Genetic counselling legislation and practice in cancer in EU Member States.

BACKGROUND: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action. METHODS: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country. RESULTS: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the 'who, what, when and where' of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the 'most important change' which would improve practice. CONCLUSIONS: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.

Unlocking the genomic landscape: Results of the Beyond 1 Million Genomes (B1MG) pilot in Belgium towards Genomic Data Infrastructure (GDI).

Genomic medicine has great potential to offer insights into how humans' genetic variation can affect their health, prevention options and treatment responses. The Beyond 1 Million Genomes (B1MG) project was kicked off in 2020 with the aim of building a federated network of genomic data in Europe, in which Belgium took part as a piloting country. B1MG developed a framework to enable all interested countries to self-evaluate the level of maturity of national genomic medicine practices following a common matrix, called Maturity Level Model (MLM), that contained 49 indicators across eight domains: I. Governance and strategy; II. Investment and economic model; III. Ethics, legislation and policy; IV. Public awareness and acceptance; V. Workforce skills and organisation; VI. Clinical organisation, infrastructure and tools; VII. Clinical genomics guidelines and infrastructure; and VIII. Data management, standards and infrastructure. The ongoing Genomic Data Infrastructure (GDI) project aims to capitalise on the experience of B1MG piloting countries and their MLM results. In this paper, we present the qualitative and quantitative outcomes of B1MG MLM assessment in Belgium and discuss their relevance to GDI. The insights gained from this study can be helpful for steering future policy directions and interventions on genomics in Belgium and beyond.

Epidemiological Trends of Haematological Malignancies in Belgium 2004-2018: Older Patients Show the Greatest Improvement in Survival.

(1) Background: Haematological malignancies (HMs) represent a heterogeneous group of mostly rare cancers that differ in pathophysiology, incidence, and outcome. (2) Methods: Our study aims to understand the epidemiological situation and trends of 24 main types of HMs in Belgium over a 15-year period, with a focus on the impact of age. Age-standardised incidence, average annual percentage change (AAPC), 5- and 10-year relative survival (RS) and RS trends were estimated for all HMs (N = 94,415) diagnosed between 2004 and 2018. (3) Results: Incidence rates of HM increased, mainly in the 70+ age group (AAPC: 3%). RS varied by age and HM type. For each HM type, outcome decreased with age. The greatest decrease with age in 5-year RS is observed for aggressive HM, acute myeloid leukaemia (AML), acute lymphoblastic leukaemia, and Burkitt lymphoma, from 67%, 90%, and 97% below 20 years, to 2%, 12%, and 16% above 80 years of age, respectively. The moderate improvement in 5-year RS over the 2004-2018 period for all HMs, of +5 percentage point (pp), masks highly heterogenous outcomes by HM type and age group. The most impressive improvements are observed in the 80+ group: +45, +33, +28, and +16 pp for Hodgkin lymphoma, immunoproliferative disorders, follicular lymphoma, and chronic myeloid leukaemia, respectively. (4) Conclusions: The increasing incidence and survival over the 2004-2018 period are likely explained by diagnostic and therapeutic innovations, which have spread to populations not targeted by clinical trials, especially older adults. This real-world population-based study highlights entities that need significant improvement, such as AML.

Benchmarking of survival outcomes following Haematopoietic Stem Cell Transplantation (HSCT): an update of the ongoing project of the European Society for Blood and Marrow Transplantation (EBMT) and Joint Accreditation Committee of ISCT and EBMT (JACIE).

From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems.

Clear Improvement in Real-World Chronic Myeloid Leukemia Survival: A Comparison With Randomized Controlled Trials.

