Publications by authors named "Tanja Cufer"

79 Publications

Immunotherapy for metastatic non-small cell lung cancer: Real-world data from an academic Central and Eastern European centre.

Oncologist 2021 Jul 19. Epub 2021 Jul 19.

University Clinic Golnik, Slovenia.

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) recently became the standard treatment for advanced non-small cell lung cancer (NSCLC) patients. Here, we present the first results of a real-world observational study on the effectiveness of ICI monotherapy in advanced NSCLC patients treated at a single academic centre in a Central and Eastern European (CEE) country.

Methods: Overall, 66 consecutive advanced NSCLC patients treated with ICIs in everyday clinical practice, either with first-line pembrolizumab (26 patients) or second-line atezolizumab, nivolumab or pembrolizumab (40 patients), from August 2015 to November 2018, were included. All data were retrieved from a hospital lung cancer registry, where the data is collected prospectively.

Results: Included patients had a median age of 64 years, most were male (55 %), 6 % were in performance status ≥ 2, and 18 % had controlled CNS metastases at baseline. In first-line, the median progression-free survival (mPFS) was 9.3 months, while the median overall survival (mOS) was not reached. The 1-year OS was 62 %. In second-line, the mPFS and mOS were 3.5 months and 9.9 months, respectively, with a 1-year OS of 35 %. In the overall population, adverse events of any grade were recorded in 79 % of patients and of severe grade (3 - 4) in 12 % of patients.

Conclusion: The first real-world outcomes of NSCLC immunotherapy from a CEE country suggest comparable effectiveness to those observed in clinical trials and other real-world series, mainly coming from North America and Western European countries. Further data to inform on the real-world effectiveness of immunotherapy worldwide are needed.

Implications For Practice: Following the results from pivotal trials, immunotherapy became a standard treatment of advanced NSCLC. The real-world data on immunotherapy effectiveness in everyday clinical practice is still limited. This article presents the first data on the effectiveness of mono-immunotherapy with ICIs for patients with advanced NSCLC treated at a single academic centre in a CEE country. The survival rates and observed toxicity are comparable to those achieved in randomized clinical trials and other real-world series, coming mainly from North America and Western European countries. There is a pressing need to gather further data on the effectiveness of immunotherapy in everyday practice worldwide.
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http://dx.doi.org/10.1002/onco.13909DOI Listing
July 2021

Gene Expression Levels of the Prolyl Hydroxylase Domain Proteins and but Not Are Decreased in Primary Tumours and Correlate with Poor Prognosis of Patients with Surgically Resected Non-Small-Cell Lung Cancer.

Cancers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia.

Background: Hypoxia correlates with poor prognosis in several cancer types, including lung cancer. Prolyl hydroxylase domain proteins (PHDs) play a role in cell oxygen sensing, negatively regulating the hypoxia-inducible factor (HIF) pathway. Our study aim was to evaluate , and mRNA expression levels in primary tumours and normal lungs of non-small-cell lung cancer (NSCLC) patients and to correlate it with selected regulators of HIF signalling, with clinicopathological characteristics and overall survival (OS).

Methods: Tumour tissue samples were obtained from 60 patients with surgically resected NSCLC who were treated with radical surgery. In 22 out of 60 cases, matching morphologically normal lung tissue was obtained. , and mRNA expressions were measured using RT-qPCR.

Results: The and mRNA levels in primary tumours were significantly decreased compared to those in normal lungs (both < 0.0001). and expression in tumours was positively correlated ( = 0.82; < 0.0001) and correlated well with HIF pathway downstream genes , and . Decreased and were associated with larger tumour size, higher tumour stage ( only) and squamous cell carcinoma. Patients with low and patients with low expression had shorter OS than patients with high ( = 0.02) and expression ( = 0.01). showed borderline independent prognostic values in multivariate analysis ( = 0.06). In contrast, we found no associations between expression and any of the observed parameters.

Conclusions: Our results show that reduced expression of and is associated with the development and progression of NSCLC. could be further assessed as a prognostic marker in NSCLC.
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http://dx.doi.org/10.3390/cancers13102309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150639PMC
May 2021

Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study.

Transl Lung Cancer Res 2021 Apr;10(4):1594-1607

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

Background: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM).

Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome.

Results: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS.

Conclusions: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.
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http://dx.doi.org/10.21037/tlcr-20-1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107750PMC
April 2021

Sequential afatinib and osimertinib in patients with mutation-positive non-small-cell lung cancer: final analysis of the GioTag study.

Future Oncol 2020 Dec 28;16(34):2799-2808. Epub 2020 Aug 28.

University Clinic Golnik, University of Ljubljana, 4204 Ljubljana, Slovenia.

Final overall survival (OS) and time on treatment analysis of patients with mutation-positive non-small-cell lung cancer (NSCLC) who received sequential afatinib and osimertinib. Patients (n = 203) had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months before data entry. Primary outcome was time on treatment; OS analysis was exploratory. Median time on treatment with afatinib and osimertinib was 27.7 months (90% CI: 26.7-29.9). Median OS was 37.6 months (90% CI: 35.5-41.3); median OS was 41.6 and 44.8 months in Del19-positive patients and Asian patients, respectively. In real-world clinical practice, sequential afatinib and osimertinib was associated with encouraging outcomes in patients with mutation-positive NSCLC, especially in Del19-positive patients and Asian patients. NCT03370770 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0740DOI Listing
December 2020

Access to Novel Drugs for Non-Small Cell Lung Cancer in Central and Southeastern Europe: A Central European Cooperative Oncology Group Analysis.

