The advent of personalized medicine and ever-increasing numbers of available cancer drugs necessitate better prognostic and predictive biomarkers. In turn, this requires a deeper profiling and understanding of tumors and the tumor microenvironment (TME). To address this challenge the Integrated iMMUnoprofiling of large adaptive CANcer patient cohorts (IMMUcan) consortium collects samples and longitudinal clinical data from up to 3000 patients. All samples undergo bulk RNA-seq and whole exome sequencing (WES) for molecular profiling, whole slide multiplexed immunofluorescence (mIF) for broad and imaging mass cytometry (IMC) for detailed cellular profiling. We analyzed a retrospective sub-cohort of non-small cell lung cancer (NSCLC) consisting of stage I-IIIA resected tumor samples from 192 patients collected between 2012 and 2018 under the EORTC-SPECTA protocol (NCT 02214134). Median follow up was 2.8 years and 42 patients died of the disease. Bulk RNA-seq and WES data were processed using standard tools. An image analysis workflow for mIF and IMC data paired with a tiling approached from ecology and spatial data analysis were used for feature extraction and subsequent multivariate cox proportional hazard modeling. The TME did not differ across clinical stage, smoking status or driver mutations. The TME of squamous cell carcinoma (LUSC) subtypes was enriched for immune suppressed cell types compared to adenocarcinoma (LUAD) subtypes in mIF and IMC data. Most samples (78%) contained B cell aggregates or tertiary lymphoid structures but their amount, size and location were not prognostic for overall survival (OS). In this cohort, not the density of CD8+ T cells but the variability of CD8+ T cell density across tissue sections, next to factors such as CD8+ T cell exclusion and broad T cell activation/exhaustion were strong prognostic factors for OS. Finally, we highlight results obtained from multi-modal data integration for the identification of the strongest prognostic features. Our analyses reveal the potential of multi-modal data analysis and integration, and form the basis for analyses of all molecular and cellular profiling data from IMMUcan patients for biomarker discovery.

Immune checkpoint blockers have changed the treatment landscape for patients with NSCLC, however, response is often limited. PD-L1 protein expression is the only validated biomarker to enrich in responders and understanding resistance mechanisms to propose rationally driven combination therapies is clearly needed. To this end, IMMUcan, a pan-European consortium, is aiming at gaining a better understanding of the tumor microenvironment (TME) by combining broad molecular profiles of the tumor with spatially resolved cellular information of the TME and clinical information for 3,000 patients, with NSCLC a core indication of this project. The first NSCLC cohort is composed of 191 patients from the EORTC SPECTAlung (NCT02214134) program, and 48 patients prospectively recruited in SPECTA (NCT02834884). All patients were diagnosed with NSCLC (any histology, any stage), FFPE material was collected at time of diagnosis, prior to treatment. Whole exome sequencing (WES), total RNA sequencing (RNAseq), multiplex immunofluorescence (mIF) and imaging mass cytometry (IMC) data was collected for each patient and analysed. The cohort contains a majority of adenocarcinoma (153 adenocarcinoma, 55 squamous carcinoma, 31 other) and early stage disease patients (74 stage I, 57 stage II, 63 stage III and 44 stage IV, 1 unknown). Median age at registration was 67, 100 patients were female and 139 male, and the majority were current or former smoker (163 patients). Stage is the strongest clinical predictor or survival (64.1 months for stage 1, 60.8 for stage 2, 58.3 for stage 3 and 14.1 for stage 4). 15% of adenocarcinoma patients had a driver mutation (EGFR, BRAF) and stage and histology are the main drivers of heterogeneity for RNAseq. T cell infiltration was assessed on all FFPE samples and is associated with improved overall survival. Tertiary lymphoid structures were identified in the majority of samples (∼70%), with various number of B cells and differing expression of lymphocyte maturation markers. Further integration of the cellular and molecular data are ongoing and additional biomarkers will be presented at the conference.

