Advancing HER2-low breast cancer management: enhancing diagnosis and treatment strategies.

BACKGROUND: Recent evidence brought by novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates is leading to significant changes in HER2-negative breast cancer (BC) best practices. A new targetable category termed 'HER2-low' has been identified in tumors previously classified as 'HER2-negative'. Daily practice in pathology and medical oncology is expected to align to current recommendations, but patient access to novel anticancer drugs across geographies might be impeded due to local challenges. MATERIALS AND METHODS: An expert meeting involving ten regional pathology and oncology opinion leaders experienced in BC management in four Central and Eastern Europe (CEE) countries (Bulgaria, Croatia, Serbia, Slovenia) was held. Herein we summarized the current situation of HER2-low metastatic BC (mBC), local challenges, and action plans to prevent delays in patient access to testing and treatment based on expert opinion. RESULTS: Gaps and differences at multiple levels were identified across the four countries. These included variability in the local HER2-low epidemiology data, certification of pathology laboratories and quality control, and reimbursement conditions of testing and anticancer drugs for HER2-negative mBC. While clinical decisions were aligned to international guidelines in use, optimal access to testing and innovative treatment was restricted due to significant delays in reimbursement or limitative reimbursement conditions. CONCLUSIONS: Preventing delays in HER2-low mBC patient access to diagnosis and novel treatments is crucial to optimize outcomes. Multidisciplinary joint efforts and pro-active discussions between clinicians and decision makers are needed to improve care of HER2-low mBC patients in CEE countries.

Unmet needs in EGFR exon 20 insertion mutations in Central and Eastern Europe: reimbursement, diagnostic procedures, and treatment availability.

Lung cancer remains the leading cause of cancer-related deaths in Europe, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. NSCLC is a heterogeneous disease encompassing various oncogenic alterations. Among them, EGFR exon 20 insertion mutations, constituting 0.3-2.2% of NSCLC cases, rank as the third most common EGFR alteration after exon 19 deletions and the L858R point mutation in exon 21, also known as "typical" EGFR alterations. Recent advancements in understanding the molecular pathogenesis of NSCLC have led to significant breakthroughs in targeted therapies, revolutionizing treatment options for patients with specific genetic alterations.This article presents the outcomes of a Virtual Meeting conducted on the online platform (provided Within3©) from September 19 to October 30, 2022. The meeting focused on addressing the challenges in the diagnosis and treatment of NSCLC patients with EGFR exon 20 insertion mutations. The participants consisted of healthcare professionals from ten Central and Eastern European countries who shared their experiences and opinions on various aspects, including epidemiology, treatment options, and diagnostic approaches employed in their respective healthcare institutions. The discussions were facilitated through open-ended and multiple-choice questions.The primary objective of this article is to provide an overview of the identified challenges associated with the diagnosis and treatment of this heterogeneous disease, based on the assessments of the meeting participants. Among the major emerging challenges discussed, the reimbursement issues concerning next-generation sequencing (NGS), a recommended method in NSCLC molecular diagnosis, and the availability of approved targeted treatments to enhance patient outcomes were of paramount importance. Furthermore, fostering community awareness of lung cancer and promoting harmonized lung cancer care were identified as areas deserving greater attention. Notably, the rapidly evolving treatment landscape, particularly with NGS for NSCLC patients with genomic alterations like EGFR, ALK, RET, MET, NTRK, and ROS1, necessitates prioritizing the development of new drugs, even for the relatively smaller subgroup with exon 20 insertion mutations.

Diagnostic and clinical value of [18F]FDG PET/CT in the follow-up regimen in IIA-IIID stage cutaneous malignant melanoma after first regional recurrence.