Oncologist 2020 03 29;25(3):e598-e601. Epub 2019 Nov 29.

Vienna Cancer Center, Medical University of Vienna - General Hospital, Vienna, Austria and Central European Cooperative Oncology Group (CECOG).

Background: Treatment of non-small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune-oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries.

Material And Methods: The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries.

Results: Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies-even for ALK inhibitors and checkpoint inhibitors in first-line-there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries.

Conclusion: The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making.
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http://dx.doi.org/10.1634/theoncologist.2019-0523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066717PMC
March 2020

Time to access to novel anticancer drugs and the correlation with ESMO-Magnitude of Clinical Benefit Scale in Slovenia.

Expert Rev Pharmacoecon Outcomes Res 2019 Dec 11;19(6):717-723. Epub 2019 Dec 11.

Department of Medical Oncology, University Clinic Golnik, Golnik, Slovenia.

: Timely access to novel anticancer drugs is challenging and value frameworks such as the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) could assist in drug prioritization. We assessed the overall time to access to novel anticancer drugs in Slovenia and its correlation with ESMO-MCBS scores.: Anticancer drugs with European Medicines Agency marketing authorization (EMA MA), applying for national reimbursement approval (NRA) in the period 2008-2018 with assigned ESMO-MCBS score, were included. Publically available data from EMA and the Slovenian National Health Insurance Institute were used for time calculations.: Among 53 studied drugs; a majority (47) of them obtained reimbursement approval within the observed time. The median time to EMA MA was 397 (range 98-615) days with the NRA requiring additional 422 (range 154-892) days. Neither time to EMA MA nor NRA correlated with ESMO-MCBS substantial clinical benefit ( = 0.332 and = 0.965, respectively).: In Slovenia, time to access to novel anticancer drugs exceeds two years and, more importantly, is equally long for drugs with or without substantial clinical benefit. Integration of the ESMO-MCBS into reimbursement deliberations could improve access to drugs with substantial clinical benefit.
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http://dx.doi.org/10.1080/14737167.2019.1702879DOI Listing
December 2019

Expression of FGFR1-4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity.

Cells 2019 09 16;8(9). Epub 2019 Sep 16.

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1-FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1-4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1-4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not sufficient to predict FGFR inhibitor response in MPM cell lines.
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http://dx.doi.org/10.3390/cells8091091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769772PMC
September 2019

Definition of Synchronous Oligometastatic Non-Small Cell Lung Cancer-A Consensus Report.

J Thorac Oncol 2019 12 6;14(12):2109-2119. Epub 2019 Aug 6.

Thoracic Surgery Dept. University and Hospital Trust - Ospedale Borgo Trento, Verona, Italy.

Introduction: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process.

Methods: A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting.

Results: It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits.

Conclusion: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials.
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http://dx.doi.org/10.1016/j.jtho.2019.07.025DOI Listing
December 2019

Sequential afatinib and osimertinib in patients with mutation-positive non-small-cell lung cancer: updated analysis of the observational GioTag study.

Future Oncol 2019 Sep 2;15(25):2905-2914. Epub 2019 Aug 2.

University Clinic Golnik, University of Ljubljana, Ljubljana, Slovenia.

Overall survival (OS) and updated time to treatment failure (TTF) analysis of patients with mutation-positive (Del19, L858R) non-small-cell lung cancer who received sequential afatinib/osimertinib in the real-world GioTag study. Patients had T790M-positive disease following first-line afatinib and received osimertinib treatment (n = 203). Primary outcome was TTF. The OS analysis was exploratory. Median OS was 41.3 months (90% CI: 36.8-46.3) overall and 45.7 months (90% CI: 45.3-51.5) in patients with Del19-positive tumors (n = 149); 2-year survival was 80 and 82%, respectively. Updated median TTF with afatinib and osimertinib was 28.1 months (90% CI: 26.8-30.3). Sequential afatinib/osimertinib was associated with encouraging OS/TTF in patients with T790M-positive non-small-cell lung cancer, especially in patients with Del19-positive tumors. NCT03370770.
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http://dx.doi.org/10.2217/fon-2019-0346DOI Listing
September 2019

Lung Cancer in Slovenia.

J Thorac Oncol 2019 08;14(8):1327-1331

Institute of Oncology, Ljubljana, Slovenia.

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http://dx.doi.org/10.1016/j.jtho.2019.02.025DOI Listing
August 2019

Achieving Thoracic Oncology data collection in Europe: a precursor study in 35 Countries.

BMC Cancer 2018 Nov 20;18(1):1144. Epub 2018 Nov 20.

University of Tirana, Service of Pulmonology, Tirana, Albania.

Background: A minority of European countries have participated in international comparisons with high level data on lung cancer. However, the nature and extent of data collection across the continent is simply unknown, and without accurate data collection it is not possible to compare practice and set benchmarks to which lung cancer services can aspire.

Methods: Using an established network of lung cancer specialists in 37 European countries, a survey was distributed in December 2014. The results relate to current practice in each country at the time, early 2015. The results were compiled and then verified with co-authors over the following months.