Background: With the implementation of multidisciplinary treatment and development of multiple novel anticancer drugs in parallel with expanding knowledge of supportive and palliative care, a need for separate training and specialisation in medical oncology emerged. A Global Curriculum (GC) in medical oncology, developed and updated by a joint European Society for Medical Oncology/American Society of Clinical Oncology (ESMO/ASCO) GC Task Force/Working Group (GC WG), greatly contributed to the recognition of medical oncology worldwide. Material and methods: ESMO/ASCO GC WG carried out a global survey on medical oncology recognition and GC adoption in 2019. Results: Based on our survey, medical oncology is recognised as a separate specialty or sub-specialty in 47/62 (75%) countries participating in the survey; with a great majority of them (39/47, 83%) recognising medical oncology as a standalone specialty. Additionally, in 9 of 62 (15%) countries, medical oncology is trained together with haematology as a specialty in haemato-oncology or together with radiotherapy as a specialty in clinical oncology. As many as two-thirds of the responding countries reported that the ESMO/ASCO GC has been either fully or partially adopted or adapted in their curriculum. It has been adopted in a vast majority of countries with established training in medical oncology (28/41; 68%) and adapted in 12 countries with mixed training in haemato-oncology, clinical oncology or other specialty responsible for training on systemic anticancer treatment. Conclusions: With 75% of participating countries reporting medical oncology as a separate specialty or sub-specialty and as high as 68% of them reporting on GC adoption, the results of our survey on global landscape are reassuring. Despite a lack of data for some regions, this survey represents the most comprehensive and up-to-date information about recognition of medical oncology and GC adoption worldwide and will allow both societies to further improve the dissemination of the GC and global recognition of medical oncology, thus contributing to better cancer care worldwide.

Second- (afatinib and dacomitinib) and third-generation (osimertinib) EGFR tyrosine kinase inhibitors (TKIs) have demonstrated superior efficacy versus the first-generation EGFR TKIs (erlotinib and gefitinib) for EGFRm+ NSCLC. However, TKI resistance is inevitable and up to 75% of afatinib-treated patients develop the T790M mutation. Hence, questions remain about the optimal sequence of EGFR TKIs. The observational GioTag study investigated outcomes in patients with EGFRm+ NSCLC treated with sequential afatinib and osimertinib in a ‘real-world’ setting. Time to treatment failure (TTF) and overall survival (OS) were encouraging (Hochmair et al Future Oncol 2019). Here, we report final TTF and OS data for Asian patients. Data were retrospectively collected for patients with EGFRm+ (Del19, L858R) NSCLC who had T790M+ disease after first-line afatinib and then received osimertinib. TTF was the primary outcome; OS analysis was exploratory. 203 patients were included in the global GioTag study; of these, 50 were Asian. After a median follow-up of 33.9 months, median TTF was 37.1 months (90% CI: 28.1–40.3) and median OS was 44.8 months (90% CI: 37.0–57.8) in Asian patients (overall global study population: median TTF 27.7 months [90% CI: 26.7–29.9], median OS 37.6 months [90% CI: 35.5–41.3]). Clinical benefit was particularly encouraging in Asian patients with Del19-positive disease (n=31): median TTF 40.0 months (90% CI: 36.4–45.0), median OS 45.7 months (90% CI: 38.2–57.8). Median TTF and OS were 38.2 months (90%: 28.9–40.3) and 44.8 months (90% CI: 38.2–57.8), respectively, in Asian patients who received a starting dose of afatinib 40 mg (n=46), and 36.4 months (90% CI: 28.1–41.7) and 41.3 months (90% CI: 36.9–57.8), respectively, in Asian patients with ECOG performance status 0/1 (n=45). In a real-world clinical practice setting, sequential afatinib and osimertinib is effective, particularly in Asian patients with EGFRm+ NSCLC who develop T790M. Median OS was nearly 4 years in those with Del19+ disease, suggesting sequential TKI use could potentially allow these patients to receive long-term chemotherapy-free treatment.