BACKGROUND: Malignant melanoma stands out as a disease with highly aggressive behavior and frequent recurrences. It is crucial to find a non-invasive method for early recurrence detection which allows early and radical treatment. Our aim was to assess the diagnostic and clinical value of [18F]FDG PET/CT in the follow-up regimen of patients after radically treated first regional recurrence and for early detection of operable disease progression. MATERIAL AND METHODS: We performed [18F]FDG PET/CT in 96 consecutive patients who had a histologically proven regional recurrent disease that was radically treated. In 46 patients [18F]FDG PET/CT was used in the follow-up regimen and in the other 50 it was used for clarification of suspicious lesions seen in conventional studies. We explored the diagnostic performance of [18F]FDG PET/CT. We also compared the results with conventional studies and explored the clinical impact of [18F]FDG PET/CT by its ability to find localized disease progression in those groups. RESULTS: [18F]FDG PET/CT had better sensitivity, specificity, PPV and NPV, and accuracy in patients with symptoms. This good results in the second group had a high price for the patients, as there was a prevalence of distant metastatic disease in the second group - 64.0% vs. 28.3% in the surveillance group (p = 0.001). [18F]FDG PET/CT revealed more of the distant and in-transit lesions and assisted in lymph node detection by guiding the ultrasonography. Owing to the [18F]FDG PET/CT surveillance, 64.5% of all operable lesions were found in the surveillance group vs. only 35.5% in the second group, where the distant metastatic disease was prevalent. CONCLUSIONS: [18F]FDG PET/CT used as a follow-up tool in the surveillance regimen of patients after the first recurrence showed excellent performance in timely and accurate recognition of operable lesions. It had significantly better performance than conventional studies in the follow-up regimen of the patients in this high risk of progression group.

Warty carcinoma of the uterine cervix: a virus-induced disease?

Introduction: Warty carcinoma (WC) of the uterine cervix is a rare subtype of squamous-cell carcinoma (SCC), and its frequency, clinical behaviour, and aetiology are obscure. It originates from condylomas, and a viral carcinogenesis seems logical. Material and methods: Retrospective analysis was performed of all cervical carcinomas (CC), diagnosed at a single institution for a 10-year period. Analysed patients had stage I carcinoma. Patients with WC were identified, and their tumour samples were tested for high-risk HPV (hr-HPV) and EBV, using PCR and ISH. Clinical characteristics and WC rates across all stage I CC patients were assessed. All patients had minimum 3-year follow-up, and overall survival (OS) and 5-year survival rates were calculated. Results: WC comprised 2.2% of all stage I CC (n = 630). The mean age of the patients was 48 years (range: 29-72). The primary tumour size was 2 cm in 4 (28.6%) patients, 2-4 cm in 2 (14.3%) patients, and 4 cm in 8 (57.1%) patients. Lymph node metastasis was found in 1 (7.1%) patient. EBV or hr-HPV were detected in 2 (18.2%) patients using ISH, with no coinfection reported. Hr-HPV was detected in 2 (18.2%) patients; EBV in 4 (36.4%) cases, and in 2 of them (18.2%) there was a co-infection. Thirteen patients had a follow-up of ≥ 5 years and their 5-year OS was 100%. Conclusions: WC is a rare subtype of SCC with good prognosis, regardless of viral status. In contrast to SCC, its aetiology is not related to hr-HPV. The role of EBV remains unclear and cannot currently be denied.

Lymphoepithelioma-like Carcinoma of the Breast Synchronous with a High-Grade Invasive Ductal Carcinoma and Ductal Carcinoma in Situ in a Different Quadrant of the Same Breast: A Case Report.

Lymphoepithelioma-like breast carcinoma (LELC) is a rare type of malignant breast tumor that is not included in the current edition of the World Health Organization (WHO) classification of breast tumors. Currently, there are no clearly defined therapeutic strategies, and the general information on breast LELC is based on sporadic clinical cases described in the medical literature. We present a clinical case that describes a 49-year-old woman with a tumor formation in the right breast, histologically verified as LELC, together with a non-palpable, synchronous high-grade invasive ductal carcinoma and ductal carcinoma in situ Grade 2 (DCIS G2) in a different quadrant of the same breast. To our knowledge, this is the first case described in the literature that combines a LELC with a synchronous carcinoma in the same breast.

Re-excision within a radius of 2 cm in patients with melanoma of the skin - sufficient for local oncological radicalness.