Results: Thirty-five completed surveys were received which describe a range of current practice for lung cancer data collection. Thirty countries have data collection at the national level, but this is not so in Albania, Bosnia-Herzegovina, Italy, Spain and Switzerland. Data collection varied from paper records with no survival analysis, to well-established electronic databases with links to census data and survival analyses.

Conclusion: Using a network of committed clinicians, we have gathered validated comparative data reporting an observed difference in data collection mechanisms across Europe. We have identified the need to develop a well-designed dataset, whilst acknowledging what is feasible within each country, and aspiring to collect high quality data for clinical research.
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http://dx.doi.org/10.1186/s12885-018-5009-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247748PMC
November 2018

Mapping cancer research across Central and Eastern Europe, the Russian Federation and Central Asia: Implications for future national cancer control planning.

Eur J Cancer 2018 11 20;104:127-136. Epub 2018 Oct 20.

Institute of Cancer Policy, Cancer Epidemiology, Population & Global Health, School of Cancer Sciences, King's College London & Guy's & St.Thomas' NHS Trust, London, UK. Electronic address:

Cancer research is an essential part of national cancer control programmes, and the emerging economies of Central and Eastern Europe (CEE) and the Russian Federation and Central Asia (R-CA) (Commonwealth of Independent States) remain relatively understudied. Here, we map the cancer research activity from the 29 countries across these regions over a 10-year period (2007-2016), using a standard scientometric approach. Research activity was compared with the countries' wealth and with the disease burden from different cancers, and analyses were also performed by the research domain (e.g. fundamental cancer biology, surgery). We found that although there was a correlation between outputs and national wealth, there were many outliers; the CEE countries publishing relatively more, and the R-CA, less. Outputs reflected cancer burdens, but there was a relative paucity of research on lung, colorectal, gastric and pancreatic cancer, as well as research domains such as screening and palliative care. Clinical trials accounted for only 3% of all research outputs from all countries, and were very international, with on average 1.5 CEE countries and 8.0 others involved in each article, and they were heavily cited (on average, 84 times in 5 years). Poland was by far the most research-active country, but significant needs and opportunities have been identified to expand the cancer research activity in all CEE and R-CA countries to enhance national cancer control planning.
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http://dx.doi.org/10.1016/j.ejca.2018.08.024DOI Listing
November 2018

Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: an observational study.

Future Oncol 2018 Nov 19;14(27):2861-2874. Epub 2018 Oct 19.

Medical Faculty, University Clinic Golnik, University of Ljubljana, Ljubliana, Slovenia.

Aim: To assess outcomes in patients with EGFR mutation-positive (Del19, L858R) non-small-cell lung cancer receiving sequential afatinib and osimertinib in a real-world clinical setting. Materials & methods: In this retrospective, observational, multicenter study, patients (n = 204) had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months prior to data entry. Primary outcome was time on treatment.

Results: Overall median time on treatment was 27.6 months (90% CI: 25.9-31.3), 30.3 months (90% CI: 27.6-44.5) in Del19-positive patients and 46.7 months (90% CI: 26.8-not reached) in Asians. The 2-year overall survival was 78.9%.

Conclusion: In real-world clinical practice, sequential afatinib and osimertinib facilitates prolonged, chemotherapy-free treatment in patients with T790M acquired resistance, and is a potentially attractive strategy, especially for Del19-positive tumors.

Trial Registration Number: NCT03370770.
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http://dx.doi.org/10.2217/fon-2018-0711DOI Listing
November 2018

Expenditures on Oncology Drugs and Cancer Mortality-to-Incidence Ratio in Central and Eastern Europe.

Oncologist 2019 01 4;24(1):e30-e37. Epub 2018 Sep 4.

Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

Background: There is a steady decline in cancer mortality in Western Europe (WE), but this trend is not so obvious in Central and Eastern Europe (CEE). One of the largest discrepancies between WE and CEE is the level of investment in cancer care. The objective of our analysis was to examine the correlation between mortality-to-incidence (M/I) ratio and expenditures on oncology drugs in CEE and WE.

Materials And Methods: This cross-sectional analysis was done on publicly available data. Data on expenditures for oncology drugs were obtained from QuintilesIMS, and data on M/I ratio from Globocan. The main outcome was mortality-to-incidence ratio, and the primary analysis was performed by Spearman's rank correlation.

Results: There is a large discrepancy in expenditure on oncology drugs per cancer case between WE and CEE, and within CEE. Average expenditure on oncology drugs per capita as well as per new cancer case was 2.5 times higher in WE than in CEE. Availability of oncology drugs was highest in Germany (100%), relatively similar in WE (average of 91%), but in CEE it ranged from 37% to 86%, with an average of 70%. Annual expenditures on all oncology drugs per new cancer case was significantly negatively correlated with the M/I ratio (Spearman's ρ = -0.90, < .001).

Conclusion: There is a financial threshold for oncology drugs per cancer case needed to increase survival. Based on significantly lower expenditures for oncology drugs in CEE in comparison with WE, more investment for drugs as well as better, more organized, value- oriented consumption is needed.

Implications For Practice: Cancer is not treated equally successfully in Western Europe (WE) and in Central and Eastern Europe (CEE). This study showed that success in treatment of cancer is associated with the amount of money invested in oncology drugs. CEE countries spend on average 2.5 times less than WE countries for oncology drugs per new cancer case. These findings should be used by health care providers and oncologists struggling for more resources and better, more organized, evidence-based allocation of these resources as well as better oncology outcomes.
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http://dx.doi.org/10.1634/theoncologist.2018-0093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324644PMC
January 2019

NSCLC molecular testing in Central and Eastern European countries.