La séquence optimale des inhibiteurs de la tyrosine kinase (TKI) ciblant l'EGFR pour optimiser la survie globale des patients atteints d'un CBNPC avec mutation EGFR (EGFRm + ) demeure une question ouverte en situation de vie réelle. GioTag (NCT03370770) est une étude observationnelle internationale portant sur des patients atteints de CBNPC EGFRm+ qui ont été traités par afatinib suivi d'osimertinib, comprenant des patients de mauvais pronostic (ECOG PS ≥ 2 : 15 % ; métastases cérébrales stables : 10 %) [1]. Dans l'analyse primaire, le temps sous traitement (TST) était de 27,6 mois chez tous les patients, 30,3 mois chez les patients Del19+ et 46,7 mois chez les patients asiatiques. Dans cette analyse, nous rapportons la survie globale (SG) des patients de la cohorte. Les données ont été recueillies rétrospectivement entre décembre 2017 et juin 2018 à partir des données de santé électroniques (DSE ; n = 126) ou des dossiers médicaux (n = 77) des patients atteints d'un CBNPC EGFRm+ (Del19, L858R). Tous les patients étaient T790M+ après une première ligne par afatinib et ont ensuite reçu de l'osimertinib. Le critère principal était le TST ; l'analyse de la SG était exploratoire. Après un suivi médian de 34,8 mois, la SG médiane était de 41,3 mois (IC90 % : 36,8–46,3) pour l'ensemble des patients (n = 203) et de 45,7 mois (IC90 % : 45,3–51,5) pour les patients Del19+ (n = 149). Le TST actualisé était de 28,1 mois (IC90 % : 26,8–30,3) pour l'ensemble des patients et de 30,6 mois (IC90 % : 27,6–32,0) pour les patients Del19+. Parmi les 168 patients qui ont commencé l'afatinib à 40 mg, l'OS médiane était de 45,3 mois (IC90 % : 37,6–47,6) et le TST médian de 28,1 mois (IC 90 % : 26,8–30,6). Le temps médian sous osimertinib était de 15,6 mois (IC90 % : 13,8–17,1) pour l'ensemble des patients et de 16,4 mois (IC90 % : 14,9–17,9) pour les patients Del19+. Chez les patients atteints d'un CBNPC EGFRm+ T790M+, nous avons observé une SG médiane encourageante de près de 3,5 ans pour la séquence afatinib suivi par osimertinib, avec un bénéfice supérieur chez les patients Del19+. Ces données confortent la faisabilité de cette approche séquentielle. Notamment, un temps sous osimertinib prolongé, de 15,6 mois, a été observé en deuxième ligne, alors que tous les patients avaient déjà reçu de l'afatinib. L'analyse finale, prévue début 2020, apportera de nouveaux éléments sur la survie à long terme des patients traités par cette séquence afatinib-osimertinib.

The GioTag study aimed to assess outcomes in real-world patients who received first-line afatinib followed by osimertinb.

The optimal sequence of EGFR tyrosine kinase inhibitors (TKIs) to maximize survival in patients with EGFR mutation-positive (EGFRm+) NSCLC is still an open question that cannot be answered with currently-available data. GioTag (NCT03370770) is a global, observational study of patients with EGFRm+ NSCLC who were treated with sequential afatinib and osimertinib in a 'real-world' clinical setting, including patients with poor prognosis (ECOG PS ≥2: 15%; stable brain metastases: 10%).1 In the primary analysis, time to treatment failure (TTF) was 27.6 months in all patients, 30.3 months in Del19-positive patients, and 46.7 months in Asian patients. In this analysis, we report OS and updated TTF. Data were retrospectively collected between Dec 2017 and June 2018 from electronic health records (EHRs; n=126) or medical charts (n=77) of patients with EGFRm+ (Del19, L858R) NSCLC. All patients were T790M-positive after first-line afatinib and subsequently received osimertinib. TTF was the primary outcome; OS analysis was exploratory. For logistical reasons, this interim analysis includes updated data (as at April 2019) from patients with available EHRs (all from USA; n=94); the final analysis will include updated data from manual chart reviews. After a median follow-up of 30.3 months, median OS was 41.3 months (90% CI: 36.8–46.3) in the overall dataset (n=203) and 45.7 months (90% CI: 45.3–51.5) in Del19-positive patients (n=149); 2-year OS was 80%. OS in Asians was immature. Updated median TTF was 28.1 months (90% CI: 26.8–30.3) in the overall dataset, and 30.6 months (90% CI: 27.6–32.0) in Del19-positive patients. Outcomes were not affected by afatinib starting dose. Median TTF with osimertinib was 15.6 months (90% CI: 13.8–17.1) in the overall dataset, and 16.4 months (90% CI: 14.9–17.9) in Del19-positive patients. In patients with EGFR T790M-positive NSCLC, we observed encouraging median OS of almost 3.5 years with sequential afatinib and osimertinib, with even greater benefit seen in Del19-positive patients. These data support the feasibility of this sequential regimen. Notably, prolonged TTF of 15.6 months was seen with second-line osimertinib, despite all patients having received prior afatinib treatment. The final analysis, anticipated in early 2020, will provide further insights into the long-term survival of patients treated with sequential afatinib–osimertinib, including Asians. 1. Hochmair MJ, et al. Future Oncol. 2018;14:2861–74.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy.Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs).Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28.0% vs 31.4%; RR 0.86, 95% CI 0.82-0.89; p<0.0001). 10-year breast cancer mortality was similarly reduced (18.9% vs 21.3%; RR 0.87, 95% CI 0.83-0.92; p<0.0001), as was all-cause mortality (22.1% vs 24.8%; RR 0.87, 95% CI 0.83-0.91; p<0.0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4.1% vs 4.6%; RR 0.88, 95% CI 0.78-0.99; p=0.034). Recurrence reductions were similar in the seven trials (n=10004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24.0% vs 28.3%; RR 0.83, 95% CI 0.76-0.91; p<0.0001), in the six trials (n=11028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28.1% vs 31.3%; RR 0.87, 95% CI 0.80-0.94; p=0.0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30.4% vs 35.0%; RR 0.82, 95% CI 0.74-0.90; p<0.0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0.0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics.Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.