Introduction: Malignant melanoma is one of the most malignant tumours in the human body. Radical re-excision of the tumour bed is a principal part of its surgical treatment. We aim to test the hypothesis that the re-excision with a 2 cm margin in all directions to the scar from the previous biopsy of the primary tumour provides sufficient local control in patients with this disease. Material and methods: This is a prospective descriptive study using STROBE methods, including all 151 patients with malignant melanoma of the skin, diagnosed and treated at the Department of Plastic, Reconstructive, and Aesthetic Surgery, Dr Georgi Stranski University Hospital, Medical University of Pleven, Bulgaria, in the period 2012-2016. Twenty-one cases were omitted from the study during the observation period due to lack of sufficient data. The re-excision was mainly within 2 cm margins in all directions to the scar from the previous biopsy of the primary tumour. Results: Data of all 130 patients with malignant skin melanoma, diagnosed and treated at our single large centre, were prospectively registered and analysed. These were 67 male and 63 female patients with a mean age at diagnosis of 61.6 years (range: 17-91 years). Using the re-excision within 2 cm margins, we identified only 1 (0.77%) patient with a histologically confirmed residual tumour in the re-excised flap. Local recurrence was observed in 13 (10%) patients. Conclusions: Re-excision with a 2 cm margin is sufficient to achieve local surgical radicalness in the treatment of this disease without compromising oncological survival.

Intraoperative Radiotherapy with Balloon-Based Electronic Brachytherapy System-A Systematic Review and First Bulgarian Experience in Breast Cancer Patients.

(1) Background: We aimed to analyze currently available studies with intraoperative radiotherapy (IORT) as a choice of treatment where the Xoft Axxent® electronic brachytherapy (eBx) system was used as a single-dose irradiation and an exclusive radiotherapy approach at the time of surgery in patients with early breast cancer (EBC). We also compared the results of the systematic review to the Bulgarian experience. (2) Methods and Materials: We performed a systematic review of the studies published before February 2021, which investigate the application of a single-fraction 20 Gy radiation treatment, delivered at the time of lumpectomy in EBC patients with the Xoft Axxent® eBx System. A systematic search in PubMed, Scopus, and ScienceDirect was performed. The results are reported following the PRISMA guidelines. The criteria on patients' selection for IORT (the additional need for EBRT), cosmetic outcomes, and recurrence rate from the eligible studies are compared to the treatment results in Bulgarian patients. (3) Results: We searched through 1032 results to find 17 eligible studies. There are no published outcomes from randomized trials. When reported, the cosmetic outcomes in most of the studies are defined as excellent. The observed recurrence rate is low (1-5.8%). Still, the number of patients additionally referred to postoperative external breast radiotherapy (EBRT) is up to 31%. Amongst the 20 patients treated in Bulgaria, the cosmetic outcomes are also evaluated as excellent, five of which (25%) are referred for EBRT. Within median follow-up of 39 months, there was one local and one distal recurrence. (4) Conclusions: Current evidence demonstrates the Xoft Axxent® eBx system as a safe and feasible technique for IORT delivery in EBC patients. There are no randomized controlled trials conducted at this time point to prove its long-term effectiveness. Better patient selection and a reimbursement strategy have to be proposed to extend the application of this technique in Bulgaria.

Adenosquamous Carcinoma of the Uterine Cervix - Impact of Histology on Clinical Management.

INTRODUCTION: Historically, the incidence rate of cervical cancer (CC) in Eastern Europe and particularly in Bulgaria has constantly been higher than that in the other European countries. Adenosquamous carcinoma (ASC) is a rare histological subtype of CC with incidence rate of less than 6 per 100,000. We aimed to analyze the epidemiology and prognosis of all Bulgarian patients with ASC, registered at the Bulgarian National Cancer Registry (BNCR), and to compare patients' characteristics and outcomes with those of patients, treated at a large specialized institution - the Department of Gynecologic Oncology, University Hospital in Pleven, Bulgaria. MATERIALS AND METHODS: This is a retrospective study of all cases of ASC, registered at the BNCR for a 10-year period of time. The Kaplan-Meier analysis with Log rank test was used to estimate the significant differences. RESULTS: The incidence rate of ASC was calculated as 3.2% of all CC registered in BNCR and 4.97% of all stage I patients, treated in our department. The 5-year overall survival (OS) rate of all patients with ASC tumors from the registry was 50.5%. A total of 171 (48.4%) of the patients had T1 tumors and a 5-year OS of 67.1%. Lymph node status was a significant prognostic factor for OS (p=0.001). Thirty-one patients with T1 tumors and ASC histology were treated in our department for the same period of time. Lymph node metastases were found in 10 of them (32.2%). The 5-year observed OS in ASC group was 74.19%. CONCLUSION: The histological subtype of cancer of the uterine cervix has an impact on prognosis and should not be simply considered as a descriptive characteristic but a poor prognostic feature and should be an integral part of the decision-making in clinical management of patients.