BMC Cancer 2018 03 9;18(1):269. Epub 2018 Mar 9.

1st Institute of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.

Background: The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines.

Methods: A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period.

Results: A very high proportion of lung cancer cases are confirmed histologically/cytologically (75-100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75-100% of cases being discussed at a multidisciplinary tumor board at specialized centers.

Conclusions: Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges.
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http://dx.doi.org/10.1186/s12885-018-4023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845184PMC
March 2018

PD-L1 Expression in Squamous-cell Carcinoma and Adenocarcinoma of the Lung.

Radiol Oncol 2017 Sep 14;51(3):357-362. Epub 2017 Sep 14.

Department of Medical Oncology, University Clinic Golnik, Golnik, Slovenia.

Background: With introduction of immunotherapy (IT) into the treatment of advanced non-small-cell lung cancer (NSCLC), a need for predictive biomarker became apparent. Programmed death ligand 1 (PD-L1) protein expression is most widely explored predictive marker for response to IT. We assessed PD-L1 expression in tumor cells (TC) and immune cells (IC) of squamous-cell carcinoma (SCC) and adenocarcinoma (AC) patients.

Patients And Methods: We obtained 54 surgically resected tumor specimens and assessed PD-L1 expression by immunohistochemistry after staining them with antibody SP142 (Ventana, USA). Clinicopathological characteristics were acquired from the hospital registry database. Results were analyzed according to cut-off values of ≥ 5% and ≥ 10% of PD-L1 expression on either TC or IC.

Results: 29 (54%) samples were AC and 25 (46%) were SCC. PD-L1 expression was significantly higher in TC of SCC compared to AC at both cut-off values (52% vs. 17%, p = 0.016 and 52% vs. 14%, p = 0.007, respectively) no difference in PD-L1 expression in IC of SCC and AC was found. In AC alone, PD-L1 expression was significantly higher in IC compared to TC at both cut-off values (72% vs. 17%, p < 0.001 and 41% vs. 14%, p = 0.008, respectively), while no significant difference between IC and TC PD-L1 expression was revealed in SCC.

Conclusions: Our results suggest a significantly higher PD-L1 expression in TC of SCC compared to AC, regardless of the cut-off value. PD-L1 expression in IC is high in both histological subtypes of NSCLC, and adds significantly to the overall positivity of AC but not SCC.
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http://dx.doi.org/10.1515/raon-2017-0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612001PMC
September 2017

Insulin-like Growth Factor 1 Receptor Expression in Advanced Non-small-cell Lung Cancer and its Impact on Overall Survival.

Radiol Oncol 2017 Jun 26;51(2):195-202. Epub 2017 Apr 26.

University Clinic Golnik, Golnik, Slovenia.

Background: The insulin-like growth factor 1 receptor (IGF1R) expression has been addressed as a potential prognostic marker in non-small-cell lung cancer (NSCLC) in various studies; however, the associations between IGF1R expression and prognosis of advanced NSCLC patients is still controversial. The aim of our observational, cohort study was to evaluate the expression of IGF1R in advanced NSCLC and its prognostic role. A subgroup analysis was performed to address the influence of pre-existing type 2 diabetes mellitus (T2DM) status on IGF1R expression and overall survival (OS).

Patients And Methods: IGF1R expression was evaluated in 167 consecutive advanced NSCLC patients (stage IIIB and IV), diagnosed and treated at one university institution, between 2005 and 2010. All patients received at least one line of standard cytotoxic therapy and 18 of them had pre-existing T2DM. IGF1R expression was determined by immunohistochemical (IHC) staining, with score ≥ 1+ considered as positive. Information on baseline characteristics, as well as patients' follow-up data, were obtained from the hospital registry. Associations of IGF1R expression with clinical characteristics and overall survival were compared.

Results: IGF1R expression was positive in 79.6% of patients, significantly more often in squamous-cell carcinoma (SCC) compared to non-squamous-cell (NSCC) histology (88.7% vs. 74.3%; P = 0.03). IGF1R positivity did not correlate with T2DM status or with other clinical features (sex, smoking status, performance status). Median OS was similar between IGF1R positive and IGF1R negative group (10.2 vs. 8.5 months, = 0.168) and between patients with or without T2DM (8.7 vs. 9.8 months, 0.575). Neither IGF1R expression nor T2DM were significant predictors of OS.

Conclusions: IGF1R or T2DM status were not significantly prognostic in described above collective of advanced NSCLC treated with at least one line of chemotherapy. In addition, no association between T2DM status and IGF1R expression was found. Further studies on IGF1R expression and its prognostic as well as therapeutic consequences in a larger collective of advanced NSCLC patients, with or without T2DM, are needed.
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http://dx.doi.org/10.1515/raon-2017-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514660PMC
June 2017

High BMI1 mRNA expression in peripheral whole blood is associated with favorable prognosis in advanced non-small cell lung cancer patients.

Oncotarget 2017 Apr;8(15):25384-25394

University Clinic Golnik, Golnik, Slovenia.