Tyrosine kinase inhibitors (TKIs) have been improving the prognosis of patients with chronic myeloid leukemia (CML), but there are still large differences in survival among European countries. This raises questions on the added value of results from population-based studies, which use real-world data, compared to results of randomized controlled trials (RCTs) involving patients with CML. There are also questions about the extent of the findings on RCTs effectiveness for patients in the general population. We compare survival data extracted from our previous systematic review and meta-analysis of CML RCTs with the latest updated population-based survival data of EUROCARE-6, the widest collaborative study on cancer survival in Europe. The EUROCARE-6 CML survival estimated in patients (15-64 years) diagnosed in 2000-2006 vs. 2007-2013 revealed that the prognostic improvement highlighted by RCTs was confirmed in real-world settings, too. The study shows, evaluating for the first time all European regions, that the optimal outcome figures obtained in controlled settings for CML are also achievable (and indeed achieved) in real-world settings with prompt introduction of TKIs in daily clinical practice. However, some differences still persist, particularly in Eastern European countries, where overall survival values are lower than elsewhere, probably due to a delayed introduction of TKIs. Our results suggest an insufficient adoption of adequate protocols in daily clinical practice in those countries where CML survival values remain lower in real life than the values obtained in RCTs. New high-resolution population-based studies may help to identify failures in the clinical pathways followed there.

Real-World Estimation of First- and Second-Line Treatments for Diffuse Large B-Cell Lymphoma Using Health Insurance Data: A Belgian Population-Based Study.

We determined first- and second-line regimens, including hematopoietic stem cell transplantations, in all diffuse large B cell lymphoma (DLBCL) patients aged ≥20 yr (n = 1,888), registered at the Belgian Cancer Registry (2013-2015). Treatments were inferred from reimbursed drugs, and procedures registered in national health insurance databases. This real-world population-based study allows to assess patients usually excluded from clinical trials such as those with comorbidities, other malignancies (12%), and advanced age (28% are ≥80 yr old). Our data show that the majority of older patients are still started on first-line regimens with curative intent and a substantial proportion of them benefit from this approach. First-line treatments included full R-CHOP (44%), "incomplete" (R-)CHOP (18%), other anthracycline (14%), non-anthracycline (9%), only radiotherapy (3%), and no chemo-/radiotherapy (13%), with significant variation between age groups. The 5-year overall survival (OS) of all patients was 56% with a clear influence of age (78% [20-59 yr] versus 16% [≥85 yr]) and of the type of first-line treatments: full R-CHOP (72%), other anthracycline (58%), "incomplete" (R-)CHOP (47%), non-anthracycline (30%), only radiotherapy (30%), and no chemo-/radiotherapy (9%). Second-line therapy, presumed for refractory (7%) or relapsed disease (9%), was initiated in 252 patients (16%) and was predominantly (71%) platinum-based. The 5-year OS after second-line treatment without autologous stem cell transplantation (ASCT) was generally poor (11% in ≥70 yr versus 17% in <70 yr). An ASCT was performed in 5% of treated patients (n = 82). The 5-year OS after first- or second-line ASCT was similar (69% versus 66%). After adjustment, multivariable OS analyses indicated a significant hazard ratio (HR) for, among others, age (HR 1.81 to 5.95 for increasing age), performance status (PS) (HR 4.56 for PS >1 within 3 months from incidence), subsequent malignancies (HR 2.50), prior malignancies (HR 1.34), respiratory and diabetic comorbidity (HR 1.41 and 1.24), gender (HR 1.25 for males), and first-line treatment with full R-CHOP (HR 0.41) or other anthracycline-containing regimens (HR 0.72). Despite inherent limitations, patterns of care in DLBCL could be determined using an innovative approach based on Belgian health insurance data.

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.

Machine Learning-Based Extraction of Breast Cancer Receptor Status From Bilingual Free-Text Pathology Reports.

