An EGFR-mutant lung adenocarcinoma that transformed into small-cell lung cancer. A case report.

BACKGROUND: Transformation of EGFR (epidermal growth factor receptor) - mutant non-small cell lung cancer (NSCLC) into small-cell lung cancer (SCLC) is one mechanism of resistance to tyrosine kinase inhibitor (TKI) treatment, seen in approximately 3-10% cases. Such transformed SCLC often retains the original EGFR mutation (EGFRM), which is not otherwise observed in SCLC. CASE REPORT: We present a 67 y/o woman with pulmonary adenocarcinoma (AC) and EGFRM deletion on exon 19. After initial treatment with whole brain radiotherapy and 7 months of TKI afatinib, progression was observed. Liquid biopsy detected deletion on exon 19 and T790M mutation. Chemotherapy carboplatin plus pemetrexed was administered, with no response. Genetics from a rebiopsy of lung revealed deletion on exon 19. After 12 months treatment with TKI osimertinib, a progression in lung and pancreas lesions was detected, docetaxel was used, with followig progression. The lung biopsy revealed SCLC. Significant elevation of serum markers carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) was observed at the time of the SCLC diagnosis. Treatment with carboplatin and etoposide was not effective. The next biopsy found two populations of cells: SCLC and AC. The biopsy from the pancreatic lesion revealed metastasis of SCLC. PCR confirmed EGFRM deletion on exon 19 in the lung SCLC tissue sample. The following treatment lines of topotecan, erlotinib were not effective. The patient survived 36 months from diagnosis, 7 months from detection of SCLC. CONCLUSION: Screening for transformation of EGFR-mutant NSCLC to SCLC should be considered in resistance to TKI. In the presented case, this rare transformation was confirmed by histopathologic examination and by PCR. EGFRM in the lung SCLC, identical to that found in the original lung AC, was detected. Further, the observed elevation of serum tumor markers NSE and CEA can indicate this infrequent transformation and help to decide on rebiopsy.

Establishment of a virtual transborder tumor board for cancer patients in Central and Southeastern Europe : An initiative of the Central European Cooperative Oncology Group (CECOG).

PURPOSE: To establish a transborder virtual tumor board (VTB) fostering state-of-the-art management of cancer patients by exchanging knowledge and expertise among oncologists in Central and Southeastern Europe (CEE). METHODS: We established and implemented a VTB based on the WebEx platform. This allowed for password-protected and secure upload of patient cases to be presented and discussed among colleagues from various oncology centers scattered throughout CEE in order to arrive at a recommendation for further diagnoses and/or treatment. RESULTS: A total of 73 cases from 16 oncology centers located in 11 CEE countries were uploaded by 22 physicians; 71 were discussed over the course of 17 virtual meetings between June 2018 and May 2019 and 12 different kinds of malignant diseases were discussed with lung cancer (46.6%), melanoma (19.2%) and bladder cancer (13.6%) being the most commonly presented tumor entities. Of the discussed patients, 93.3% had stage IV disease at the time of presentation, 62.6% received chemotherapy or targeted treatment and 67.1% were treated with immune checkpoint inhibitors (ICPIs). The most common causes for presentation and discussion of patient cases were related to the use of ICPIs (80%). CONCLUSION: When the need for expertise exceeds locally available resources, web-based VTBs provide a feasible way to discuss patient cases and arrive at conclusions regarding diagnoses and/or treatment across large geographic distances. Moreover, VTBs provide an innovative way for proper, state-of-the-art management of patients with malignant diseases in times of social distancing and the resulting need for restricted interaction during the current SARS-CoV­2 (severe acute respiratory syndrome coronavirus type 2) pandemic.

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

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.

NSCLC molecular testing in Central and Eastern European countries.

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.

Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer in the Real-World Setting in Central Europe: The INSIGHT Study.

The ImplementatioN of perSonalized medicine In NSCLC in Central Europe: EGFR testing, Histopathology, and clinical feaTures (INSIGHT) observational study assessed both implementation of epidermal growth factor receptor (EGFR) mutation testing and treatment of patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) in a real-world setting in Central Europe. A total of 1785 patients from 14 cancer centers of six Central European countries were enrolled. EGFR mutations were detected in tumors of 13.8% of the patients. More than 70% of patients with advanced EGFR mutation-positive NSCLC received EGFR tyrosine kinase inhibitors as first-line therapy. The INSIGHT study demonstrated the establishment of EGFR mutation testing, a mutation rate consistent with other Caucasian patients populations, and adherence to current guidelines regarding treatment of patients with EGFR mutation-positive tumors in Central Europe.

Evaluation of 2-year experience with EGFR mutation analysis of small diagnostic samples.