Polycomb group member protein BMI1 is involved in maintaining cell identity, proliferation, differentiation and human oncogenesis. In the present study, we determined BMI1 mRNA expression in whole blood and evaluated the impact of the expression level on the treatment response and survival of 96 advanced NSCLC patients treated with first-line platinum-based chemotherapy. We also determined BMI1 mRNA expression in primary tumors from 22 operable NSCLC patients treated with radical surgery. We found that compared with control subjects, BMI1 mRNA expression in whole blood of advanced NSCLC patients was decreased (P<0.001). Similarly, we observed decreased BMI1 mRNA expression in primary tumors compared to normal lungs from operable NSCLC patients (P=0.001). We found high BMI1 mRNA expression in blood was associated with longer progression-free survival (PFS) (P=0.049) and overall survival (OS) (P=0.012) in advanced NSCLC patients treated with first-line platinum-based chemotherapy. However, no association between the BMI1 mRNA level and response to chemotherapy was found (P=0.21). Multivariate Cox proportional hazards regression analysis showed elevated BMI1 mRNA level in whole blood was an independent prognostic factor for longer PFS (P=0.012) and OS (P<0.001). In conclusion, BMI1 mRNA expression in whole blood might represent a new biomarker for the diagnosis and prognosis of NSCLC.
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http://dx.doi.org/10.18632/oncotarget.15914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421938PMC
April 2017

Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial.

J Clin Oncol 2017 May 13;35(13):1421-1429. Epub 2017 Mar 13.

Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.

Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) -positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and Methods The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry-with or without metformin treatment-were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. Results A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor-positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor-positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor-positive breast cancer.
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http://dx.doi.org/10.1200/JCO.2016.69.7722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455460PMC
May 2017

Echocardiography and cardiac biomarkers in patients with non-small cell lung cancer treated with platinum-based chemotherapy.

Radiol Oncol 2017 Mar 24;51(1):15-22. Epub 2016 Jun 24.

Faculty of Medicine, Ljubljana, Slovenia; Departments of Cardiology and Research and Education, General Hospital Celje, Celje, Slovenia.

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains an important cause of cancer death worldwide. Platinum-based chemotherapy (PBC) for NSCLC can modify outcome while the risk of cardiotoxicity remains poorly researched. We aimed to evaluate the incidence and severity of cardiac injury during PBC in patients with NSCLC and to identify patients at risk.

Methods: This was a single-centre, prospective, observational study of patients with early and advanced stage NSCLC referred for PBC. In addition to standard care, patients were examined and evaluated for cardiotoxicity before the first dose (visit 1), at the last dose (visit 2) and 6 months after the last dose of PBC (visit 3). Cardiotoxicity (at visit 2 and 3) was defined as increase in the ultrasensitive troponin T, N-terminal pro-B type natriuretic peptide or decrease in left ventricular ejection fraction (LVEF).

Results: Overall, 41 patients (mean age 61 ± 9; 54% men; 68% advanced lung cancer) were included. The median number of PBC cycles was 4. During the study period, there were no incidents of heart failure, and 3 deaths caused by tumour progression were recorded. The mean values of biomarkers and LVEF did not change significantly (p > 0.20). However, 10 (25%) had cardiotoxicity which was independently associated with a history of ischemic heart disease (p = 0.026).

Conclusions: In NSCLC, cardiac assessment and lifestyle modifications may be pursued in patients with a history of cardiac disease and in patients with longer life expectancy.
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http://dx.doi.org/10.1515/raon-2016-0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330165PMC
March 2017

Extended adjuvant endocrine therapy - A standard to all or some?

Breast 2017 Apr 31;32:112-118. Epub 2017 Jan 31.

Champalimaud Clinical Center, Lisbon, Portugal.

Patients with estrogen receptor-positive (ER +) early breast cancer (EBC) are at a continuous risk for distant relapse despite 5 years of standard endocrine therapy, even after 10-15 years after primary diagnosis. Hence, large randomized clinical trials were conducted to evaluate the role of extended endocrine treatment (ET) with the primary goal to prevent or at least delay distant relapse. Two very large trials of extended tamoxifen (TAM), the ATLAS and the aTTom trial, proved the efficacy of prolonged TAM particularly important after 10 years due to the carry-over effect of the five initial years. Additionally, the extended use of AIs after 5 years of tamoxifen, also proved to be efficacious in preventing late distant relapses. For letrozole (LET) it was shown in the MA.17 trial that it also improves overall survival (OS) in node-positive BC patients. There are many options and still unanswered questions related to extended ET, which are discussed in this review. The most important issue in deciding prolonged duration of ET is undoubtfully how to identify ER+ patients who benefit most from this approach. With this purpose, not only classical pathological factors have been studied, but also molecular profiles of individual tumors, which might help us in the near future to better tailor ET. Not only efficacy, but also toxicity of such prolonged treatment is essential for optimal use, particularly maintained compliance in a routine clinical practice. These issues are discussed in this review.
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http://dx.doi.org/10.1016/j.breast.2017.01.004DOI Listing
April 2017

Immunohistochemistry for EGFR Mutation Detection in Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2017 05 2;18(3):e187-e196. Epub 2016 Dec 2.

University Clinic Golnik, Golnik, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

Introduction: The sensitivity and specificity of immunohistochemistry (IHC) was compared with the standard polymerase chain reaction (PCR)-based method for detecting common activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC). Additionally, we evaluated predictive value of IHC EGFR mutation-positive status for EGFR tyrosine kinase inhibitor (TKI) treatment outcome and estimated cost-effectiveness for the upfront IHC testing.