Uterine smooth muscle tumours of uncertain malignant potential: single-centre experience and review of the literature.

INTRODUCTION: Uterine smooth muscle tumours of uncertain malignant potential (STUMPs) are a rare histologically heterogeneous group of uterine smooth muscle tumours (SMTs). Their malignant potential and clinical differentiation between leiomyoma and leiomyosarcoma remain uncertain prior to surgical removal. AIM OF THE STUDY: To investigate the patients and tumour characteristics of patients with STUMPs and to propose algorithms for optimal diagnosis, treatment, and follow-up management. MATERIAL AND METHODS: This was a single-centre retrospective cohort study of all patients who underwent surgery for a preoperative diagnosis of uterine myoma at the University Hospital "Dr. Georgi Stranski", Pleven, Bulgaria during a period of 33 months (from January 2013 until October 2015). Data were obtained from the medical history records. We performed descriptive analysis to characterise the patient population (e.g. demographics, age, contraceptive use, and complaints that led to the diagnosis) and the tumour characteristics. Last data were obtained prior May 2019. RESULTS: A total of 320 medical records were retrospectively evaluated. The preoperative diagnosis of myoma was confirmed in 279 of the cases (89.4%). In 27 (8.3%) cases the final histological result was completely different. In 14 (2.3%) a histological postoperative diagnosis of STUMP was identified. All 14 STUMP lesions were intramural with a median size of 7.5 cm (range 3.5 to 15 cm). The median age at diagnosis of STUMP was 45.4 years (range 36 to 52 years), and 92.9% (n = 13) of the patients were premenopausal. Ultrasound data of a rapidly growing myoma were a reason for diagnosis in only three patients (25%), whereas 92.9% of the patients (n = 13) presented with heavy menstrual bleeding with or without anaemia. After surgery, none of the patients with STUMP experienced a relapse of the disease within the median follow-up time of 48 months (R = 40-78). CONCLUSIONS: STUMP tumours are rare tumours, predominantly diagnosed in premenopausal women. They define a group of patients with very good long-term prognosis. Therefore, longer follow-up is needed to allow for conclusions on recurrence rate and survival.

Mucoepidermoid Carcinoma of the Uterine Cervix-Single-Center Study Over a 10-Year Period.

Background and objectives: Adenosquamous cancer of the uterine cervix is a rare type of cervical cancer with both malignant squamous and glandular components. A very rare subtype is mucoepidermoid carcinoma (MEC), which was first described as a salivary gland tumor. It has been described as having the appearance of a squamous cell carcinoma without glandular formation and contains intracellular mucin. The postoperative evolution of this tumor and the potentially poorer prognosis may indicate an intensification of the follow-up. The objective of our study was to analyze the frequency of mucoepidermoid carcinoma in hospitalized women with cervical cancer, clinical characteristics and prognosis. Material and Methods: A retrospective study of all cases of mucoepidermoid carcinoma of the cervix at Department of Gynecologic Oncology,University Hospital-Pleven, Pleven Bulgaria between 1 January 2007 and 31 December 2016 was performed. All patients were followed-up till December 2019. We analyzed certain clinical characteristics of the patients; calculated the frequency of mucoepidermoid carcinoma of the cervix from all patients with stage I cervical cancer; and looked at the overall survival rate, correlation between overall survival, lymph node status and the size of the tumor. Results: The frequency of MEC was 1.12% of all patients with stage I cervical cancer in this study. The median age of the patients with MEC was 46.7 years (range 38-62). Four patients (57.1%) were staged as FIGO IB1, and three patients (42.8%) were FIGO IB2. The size of the primary tumor was <2 cm in 2 patients (28.57%), 2-4 cm in 2 patients (28.57%) and >4 cm in 3 patients (42.8%). Metastatic lymph nodes were found in two patients (28.57%), and nonmetastatic lymph nodes were found in five patients (71.43%). There were two (28.57%) disease-related deaths during the study period. The five-year observed survival in the MEC group was 85.7% and in the other subtypes of adenosquamous cancer group was 78.3%. Conclusions: MEC of the uterine cervix is a rare entity diagnosis. As a mucin-producing tumor, it is frequently regarded as a subtype with worse clinical behavior and patients' outcomes. Nevertheless, our data did not confirm this prognosis. New molecular markers and better stratification are needed for better selection of patients with CC, which may benefit more from additional treatment and new target therapies.

