Epidermal growth factor receptor mutations and treatment of non-small-cell lung cancer

Petletno preživetje bolnikov s pljučnim rakom je slabo, samo 12-odstotno, in se v zadnjih 15 letih ni bistveno izboljšalo. Standardno zdravljenje razsejanega nedrobnoceličnega raka pljuč (NDRP), ki je danes najpogostejši tip raka pljuč, je kemoterapija na osnovi citostatika cisplatina. S tem je citostatsko zdravljenje razsejanega NDRP najbrž doseglo največ, kar je lahko. V zadnjih letih pa smo tudi pri zdravljenju NDRP priča razmahu tarčnega zdravljenja. Kot učinkovita so se izkazala tarčna zdravila, ki delujejo na receptor za epidermalni rastni dejavnik (EGFR), in to predvsem mali molekuli, zaviralca tirozinske kinaze (TKI) erlotinib in gefitinib. EGFR je transmembranski glikoprotein, ki se nahaja tako na površini zdravih kot tudi tumorskih celic različnih rakov. Pripada družini proteinov ErbB, ki vključuje 4 receptorje. Od vseh določanj izraženosti EGFR se je določitev aktivirajočih mutacij gena za EGFR v primarnem tumorju izkazala za najboljši pozitivni napovedni dejavnik odgovora na zdravljenje s proti EGFR usmerjenimi TKI. Čeprav je bila povezava med mutacijami gena za EGFR ter nekaterimi kliničnimi in patološkimi značilnostmi NDRP dokazana, pa na podlagi kliničnih in patoloških značilnosti bolnikov ne moremo zanesljivo prepoznati tistih, ki bodo imeli največjo korist od zdravljenja s TKI. Samo z določitvijo aktivirajočih mutacij gena za EGFR je mogoče prepoznati bolnike, ki bodo značilno bolje odgovorili na zdravljenje s TKI kot na kemoterapijo in pri katerih je ob zdravljenju s proti EGFR usmerjenimi TKI utemeljeno pričakovati razmeroma dolgo preživetje in dobro kakovost življenja. Zato je danes pri vseh bolnikih s pljučnim adenokarcinomom pred uvedbo prvega sistemskega zdravljenja napredovale bolezni priporočeno določanje mutacij gena za EGFR v primarnem tumorju. Na podlagi tega podatka je namreč mogoča ustreznejša izbira prvega in tudi poznejših redov sistemskega zdravljenja pri vsakem bolniku.The 5-year relative survival rates of patients with lung cancer are approximately 12%, and have increased only by 2.2% during the last 15 years. Third generation chemotherapy based on platinum derivates is currently a standard treatment for the advanced non-small-cell lung cancer (NSCLC) but has probably reached a plateau. With the advent of targeted therapy it has been introduced into the clinical management of advanced NSCLC as well. Epidermal growth factor (EGFR) is a transmembrane glycoprotein which is expressed on the cell surface of a tumor as well as on normal cells. It belongs to the ErbB receptor family, which includes four types of receptors. In the article only EGFR (HER1/ErbB1) will be considered. Treatment with two small molecules, tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR), namely gefintib and erlotinib, already proved to be an effective treatment strategy in patients with advanced NSCLC. Among different methods used for EGFR status determination, only identification of activating mutations in the EGFR gene domain proved to be a very reliable and significant predictor for the response to EGFRdirected TKIs therapy in NSCLC. Even though the activating EGFR mutations were found to be more frequent in patients with particular clinico-pathological characteristics, such as females, non-smokers, those with adenocarcinoma histology, a selection of patients based on these characteristics does not allow for a proper selection of patients for EGFR-directed TKI therapy. Only by determining the activating EGFR mutations in the primary tumor can the identification of NSCLC patients with expected high response rates to EGFR-directed TKI therapy leading to long survival and a good quality of life be achieved. Personalized medicine for NSCLC patients is now reality, and EGFR mutation status should be determined in the primary tumor of all patients prior to any systemic therapy for advanced disease, thus allowing us a tailored first-line and subsequent lines of systemic therapy in each individual patient

Analysis of the frequency of EGFR, KRAS and ALK mutations in patients with lung adenocarcinoma in Croatia

BACKGROUND: Many studies have been published on the mutational status of patients with lung adenocarcinomas, and great population-based variability in mutation frequencies has been reported. The main objective of the present study was to analyze the EGFR, KRAS and ALK mutation status in a representative cohort of patients in Croatia with lung adenocarcinomas and to correlate the mutational status with clinical data. ----- METHODS: All patients who were newly diagnosed within 6 months with histologically proven primary lung adenocarcinomas were included. Mutational analyses for EGFR and KRAS mutations were performed in a cobas z 480 analyzer. ALK immunohistochemistry was performed using the D5F3 clone on Benchmark XT instrument. Clinical data were obtained from the medical records. ----- RESULTS: Of the 324 patients, 59.9 % were male. At the time of diagnosis, the patients ranged in age range from 35 to 88 years (median 63 years). Most of the patients were current smokers or former smokers (77.2 %). EGFR mutations were found in 15.7 % of the patients, and of these mutations, exon 19 deletion was the most common (45.1 %). KRAS mutations were present in 34.9 % of the patients, while 4.1 % of patients were ALK-positive. The statistical significance of the presence of mutations was detected for both gender and smoking. ----- CONCLUSION: The detected mutation rates demonstrated a slightly higher prevalence of KRAS mutations, but not a higher prevalence of EGFR mutations or ALK gene rearrangement, in comparison with the rates found in other European countries. EGFR and ALK mutational status showed a statistically significant correlation with gender as well as with smoking, while KRAS mutation status showed a statistically significant correlation only with smoking

