29.3 months). Patients with MGMT promoter methylation survived significantly longer (33.4 months; 95% CI: 21.2-45.5 months) compared to patients without MGMT promoter methylation (16.0 months; 95% CI: 8.0-23.9 months).

Conclusion: GKRS seems to be a relatively safe salvage treatment option for recurrent glioblastoma for highly selected patients but must be seen as part of a multimodal treatment algorithm.
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http://dx.doi.org/10.1159/000448924DOI Listing
September 2017

Personalized treatment of advanced non-small-cell lung cancer in routine clinical practice.

Cancer Metastasis Rev 2016 Mar;35(1):141-50

Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Personalized treatment of patients with advanced non-small-cell lung cancer based on clinical and molecular tumor features has entered clinical routine practice. The 2015 pathological classification of lung cancer mandates immunohistochemical and molecular analysis. Therapeutic strategies focused on inhibition of angiogenesis and growth factor receptor signaling. Inhibitors of angiogenesis and monoclonal antibodies directed against the epidermal growth factor receptor have shown efficacy in combination with chemotherapy. Mutations in the epidermal growth factor receptor and anaplastic lymphoma kinase have become clinically relevant therapeutic targets. Immune checkpoint inhibitors are also entering routine clinical practice. Identification of predictive biomarkers is essential and faces several challenges including tumor heterogeneity and dynamic changes of tumor features over time. Liquid biopsies may overcome some of these challenges in the future.
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http://dx.doi.org/10.1007/s10555-016-9612-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821865PMC
March 2016