As part of its core business of gathering population-based information on new cancer diagnoses, the Belgian Cancer Registry receives free-text pathology reports, describing results of (pre-)malignant specimens. These reports are provided by 82 laboratories and written in 2 national languages, Dutch or French. For breast cancer, the reports characterize the status of estrogen receptor, progesterone receptor, and Erb-b2 receptor tyrosine kinase 2. These biomarkers are related with tumor growth and prognosis and are essential to define therapeutic management. The availability of population-scale information about their status in breast cancer patients can therefore be considered crucial to enrich real-world scientific studies and to guide public health policies regarding personalized medicine. The main objective of this study is to expand the data available at the Belgian Cancer Registry by automatically extracting the status of these biomarkers from the pathology reports. Various types of numeric features are computed from over 1,300 manually annotated reports linked to breast tumors diagnosed in 2014. A range of popular machine learning classifiers, such as support vector machines, random forests and logistic regressions, are trained on this data and compared using their F 1 scores on a separate validation set. On a held-out test set, the best performing classifiers achieve F 1 scores ranging from 0.89 to 0.92 for the four classification tasks. The extraction is thus reliable and allows to significantly increase the availability of this valuable information on breast cancer receptor status at a population level.

Benchmarking of survival outcomes following haematopoietic stem cell transplantation: A review of existing processes and the introduction of an international system from the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).

In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT.

Correction: Benchmarking of survival outcomes following haematopoietic stem cell transplantation: A review of existing processes and the introduction of an international system from the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Providing both autologous and allogeneic hematopoietic stem cell transplants (HSCT) may have a stronger impact on the outcome of autologous HSCT in adult patients than activity levels or implementation of JACIE at Belgian transplant centres.

While performance since the introduction of the JACIE quality management system has been shown to be improved for allogeneic hematopoietic stem cell transplants (HSCT), impact on autologous-HSCT remains unclear in Europe. Our study on 2697 autologous-HSCT performed in adults in 17 Belgian centres (2007-2013) aims at comparing the adjusted 1 and 3-yr survival between the different centres & investigating the impact of 3 centre-related factors on performance (time between JACIE accreditation achievement by the centre and the considered transplant, centre activity volume and type of HSCT performed by centres: exclusively autologous vs both autologous & allogeneic). We showed a relatively homogeneous performance between Belgian centres before national completeness of JACIE implementation. The 3 centre-related factors had a significant impact on the 1-yr survival, while activity volume and type of HSCT impacted the 3-yr survival of autologous-HSCT patients in univariable analyses. Only activity volume (impact on 1-yr survival only) and type of HSCT (impact on 1 and 3-yr survivals) remained significant in multivariable analysis. This is explained by the strong relationship between these 3 variables. An extended transplantation experience, i.e., performing both auto & allo-HSCT, appears to be a newly informative quality indicator potentially conveying a multitude of underlying complex factors.

Characterization of two new high-grade B-cell lymphoma cell lines with MYC and BCL2 rearrangements that are suitable for in vitro drug sensitivity studies.

High-grade B-cell lymphomas with MYC and BCL2 or BCL6 rearrangements are highly aggressive B-cell lymphomas called double-hit lymphomas (HGBL-DH). They are particularly refractory to standard treatments and carry a poor prognosis. Fragments of resected tumoral lymph nodes from two HGBL-DH patients were put in culture. Continuously proliferating cells were characterized and compared with the original tumors. In both cases, the proliferating cells and the tumor displayed MYC and BCL2 rearrangements. Both cell lines (called LB5848-LYMP and LB5871-LYMP) presented a high proliferation rate and were maintained in culture for more than one year. Upon injection in immunodeficient mice, LB5848-LYMP gave rise to lymphoid tumors. In vitro treatment of these cell lines with a BCL2-inhibitory drug (ABT-199) selectively stopped their proliferation. These new cell lines represent valuable tools for studying HGBL-DH and for the in vitro testing of candidate therapies targeting HGBL-DH. LB5848-LYMP is also suitable for similar experiments in vivo.

Case Reports in Oncological Medicine Myoepithelioma: A New Rearrangement Involving the LPP Locus in a Case of Multiple Bone and Soft Tissue Lesions.