Methods: The trial included 79 consecutive EGFR mutation-positive and 29 EGFR mutation-negative NSCLC cases diagnosed with reflex PCR-based testing. Two mutation-specific antibodies against the most common exon 19 deletion, namely E746-A750del (clone SP111) and L858R mutation (clone SP125) were tested by using automated immunostainer. Sixty of 79 EGFR mutation-positive cases were treated with EGFR TKIs for advanced disease and included in treatment outcome analysis. A decision tree was used for the cost-effectiveness analysis.

Results: The overall sensitivity and specificity of the IHC-based method compared with the PCR-based method were 84.8% (95% confidence interval [CI] 74.6-91.6) and 100% (95% CI 85.4-100), respectively. The median progression-free survival (PFS) and overall survival (OS) of patients with IHC-positive EGFR mutation status were highly comparable to the total cohort (PFS: 14.3 vs. 14.0 months; OS: 34.4 vs. 34.4 months). The PCR and IHC cost ratio needs to be approximately 8-to-1 and 4-to-1 in White and Asian populations, respectively, to economically justify upfront use of IHC.

Conclusion: The trial confirmed an excellent specificity with fairly good sensitivity of IHC with mutation-specific antibodies for common EGFR mutations and the accuracy of IHC testing for predicting response to EGFR TKIs. The use of upfront IHC depends mainly on the population EGFR mutation positivity probability.
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http://dx.doi.org/10.1016/j.cllc.2016.11.021DOI Listing
May 2017

Cancer Control in Central and Eastern Europe: Current Situation and Recommendations for Improvement.

Oncologist 2016 10 8;21(10):1183-1190. Epub 2016 Jul 8.

Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

: The incidence of many cancers is higher in Western European (WE) countries, but mortality is frequently higher in Central and Eastern European (CEE) countries. A panel of oncology leaders from CEE countries participating in the South Eastern European Research Oncology Group (SEEROG) was formed in 2015, aiming to analyze the current status and trends of oncology care in CEE and to propose recommendations leading to improved care and outcomes. The SEEROG panel, meeting during the 11th Central European Oncology Congress, proposed the following: (a) national cancer control plans (NCCPs) required in all CEE countries, defining priorities in cancer care, including finance allocation considering limited health care budgets; (b) national cancer registries, describing in detail epidemiological trends; (c) efforts to strengthen comprehensive cancer centers; (d) that multidisciplinary care should be mandated by the NCCPs; (e) that smaller hospitals should be connected to multidisciplinary tumor boards via the Internet, providing access to specialized expertise; (f) nationwide primary prevention programs targeting smoking, obesity, and alcohol consumption and centrally evaluated secondary prevention programs for cervical, colorectal, and breast cancers; (g) prioritize education for all involved in cancer care, including oncology nurses, general practitioners, and palliative care providers; (h) establish outpatient care in day hospitals to reduce costs associated with the current inpatient model of care in CEE countries and to improve patients' quality of life; (i) long-term pharmacoeconomic evaluations of new therapies in CEE countries; (j) increase national oncology budgets in view of the higher mortality rates in CEE compared with WE countries; and (k) CEE countries urgently need help from the European Union to increase and monitor overall investment in cancer care.

Implications For Practice: Significant differences in cancer incidence and mortality have been observed between European countries. While the incidence of many cancer types is higher in Western European (WE) countries, the mortality is generally higher in Central and Eastern Europe (CEE). The primary purpose of this review was to describe the current status and trends of oncology care in the CEE region, to raise awareness among physicians, regulators, and payers, and to propose the most needed changes in order to make the oncology care in CEE closer to the WE standards.
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http://dx.doi.org/10.1634/theoncologist.2016-0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061531PMC
October 2016

The prognostic value of whole blood SOX2, NANOG and OCT4 mRNA expression in advanced small-cell lung cancer.

Radiol Oncol 2016 Jun 23;50(2):188-96. Epub 2016 Apr 23.

University Clinic Golnik, Golnik, Slovenia.

Background: The data on expression and clinical impact of cancer stem cell markers SOX2, NANOG and OCT4 in lung cancer is still lacking. The aim of our study was to compare SOX2, NANOG and OCT4 mRNA expression levels in whole blood between advanced small-cell lung cancer (SCLC) patients and healthy controls, and to correlate mRNA expression with progression-free survival (PFS) after first-line chemotherapy and overall survival (OS) in advanced SCLC patients.

Patients And Methods: 50 advanced SCLC patients treated with standard chemotherapy and followed at University Clinic Golnik, Slovenia, between 2009 and 2013 were prospectively included. SOX2, NANOG and OCT4 mRNA expression levels were determined using TaqMan qPCR in whole blood collected prior to chemotherapy. Whole blood of 34 matched healthy individuals with no cancerous disease was also tested.

Results: SOX2 mRNA expression was significantly higher in whole blood of SCLC patients compared to healthy controls (p = 0.006). Significant correlation between SOX2 mRNA expression levels and the number of distant metastatic sites was established (p = 0.027). In survival analysis, patients with high SOX2 expression had shorter OS (p = 0.017) and PFS (p = 0.046). In multivariate Cox analysis, an independent value of high SOX2 expression for shorter OS (p = 0.002), but not PFS was confirmed. No significant differences were observed for NANOG or OCT4 expression levels when comparing SCLC patients and healthy controls neither when analysing survival outcomes in SCLC patients.