Single-Center Study of Lymphoepithelioma-Like Carcinoma of Uterine Cervix over a 10-Year Period.

Background and objectives: Lymphoepithelioma-like carcinoma (LELC) is a histological type of malignant tumor arising from the uncontrolled mitosis of transformed cells originating in epithelial tissue. It is a rare subtype of squamous cell carcinoma of the uterine cervix. There are significant differences in frequency, mean age, viral status, and outcomes in Asian or Caucasian patients. Materials and Methods: A retrospective study of all cases of lymphoepithelioma-like carcinoma of the cervix at the Clinic of Oncogynecology, University Hospital, Pleven, Bulgaria between 1 January 2007 and 31 December 2016 was performed. All patients were followed-up till March 2019. We analyzed some clinical characteristics of the patients, calculated the frequency of lymphoepithelioma-like carcinoma of the cervix from all patients with stage I cervical cancer, and looked at the overall survival rate, the 5-year survival rate, and the correlation between overall survival, lymph node status, and the size of the tumor. Results: The frequency of lymphoepithelioma-like carcinoma was 3.3% for all cases with cervical carcinoma at stage I. The mean age of the patients with LELC was 49.6 years (range 32-67). Fourteen patients (82.4%) were in the FIGO IB1 stage, three patients (17.6%) were in the FIGO IB2 stage. Lymph nodes were metastatic in three patients (17.6%), non-metastatic in 13 patients (76.5%), and unknown in one patient. The overall survival rate was 76.47% for the study period and the 5-year survival rate of the patients that were followed-up until the 5th year (14 patients) was 69.23%. Conclusions: Lymphoepithelioma-like carcinoma is a rare SCC subtype, but it could be more frequent among western patients than previously thought. Our results do not confirm the data showing low risk of lymph metastasis and good prognosis of LELC, which is why we think that the treatment in these cases has to be more aggressive than is reported in the literature.

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

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.

ERS statement on harmonised standards for lung cancer registration and lung cancer services in Europe.

The European Respiratory Society (ERS) task force for harmonised standards for lung cancer registration and lung cancer services in Europe recognised the need to create a single dataset for use in pan-European data collection and a manual of standards for European lung cancer services.The multidisciplinary task force considered evidence from two different sources, reviewing existing national and international datasets alongside the results of a survey of clinical data collection on lung cancer in 35 European countries. A similar process was followed for the manual of lung cancer services, with the task force using existing guidelines and national or international recommendations for lung cancer services to develop a manual of standards for services in Europe.The task force developed essential and minimum datasets for lung cancer registration to enable all countries to collect the same essential data and some to collect data with greater detail. The task force also developed a manual specifying standards for lung cancer services in Europe.Despite the wide variation in the sociopolitical landscape across Europe, the ERS is determined to encourage the delivery of high-quality lung cancer care. Both the manual of lung cancer services and the minimum dataset for lung cancer registration will support this aspiration.

The European initiative for quality management in lung cancer care.

Lung cancer is the commonest cause of cancer-related death worldwide and poses a significant respiratory disease burden. Little is known about the provision of lung cancer care across Europe. The overall aim of the Task Force was to investigate current practice in lung cancer care across Europe. The Task Force undertook four projects: 1) a narrative literature search on quality management of lung cancer; 2) a survey of national and local infrastructure for lung cancer care in Europe; 3) a benchmarking project on the quality of (inter)national lung cancer guidelines in Europe; and 4) a feasibility study of prospective data collection in a pan-European setting. There is little peer-reviewed literature on quality management in lung cancer care. The survey revealed important differences in the infrastructure of lung cancer care in Europe. The European guidelines that were assessed displayed wide variation in content and scope, as well as methodological quality but at the same time there was relevant duplication. The feasibility study demonstrated that it is, in principle, feasible to collect prospective demographic and clinical data on patients with lung cancer. Legal obligations vary among countries. The European Initiative for Quality Management in Lung Cancer Care has provided the first comprehensive snapshot of lung cancer care in Europe.