We report a case of multiple myoepithelioma with synchronous bone and soft tissue tumors, associated with a new genomic alteration of the LPP locus. The lesions occurred in the foot by presenting one lump in the plantar soft tissue, and three lesions were detected in the calcaneus and in the navicular bone. All tumors showed the double immunophenotype of epithelial markers and S100 protein expression. No rearrangement of the EWSR1 and FUS loci was detected as reported in myoepitheliomas. However, molecular karyotyping detected an unbalanced rearrangement of the LPP locus, not involving the HMGA2 locus, which is the most frequent translocation partner observed in benign mesenchymal tumors such as lipomas (of soft tissue as well as parosteal) and pulmonary chondroid hamartoma.

Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients.

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.

Evaluation of Potential Mechanisms Controlling the Catalase Expression in Breast Cancer Cells.

Development of cancer cell resistance against prooxidant drugs limits its potential clinical use. MCF-7 breast cancer cells chronically exposed to ascorbate/menadione became resistant (Resox cells) by increasing mainly catalase activity. Since catalase appears as an anticancer target, the elucidation of mechanisms regulating its expression is an important issue. In MCF-7 and Resox cells, karyotype analysis showed that chromosome 11 is not altered compared to healthy mammary epithelial cells. The genomic gain of catalase locus observed in MCF-7 and Resox cells cannot explain the differential catalase expression. Since ROS cause DNA lesions, the activation of DNA damage signaling pathways may influence catalase expression. However, none of the related proteins (i.e., p53, ChK) was activated in Resox cells compared to MCF-7. The c-abl kinase may lead to catalase protein degradation via posttranslational modifications, but neither ubiquitination nor phosphorylation of catalase was detected after catalase immunoprecipitation. Catalase mRNA levels did not decrease after actinomycin D treatment in both cell lines. DNMT inhibitor (5-aza-2'-deoxycytidine) increased catalase protein level in MCF-7 and its resistance to prooxidant drugs. In line with our previous report, chromatin remodeling appears as the main regulator of catalase expression in breast cancer after chronic exposure to an oxidative stress.

A phase II study of the oral JAK1/JAK2 inhibitor ruxolitinib in advanced relapsed/refractory Hodgkin lymphoma.

JAK2 constitutive activation/overexpression is common in classical Hodgkin lymphoma, and several cytokines stimulate Hodgkin lymphoma cells by recognizing JAK1-/JAK2-bound receptors. JAK blockade may thus be therapeutically beneficial in Hodgkin lymphoma. In this phase II study we assessed the safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in patients with relapsed/refractory Hodgkin lymphoma. The primary objective was overall response rate according to the International Harmonization Project 2007 criteria. Thirty-three patients with advanced disease (median number of prior lines of treatment: 5; refractory: 82%) were included; nine (27.3%) received at least six cycles of ruxolitinib and six (18.2%) received more than six cycles. The overall response rate after six cycles was 9.4% (3/32 patients). All three responders had partial responses; another 11 patients had transient stable disease. Best overall response rate was 18.8% (6/32 patients). Rapid alleviation of B-symptoms was common. The median duration of response was 7.7 months, median progression-free survival 3.5 months (95% CI: 1.9-4.6), and the median overall survival 27.1 months (95% CI: 14.4-27.1). Forty adverse events were reported in 14/33 patients (42.4%). One event led to treatment discontinuation, while 87.5% of patients recovered without sequelae. Twenty-five adverse events were grade 3 or higher. These events were mostly anemia (n=11), all considered related to ruxolitinib. Other main causes of grade 3 or higher adverse events included lymphopenia and infections. Of note, no cases of grade 4 neutropenia or thrombocytopenia were observed. Ruxolitinib shows signs of activity, albeit short-lived, beyond a simple anti-inflammatory effect. Its limited toxicity suggests that it has the potential to be combined with other therapeutic modalities. ClinicalTrials.gov: NCT01877005.