Conclusions: SOX2 mRNA expression in whole blood might be a promising non-invasive marker for molecular screening of SCLC and important prognostic marker in advanced chemotherapy-treated SCLC patients, altogether indicating important role of cancer stem-like cell (CSC) regulators in cancer spread. Further evaluation of SOX2 as a possible screening/prognostic marker and a therapeutic target of SCLC is warranted.
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http://dx.doi.org/10.1515/raon-2015-0027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852967PMC
June 2016

BMI1, ALDH1A1, and CD133 Transcripts Connect Epithelial-Mesenchymal Transition to Cancer Stem Cells in Lung Carcinoma.

Stem Cells Int 2016 7;2016:9714315. Epub 2015 Dec 7.

University Clinic Golnik, Golnik 36, SI-4204 Golnik, Slovenia.

Epithelial-mesenchymal transition (EMT) is the underlying mechanism of tumor invasion and metastasis. Evidences from lung cancer cellular models show EMT can trigger conversion to a cancer stem cell (CSC) phenotype. In this study, we assessed mRNA expression levels of EMT-inducing transcription factors (BMI1, TWIST1), CSC (CD133, ALDH1A1), and epithelial (EpCAM) markers in primary tumor and whole blood samples obtained from 57 patients with operable non-small-cell lung cancer (NSCLC) as well as in circulating tumor cells (CTCs) of 13 patients with metastatic disease; then possible associations between marker expressions were evaluated. In primary tumors as well as in whole blood, correlations between BMI1 and ALDH1A1 and between BMI1 and CD133 mRNA expressions were identified. No correlations between TWIST1 and CSC markers were observed. BMI1 mRNA expression in tumors positively correlated with BMI1 mRNA expression in blood. The immunohistochemical analysis confirmed coexpression of BMI1 and CSC markers in tumors. Gene expression profiling in CTCs revealed upregulated expression of EMT/CSC markers in CTCs. Our results suggest CSCs are present in both, tumor tissue and blood of NSCLC patients, whereas Bmi1 may play an important role in initiation and maintenance of CSCs and might be involved in the blood-borne dissemination of NSCLC.
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http://dx.doi.org/10.1155/2016/9714315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685144PMC
January 2016

A European Organisation for Research and Treatment of Cancer randomized, double-blind, placebo-controlled, multicentre phase II trial of anastrozole in combination with gefitinib or placebo in hormone receptor-positive advanced breast cancer (NCT00066378).

Eur J Cancer 2016 Jan 24;53:144-54. Epub 2015 Dec 24.

NHS-Lothian, University of Edinburgh, Edinburgh, United Kingdom. Electronic address:

Background: Preclinical data suggest that epidermal growth factor receptor (EGFR) inhibitors (e.g. gefitinib) can delay endocrine resistance in breast cancer. A double-blind, placebo-controlled, phase II trial investigated whether adding gefitinib (G) to anastrozole (A) would improve outcome in advanced breast cancer (ABC).

Methods: Postmenopausal pre-treated hormone receptor-positive ABC patients (locally recurrent or metastatic) were 1:1 randomized to A (1 mg/d) plus G 250 mg/d or plus placebo (P). Patients who had prior treatment with an aromatase inhibitor in metastatic setting or with trastuzumab, anti-EGFR or anti-VEGF agents were excluded. Treatment was given until disease progression, unacceptable toxicity or patient withdrawal. Progression-free survival (PFS) rate at 1 year was assessed according to Response Evaluation Criteria in Solid Tumours, version 1.0.

Results: Of 108 planned patients, 71 were recruited (36 in A/G and 35 in A/P). The trial closed prematurely due to slow recruitment; 31 patients had prior chemotherapy and 53 prior endocrine therapy (all except one received tamoxifen); 60% in adjuvant and 16% in metastatic setting received tamoxifen; 59 patients had visceral disease. Median follow-up was 18 months. PFS rate at 1 year was 35% for A/G and 32% for A/P arm. Objective responses were six (22%) in the A/G and nine (28%) in the A/P arm. Median duration of response was 13.8 and 18.6 months in the A/G and A/P arms, respectively. Fatigue (35%), diarrhoea (31%), rash (32%), dry skin (27%), and arthralgia/myalgia (27%) were the commonest adverse events in the A/G arm.

Conclusions: This phase II study, although prematurely closed, did not show a signal that adding G to A improves PFS at 1 year and its use is not supported. Gastrointestinal and skin toxicities were more pronounced with G resulting in premature therapy interruption in almost 1 in 3 patients (ClinicalTrials.gov number, NCT00066378).
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http://dx.doi.org/10.1016/j.ejca.2015.10.012DOI Listing
January 2016

The American Society of Clinical Oncology's Efforts to Support Global Cancer Medicine.

J Clin Oncol 2016 Jan 17;34(1):76-82. Epub 2015 Nov 17.