With three generations of EGFR tyrosine kinase inhibitors (TKIs) now available for the treatment of EGFR mutation-positive (EGFRm+) NSCLC, it will be important to identify the optimal sequence of EGFR TKIs to maximise survival. The observational GioTag study (NCT03370770) investigated outcomes in patients with EGFRm+ NSCLC who were treated with sequential afatinib and osimertinib in a ‘real-world’ clinical setting, including patients with poor prognosis (ECOG PS ≥2: 15%; stable brain metastases: 10%).1 Time to treatment failure (TTF) was encouraging (overall: 27.6 months; Del19-positive patients: 30.3 months; Asians: 46.7 months). In this updated analysis, we report OS and updated TTF. Data were retrospectively collected between Dec 2017 and June 2018 for 203 pts with EGFRm+ (Del19, L858R) NSCLC who had T790M-positive disease after first-line afatinib and subsequently received osimertinib. TTF was the primary outcome; OS analysis was exploratory. Data were collected from electronic health records (EHRs; n=126) or medical charts (n=77). For logistical reasons, this interim analysis includes updated data (as at April 2019) from patients with available EHRs (all from USA; n=94); final analysis incorporating updated data from manual chart reviews is anticipated in early 2020. After a median follow-up of 30.3 months, median OS was 41.3 months (90% CI: 36.8–46.3) in the overall dataset (n=203) and 45.7 months (90% CI: 45.3–51.5) in Del19-positive patients (n=149); 80% of patients were alive after 2 years. OS in Asians was immature. Updated median TTF was 28.1 months (90% CI: 26.8–30.3) in the overall dataset, and 30.6 months (90% CI: 27.6–32.0) in Del19-positive patients. Outcomes were not affected by afatinib starting dose. Median TTF with osimertinib was 15.6 months (90% CI: 13.8–17.1) in the overall dataset, and 16.4 months (90% CI: 14.9–17.9) in Del19-positive patients. Sequential afatinib and osimertinib is associated with encouraging OS and TTF in pts with EGFR T790M-positive NSCLC, especially in Del19-positive patients, indicating that the sequential regimen is a feasible option in this setting. Of note, prior treatment with afatinib did not preclude prolonged TTF with second-line osimertinib (15.6 months overall; 16.4 months in Del19-positive patients). The final analysis will provide further insights into the long-term OS of patients treated with sequential afatinib–osimertinib, including Asians. 1. Hochmair MJ, et al. Future Oncol. 2018;14:2861–74.

Current guidelines recommend routine molecular testing for EGFR, ALK, ROS1 and BRAF alterations in patients with advanced non-squamous non-small cell lung cancer (NSCLC) and in squamous NSCLC presenting specific clinical features. Precision medicine reflects the selection of appropriate targeted therapies (TTs) and immune-oncology (IO) treatment based on molecular testing. To provide an overview of current situation, the Central European Cooperative Oncology Group (CECOG) has developed a survey with participation of national experts in the field of molecular pathology and oncology from 10 countries: Austria, Bulgaria, Croatia, Czech Republic, Hungary, Poland, Romania, Serbia, Slovakia, and Slovenia. First part of the survey referred to availability and reimbursement of molecular diagnosis in NSCLC, including testing policy (“reflex” vs “on demand”, parallel vs subsequent) and turnaround times. The second part evaluated the access and reimbursement of targeted and IO therapies. There is large variability regarding molecular testing for NSCLC patients in CEE countries, both from access and reimbursement, and from the pattern of recommendation by oncologists. EGFR testing is reflex in Austria, Slovenia, Croatia, Czech Republic, and Slovakia and on demand in Bulgaria, Hungary, Poland, Romania, and Serbia, being fully covered by the public health system only in Austria and Slovenia. Similar situation is reported for ALK testing. ROS1, BRAF and PD-L1 are mainly tested on demand, once testing results for EGFR and ALK are found negative. Turnaround time ranges between 5 and 10 days for reflex testing influenced by technology, with delays for on demand testing. In the first line, EGFR TKIs are available and reimbursed, while IO is reimbursed only in 5 out of 10 countries. The majority of second line TTs and IOs are registered, but not yet reimbursed in many CEE markets, despite the unmet medical need. Austria can be a model in CEE, having rapid access and implementation of the new standards in testing and treatment (all second line TTs and IO available). Slovenia and Hungary follow with 7 out of 10 second line available novel treatments. Time from registration to reimbursement of targeted treatment is usually long, lasting 1 year or more. This survey provides updated overview on availability and reimbursement of molecular diagnostic and precision medicines in CEE countries, for NSCLC patients. There is a strong need to standardize management and to facilitate access to novel therapies in routine clinical practice for better patient outcomes. Experts network, like CECOG, can facilitate regional dialogue.