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future

Background: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. Materials and methods: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID- 19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. Results: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. Conclusions: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe

Allergic bronchopulmonary aspergillosis with coexistant aspergilloma: a case report

<p>Abstract</p> <p>Introduction</p> <p>The coexistence of allergic bronchopulmonary aspergillosis and aspergilloma is rare.</p> <p>Case presentation</p> <p>We present the case of a 56-year-old Caucasian man who worked as a farmer, with infiltrates in the right lower and middle lung lobes, partial consolidation of the middle lobe and with previous diagnosis of chronic obstructive bronchitis. Evaluation of our patient led to the diagnosis of allergic bronchopulmonary aspergillosis with coexistent aspergilloma in the right lower lobe. He was treated with oral methylprednisolone and itraconazole. At the five-year follow-up he is without any sign of recurrence.</p> <p>Conclusion</p> <p>Aspergillus infection after the inhalation of spores in the form of a hypersensitivity reaction and saprophytic colonization can be coexistent.</p

Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma

Aims: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study. Methods and results: Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours. Conclusions: Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches

Lung cancer biomarker testing : perspective from Europe

A questionnaire on biomarker testing previously used in central European countries was extended and distributed in Western and Central European countries to the pathologists participating at the Pulmonary Pathology Society meeting 26-28 June 2019 in Dubrovnik, Croatia. Each country was represented by one responder. For recent biomarkers the availability and reimbursement of diagnoses of molecular alterations in non-small cell lung carcinoma varies widely between different, also western European, countries. Reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. The support for testing from alternative sources, such as the pharmaceutical industry, is no doubt partly compensating for the lack of public health system support, but it is not a viable or long-term solution. Ideally, a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. As biomarker enabled therapies deliver a 50% better probability of outcome success, improved and unbiased reimbursement remains a major challenge for the future.Peer reviewe

Mnenje za spremljanje bolnikov po preboleli covidni pljučnici

Pljučnica je najpogostejši vzrok za težji potek okužbe z virusom SARS-CoV-2 in s hospitalizacijo. Potek covidne pljučnice je lahko različen; infiltrati, vidni na rentgenski sliki, se lahko resorbirajo spontano, včasih pa je potrebno zdravljenje s sistemskimi glukokortikoidi. Ob odpustu iz bolnišnice zdravljenje običajno še ni končano, zato je Združenje pulmologov Slovenije v želji po enotnem obravnavanju bolnikov s covidno pljučnico izdelalo mnenje za obravnavo in sledenje bolnikov po odpustu iz bolnišnice. Zavedamo se, da ob novi bolezni ne gre za dokončno mnenje, saj bodo nova spoznanja o covidni pljučnici zanesljivo zahtevala obnavljanje mnenj

Multicenter Evaluation of the Fully Automated PCR-Based Idylla EGFR Mutation Assay on Forman-Fixed, Paraffin-Embedded Tissue of Human Lung Cancer

Before initiating treatment of advanced non-small-cell lung cancer with tyrosine kinase inhibitors (eg, erlotinib, gefitinib, osimertinib, and afatinib), which inhibit the catalytic activity of epidermal growth factor receptor (EGFR), clinical guidelines require determining the EGFR mutational status for activating (EGFR exons 18, 19, 20, or 21) and resistance (EGFR exon 20) mutations. The EGFR resistance mutation T790M should be monitored at cancer progression. The Idylla EGFR Mutation Assay, performed on the Idylla molecular diagnostics platform, is a fully automated (<2.5 hours turnaround time) sample-to-result molecular test to qualitatively detect 51 EGFR oncogene point mutations, deletions, or insertions. In a 15-center evaluation, Idylla results on 449 archived formalin-fixed, paraffin-embedded tissue sections, originating from non-small-cell lung cancer biopsies and resection specimens, were compared with data obtained earlier with routine reference methods, including next-generation sequencing, Sanger sequencing, pyrosequencing, mass spectrometry, and PCR-based assays. When results were discordant, a third method of analysis was performed, when possible, to confirm test results. After confirmation testing and excluding invalids/errors and discordant results by design, a concordance of 97.6% was obtained between Idylla and routine test results. Even with <10 mm(2) of tissue area, a valid Idylla result was obtained in 98.9% of the cases. The Idylla EGFR Mutation Assay enables sensitive detection of most relevant EGFR mutations in concordance with current guidelines, with minimal molecular expertise or infrastructure