Mutation analysis of the epidermal growth factor receptor (EGFR) gene is an essential part of the diagnostic algorithm in patients with metastatic or recurrent non-small cell lung cancer (NSCLC). Small biopsies or cytology specimens represent >80% of the available diagnostic material. EGFR mutation analyses were realized on 835 samples (675 cytology specimens, 151 formalin-fixed paraffin-embedded blocks, 5 tumors, and 4 pleural effusions). EGFR mutation analysis was performed by high-resolution melting analysis in combination with mutant-enriched polymerase chain reaction and sequencing analysis. Because of increased risk of inaccuracy in histology diagnosis of small specimens, all subtypes of NSCLC were analyzed. EGFR mutations were detected in 83 cases (10%). EGFR mutation testing failed in 5% (42/835) and was associated with poor cellularity, low percentage of tumor cells, and bad quality of DNA. Although 281 samples were evaluated as insufficient material (poor cellularity and/or unrepresentative tumor content), mutation rates were 7%. Although only adenocarcinomas or NSCLC-not otherwise specified are recommended for EGFR mutation testing, EGFR mutations in 11% of the large cell carcinomas and 4% of the squamous cell carcinomas were observed. Our results indicate that defined algorithm for EGFR testing of small diagnostic samples is sensitive, fast, and suitable even for samples with poor cellularity. The results of this testing should be evaluated depending on tumor content and DNA quality for each sample individually. At the conclusion of our results, we recommend to realize EGFR mutation analysis of small diagnostic samples regardless of the histologic subtypes of NSCLC.

Cancer epidemiology in Central, South and Eastern European countries.

AIM: To collect cancer epidemiology data in South Eastern European countries as a basis for potential comparison of their performance in cancer care. METHODS: The South Eastern European Research Oncology Group (SEEROG) collected and analyzed epidemiological data on incidence and mortality that reflect cancer management in 8 countries - Croatia, Czech Republic, Hungary, Romania, Poland, Slovakia, and Serbia and Montenegro in the last 20-40 years. RESULTS: The most common cancer type in men in all countries was lung cancer, followed by colorectal and prostate cancer, with the exception of the Czech Republic, where prostate cancer and colorectal cancer were more common. The most frequent cancer in women was breast cancer followed by colorectal cancer, with the exceptions of Romania and Central Serbia where cervical cancer was the second most common. Cancer mortality data from the last 20-40 years revealed two different patterns in men. In Romania and in Serbia and Montenegro, there was a trend toward an increase, while in the other countries mortality was declining, after increasing for a number of years. In women, a steady decline was observed over many years in the Czech Republic, Hungary, and Slovakia, while in the other countries it remained unchanged. CONCLUSIONS: There are striking variations in the risk of different cancers by geographic area. Most of the international variation is due to exposure to known or suspected risk factors which provides a clear challenge to prevention. There are some differences in incidence and mortality that cannot be explained by exposure to known risk factors or treatment availabilities.

Rapid and efficient detection of EGFR mutations in problematic cytologic specimens by high-resolution melting analysis.

BACKGROUND AND OBJECTIVE: Chemotherapy for advanced non-small-cell lung cancer (NSCLC) remains marginally effective, with a 5-year overall survival rate of approximately 5%. Recently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib was approved in Slovakia for the treatment of metastatic NSCLC. Gefitinib is a selective EGFR inhibitor that binds to the adenosine triphosphate binding pocket of the kinase domain and blocks downstream signaling pathways. Mutations of the EGFR gene, particularly an in-frame 15 bp deletion (delE746_A750) in exon 19 and the L858R mutation in exon 21, correlate with enhanced clinical responsiveness to EGFR tyrosine kinase inhibitors. However, the detection of these mutations and thereby prediction of the therapy outcome is sometimes unreliable due to the low sensitivity of direct sequencing if the proportion of tumor cells in the tissue is less than 25%. Therefore we decided to test the applicability of other methods, particularly high-resolution melting analysis (HRMA), for detection of these mutations in clinical samples. METHODS: We analyzed 53 archival cytologic specimens for the presence of EGFR mutations, using the HRMA method. Results were verified by direct sequencing. For samples containing less than 25% tumor cells, we used mutant-enriched PCR before sequencing. We also performed a titration assay to establish the lower limit of the proportion of tumor cells for detection of EGFR mutations. RESULTS: EGFR mutations were detected in 13 cases (24%). In-frame deletions in exon 19 were detected in eight cases (15%) and the L858R mutation in exon 21 was detected in five cases (9%). The positive results of the HRMA were confirmed by direct sequencing only in five of 13 cases. In the remaining eight positive samples, HRMA results were confirmed by sequencing analysis after mutant-DNA enrichment. The titration assay established that the lower limit for detection of EGFR mutations by HMRA was 1% tumor cells in the clinical sample. CONCLUSION: Our results indicated that HRMA in combination with mutant-enriched PCR represents a sensitive method for detection of EGFR mutations from cytologic specimens. When properly executed, this protocol allows identification of EGFR mutations in specimens containing a minimal percentage of tumor cells.

Therapy of small cell lung cancer with emphasis on oral topotecan.

Systemic chemotherapy plays the major role in the management of patients with small cell lung cancer. Cisplatin plus etoposide is the most widely used regimen and is considered as standard in patients with limited disease. Cisplatin plus irinotecan improved survival compared to cisplatin plus etoposide in a Japanese trial but failed to do so in two trials in Caucasians. Cisplatin plus topotecan had similar efficacy compared to cisplatin plus etoposide in patients with extensive disease. In the second-line setting, topotecan showed similar efficacy but better tolerability compared to cyclophosphamide, doxorubin plus vincristine. Oral topotecan was as efficacious as its intravenous formulation and was shown to improve survival compared to best supportive care alone in patients previously treated with chemotherapy. Thus topotecan is considered as the standard second-line chemotherapy in patients with small cell lung cancer.