Gabriel N. Hortobagyi, University of Texas MD Anderson Cancer Center, Houston, TX; Nagi S. El-Saghir, American University of Beirut Medical Center, Beirut, Lebanon; Tanja Cufer, University of Ljubljana and University Clinic Golnik, Golnik, Slovenia; Eduardo Cazap, National Cancer Institute of Argentina, Latin American and Caribbean Society of Medical Oncology, Buenos Aires, Argentina; Roselle de Guzman, St Luke's Medical Center, Quezon City, the Philippines; Nicholas Anthony Othieno-Abinya, University of Nairobi, Nairobi, Kenya; Jose Angel Sanchez, Universidad Nacional Autonoma de Honduras, Tegucigalpa, Honduras; and Doug Pyle, American Society of Clinical Oncology, Alexandria, VA.

Despite much progress in the management of malignant diseases, the number of new cases and cancer-related deaths continues to rise around the world. More than half of new cases occur in economically developing countries, where more than two thirds of cancer deaths are expected. However, implementation of all necessary steps to accomplish the dissemination of state-of-the-art prevention, diagnosis, and management will require increased allocation of resources, and, more importantly, harmonization of the efforts of hundreds of national and international public health agencies, policy-setting bodies, governments, pharmaceutical companies, and philanthropic organizations. More than 30% of the members of the American Society of Clinical Oncology (ASCO) reside and practice outside US borders, and more than half of attendees at all of the scientific congresses and symposia organized by ASCO are international. As cancer has become an increasingly global disease, ASCO has evolved as a global organization. The ASCO Board of Directors currently includes members from France, Brazil, and Canada. In 2013, the ASCO Board of Directors identified a number of strategic priorities for the future. Recognizing the importance of non-US members to the society, their first strategic priority was improving the society's service to non-US members and defining these members' identity in the international oncology community. This article reviews current ASCO activities in the international arena and its future plans in global oncology.
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http://dx.doi.org/10.1200/JCO.2015.61.7696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320925PMC
January 2016

A simple dried blood spot method for clinical pharmacological analyses of etoposide in cancer patients using liquid chromatography and fluorescence detection.

Clin Chim Acta 2016 Jan 27;452:99-105. Epub 2015 Oct 27.

University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia. Electronic address:

Background: Therapeutic drug monitoring of etoposide is not part of the routine clinical practice, however, measuring etoposide plasma concentration may be useful to prevent chemotherapy related adverse drug reactions. This paper describes the development and validation of a dried blood spot (DBS) assay for the determination of etoposide in blood samples of lung cancer patients.

Methods: The whole blood spot was cut out of the DBS card followed by sonication assisted liquid drug extraction. Extraction solution was evaporated and re-dissolved. A high-performance-liquid-chromatography method with fluorimetric detection ( λex=230nm; λem=330nm) was used.

Results: Method met the validation criteria in terms of selectivity, linearity (0.5-20.0μg/mL), accuracy (≥96.1%), precision (≤10.1%) and stability (long term 4weeks at room temperature and 40°C). Haematocrit did not influence DBS etoposide concentration. Good correlation between measured plasma and DBS concentrations was observed. The equation considering only haematocrit value was used for conversion of DBS to plasma concentration.

Conclusions: DBS sampling method showed comparable results to plasma samples. Therefore, it can be concluded that the developed and validated DBS method, which is more patient-friendly and requires less sample handling, is a reliable alternative to conventional plasma methods for measuring etoposide concentration in clinical pharmacological analyses.
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http://dx.doi.org/10.1016/j.cca.2015.10.026DOI Listing
January 2016

Prognostic value of cytokeratin-7 mRNA expression in peripheral whole blood of advanced lung adenocarcinoma patients.

Cell Oncol (Dordr) 2015 Oct 26;38(5):387-95. Epub 2015 Aug 26.

University Clinic Golnik, Golnik 36, 4204, Golnik, Slovenia.

Background: The rarity of circulating tumour cells (CTCs) in peripheral blood requires the application of sensitive techniques for their detection. The aim of our study was to (i) first determine the sensitivity of cytokeratin-7 (KRT7) mRNA expression levels for the molecular detection of CTCs using spiked-in lung adenocarcinoma (AC)-derived A549 cells and (ii) evaluate the impact of KRT7 mRNA expression in peripheral whole blood on the response to treatment and prognosis of patients with advanced lung AC who were treated with first-line platinum-based chemotherapy.

Methods: A549 cells were micro-manipulated before being spiked into whole blood samples obtained from healthy donors. Additionally, whole blood samples from 65 lung AC patients were collected in PAXgene blood tubes before the start of first-line platinum-based chemotherapy. KRT7 mRNA expression was measured using RT-qPCR.

Results: Through the spike-in experiment we found that it is feasible to detect a single A549 tumour cell in 2.5 ml whole blood and that the KRT7 mRNA levels were linearly correlated with the number of spiked-in tumour cells with a high reproducibility. In lung AC patients, no significant differences in response rate to chemotherapy, progression-free survival or overall survival and KRT7 mRNA levels were found.

Conclusions: Our data show that KRT7 mRNA expression measured by RT-qPCR serves as a sensitive approach for the molecular detection of KRT7-positive CTC-resembling A549 cells in peripheral whole blood. The KRT7 mRNA levels measured were not significantly associated with the response to chemotherapy or the survival of patients with advanced lung AC. Additional studies are required to establish the possible clinical significance of KRT7 mRNA expression in whole blood after chemotherapy.
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http://dx.doi.org/10.1007/s13402-015-0238-4DOI Listing
October 2015