Background: In EU, novel anticancer drugs must obtain an EMA marketing authorization (EMA MA) through a centralized procedure, while their reimbursement is not centralized, thus leading to different lag times in drug access for EU citizens. In Slovenia, the reimbursement procedure is within the jurisdiction of the National Health Insurance Institute. ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) was developed to aid oncologists and patients in informed treatment decisions, but may also assist health care authorities in decision-making. Therefore, time to EMA MA and reimbursement in Slovenia were assessed in relation to ESMO-MCBS. Methods: Anticancer therapies for solid tumors with ESMO-MCBS scores determined by the ESMO expert panels and published until Dec 31st 2017 were reviewed. Drugs reimbursed before Jan 1st 2008 and before Jan 1st 2012 for oral and parenteral drugs, respectively, were excluded due to lack of publically available data on reimbursement in Slovenia. Data on EMA MA and reimbursement were retrieved from www.ema.europa.eu and www.zzzs.si. Data lock was Mar 15th 2018. Results: Overall, 51 anticancer therapies were authorized by EMA: 39 targeted, 9 immunotherapy, 3 cytostatic with each drug indication evaluated separately. Until data lock, 46/51 therapies passed national reimbursement, 1 was rejected at reimbursement and 4 were pending reimbursement decision. Of the 46 reimbursed drugs, 24 had a high ESMO-MCBS score (A-B, 4-5), indicating a substantial clinical benefit, and 22 had a low ESMO-MCBS score (C, 1-3). Their median time to EMA MA was 398 d (98 - 615 d) with no difference between high vs low ESMO-MCBS (377 vs 398 d). Median time to national reimbursement was 429 d (154 - 892 d) again with no difference between high vs low ESMO-MCBS (451 vs 416 d). This resulted in a total median time to drug access of 762 d (373 – 1426 d). Conclusions: Although most novel anticancer therapies are available in Slovenia, the median times to EMA MA and to reimbursement decision are above one year each. This is well overdue for cancer patients. Neither time seem to differ by ESMO-MCBS, possibly because the majority of drugs was not assigned a score at the time of decision-making. Hopefully, a better integration of ESMO-MCBS is forthcoming. Legal entity responsible for the study: All authors are responsible for the conduction of the study and its results. Funding: Has not received any funding. Disclosure: T. Cufer: Advisory boards and/or provided lectures: AstraZeneca, Boehringer-Ingelheim, BMS, Roche, MSD, Pfizer. All other authors have declared no conflicts of interest.

Background: Driver mutation of epidermal frowth factor (EGFR) is presented in non-small cell lung cancer (NSCLC) at about 10%. Osimertinib (Tagrisso®) is a 3rd generation tyrosine kynase inhibitor (TKI) for EGFR mutated advanced lung adenocarcinoma with or without T790M resistant mutation. Particularly osimertinib showed a good penetration through blood-brain barrier and efficacy in central nervous system (CNS) metastases. In this, single-center, retrospective study we analyzed course of the CNS disease of metastatic NSCLC patients treated with osimertinib in any line of therapy. Methods: Patients with EGFRm advanced NSCLC who received osimertinib (80 mg daily) after progression on prior EGFR TKI (n = 23) or upfront (n = 2) were analyzed. All patients performed CT or MRI before osimertinib. We collected data on: presence of CNS metastases, line of the treatment on osimertinib, previous treatment of CNS metastases, efficacy and date of progression. Responses were evaluated radiologically every 8–16 weeks according to RECIST criteria. All patients had at least one evaluation. Results: In the present study 25 patients were included which have been treated from October 2015 untill November 2017. Among analyzed patients 10/25 (40%) had CNS (brain only) metastases before initiation with osimertinib, 4/10 received prior CNS treatment with radiotheraphy or surgery. Maximum osimertinib treatment duration was 46/56 weeks for patients with/without CNS metastases, respectively. Median duration of treatment at the time of analysis was 27 weeks with 11/25 of patients still ongoing treatment. CNS objective response rate was 70% (CR 0%, PR 50%, SD 20%). Patients with progressive disaese (30%) had progression of all tumor leasons including CNS. There was no isolated CNS progression during osimertinib treament observed among all analyzed patients (n = 25). Conclusions: In our real world analysis osimertinib showed comparable CNS efficacy to clinical trial results with no CNS only progressive disease. Legal entity responsible for the study: University Clinic Golnik Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest.

CtDNA EGFR mutation (EGFRmu) analysis is used to improve detection of resistant mutations and to overcome the limitation of repeated tissue sampling after resistance to EGFR TKI develops. 50–60% of resistance mechanism is due to secondary EGFR T790M mutation. The aim of our analysis was to evaluate the type and frequency of EGFRmu in ctDNA and in tissue at disease progression on non-mutant specific EGFR TKI. Since May 2014 ctDNA EGFRmu determination is a routine clinical practice at our hospital. 41 EGFRmu positive pts with advanced NSCLC were treated with non-mutant specific EGFR TKI since then and followed up at our clinic. Blood samples for EGFRmu analysis were taken at each scheduled visit. Tissue rebiopy was also performed at disease progression when feasible for the patient. Cobas EGFR Mutation Test v1 and v2 (Roche, USA) to detect 42 mutations in exons 18 to 21 at EGFR gene was used for tissue and plasma testing. 21/41 (51%) pts experienced radiological progression with or without clinical disease progression during the observation period. In 19/21 (90.5%) pts activating EGFRmu were detected in the blood at the time of progression (+/– 1 month), in addition in 9/21 (42.9%) pts T790M mutation was also detected. In 7 pts tissue rebiopsy was also performed at the time of progression. In 2 pts, where T790M mutation was already detected in ctDNA, it was also found in the tissue. Among 5 pts, where only activating mutations were present in the ctDNA at the time of progression, 3 pts also had T790M mutations confirmed in the tissue rebiopsy. Overall, T790M mutations in ctDNA and/or tissue was detected in 12/21 (57.6%) of all our pts at the time of progression. We confirmed a high rate of ctDNA EGFRmu positivity at the time of progression on EGFR TKI in our group of routinely treated pts. The detection rate of T790M mutation was lower than expected – only 43%. However, tissue rebiopsy increased T790M mutation detection rate to 57.6%. Taking into account our limited results tissue rebiopsy is reasonable where it is feasible for the patient because further therapeutic options are available.

Development of the target therapies of lung cancer was a rapid process which fundamentally changed the pathological diagnosis as well. Furthermore, molecular pathology became essential part of the routine diagnostics of lung cancer. These changes generated several practical problems and in underdeveloped countries or in those with reimbursement problems have been combined with further challenges. The central and eastern region of Europe are characterized by similar problems in this respect which promoted the foundation of NSCLC Working Group to provide up to date protocols or guidelines. This present paper is a summary of the molecular pathology and target therapy guidelines written with the notion that it has to be upgraded continuously according to the development of the field.

As compared to tamoxifen aromatase inhibitors (AIs) may increase the risk of heart disease. Here we explored the association between the use of AIs and coronary artery disease (CAD) in a population-based observational study. In a small and heterogeneous population of 74 women with early breast cancer who received adjuvant hormonal therapy and subsequently underwent cardiac angiography, AIs significantly increased the hazard for CAD (HR 3.23, 95% confidence intervals [CI] 1.26-8.25, p = .01) compared to tamoxifen. Our results suggest that therapy with AIs may increase the risk for CAD.

Advanced Breast Cancer (ABC) is a treatable but still generally incurable disease. The goals of care are to optimize both length and quality of life. Due to continuous research, several advances have been made, particularly for the HER-2-positive and for Luminal-like subtypes. Notwithstanding these advances, median overall survival of patients with ABC is still only 2–3 years, although the range is wide [1–5], and survival may be longer for patients treated in specialized institutions [6]. Implementation of current knowledge is highly variable among countries and within each country.