Patient survey on cancer genomic medicine in Japan under the national health insurance system.

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy.

[Overview of Clinical Application of Whole Genome Analysis for Cancer].

Cancer genomic medicine in Japan began in earnest with the implementation of gene panel testing covered by national health insurance in June 2019. However, the information obtained from this testing is limited to less than 0.1% of the entire genome. To enhance the effectiveness of therapy, understand the intricate biology of cancer, and develop new therapeutic drugs, it has become essential to promote the analysis of the whole genome. In Japan, the Action Plan for Whole Genome Analysis(Version 1)was released in December 2019. In 2021, AMED project"the full-scale operation of cancer whole genome analysis"was launched. The Action Plan for Whole Genome Analysis 2022 set a goal to return the information promptly to patients and citizens. Project Implementation Preparation Office was organized in April 2023 for acceleration of the system development for the clinical whole genome analysis. This paper introduces the current efforts and discuss the future perspectives of cancer genome medicine in Japan.

[History of the Japanese Society of Medical Oncology].

The Japanese Society of Medical Oncology(JSMO)was founded in 1993 by the Research Society of Clinical Oncology, the predecessor of the Society. Twenty years have passed since the transition to JSMO in 2003. During this time, JSMO has contributed to the establishment of the academic field of medical oncology in Japan for many years. On the other hand, over the last 20 years, cancer treatment by anti-cancer agents, which forms the basis of medical oncology, has made significant progress, prolonging the survival period of many advanced cancers. In the last 5 years in particular, there have been remarkable advances in the development and clinical introduction of immune checkpoint inhibitors, cancer molecular targeted agents based on genetic abnormalities, and cancer genomic medicine. Furthermore, in addition to conventional multidisciplinary treatment with surgery, radiology, and palliative medicine, collaboration with cancer-related interdisciplinary fields has become extremely important in recent years. For this reason, there is an increasing need for medical oncologists who specialize in organ(cancer type)cross-sectional treatment including cancer genomic medicine, and treat advanced cancer as a systemic disease as a specialist in internal medicine. In this article, we review the history of the Japanese Society of Medical Oncology and the history of medical oncology in Japan and look forward to the future of medical oncology.

Future Role of Health Technology Assessment for Genomic Medicine in Oncology: A Canadian Laboratory Perspective.

Genome-based testing in oncology is a rapidly expanding area of health care that is the basis of the emerging area of precision medicine. The efficient and considered adoption of novel genomic medicine testing is hampered in Canada by the fragmented nature of health care oversight as well as by lack of clear and transparent processes to support rapid evaluation, assessment, and implementation of genomic tests. This article provides an overview of some key barriers and proposes approaches to addressing these challenges as a potential pathway to developing a national approach to genomic medicine in oncology.

Genomic medicine in neonatal care: progress and challenges.

During the neonatal period, many genetic disorders present and contribute to neonatal morbidity and mortality. Genomic medicine-the use of genomic information in clinical care- has the potential to significantly reduce morbidity and mortality in the neonatal period and improve outcomes for this population. Diagnostic genomic testing for symptomatic newborns, especially rapid testing, has been shown to be feasible and have diagnostic and clinical utility, particularly in the short-term. Ongoing studies are assessing the feasibility and utility, including personal utility, of implementation in diverse populations. Genomic screening for asymptomatic newborns has also been studied, and the acceptability and feasibility of such an approach remains an active area of investigation. Emerging precision therapies, with examples even at the "n-of-1" level, highlight the promise of precision diagnostics to lead to early intervention and improve outcomes. To sustainably implement genomic medicine in neonatal care in an ethical, effective, and equitable manner, we need to ensure access to genetics and genomics knowledge, access to genomic tests, which is currently limited by payors, feasible processes for ordering these tests, and access to follow up in the clinical and research realms. Future studies will provide further insight into enablers and barriers to optimize implementation strategies.

Precision therapy for a medically actionable ATP1A3 variant from a genomic medicine program in an underserved population.

BACKGROUND: Genomic medicine is revolutionizing the diagnosis of rare diseases, but the implementation has not benefited underrepresented populations to the same degree. Here, we report the case of a 7-year-old boy with hypotonia, global developmental delay, strabismus, seizures, and previously suspected mitochondrial myopathy. This proband comes from an underrepresented minority and was denied exome sequencing by his public insurance. METHODS: After informed consent was obtained, buccal cells from the proband were collected and whole exome sequencing was performed. Illumina Dragen and Emedgene software was used to analyze the data at Baylor Genetics. The variants were further intepreted according to ACMG guidelines and the patient's phenotype. RESULTS: Through whole-exome sequencing (WES) under the Community Texome project, he was found to have a heterozygous de novo pathogenic variant in the ATP1A3 gene located on chromosome 19q13. CONCLUSION: In retrospect, his symptomatology matches the known medical conditions associated with the ATP1A3 gene namely Alternating Hemiplegia of Childhood 2 (AHC), a rare autosomal dominant disorder with an incidence of 1 in one million. His single nucleotide variant, (c.2401G>A, p.D801N), is predicted to be damaging. The specific amino acid change p.D801N has been previously reported in ClinVar along with the allelic variant p.D801Y and both are considered pathogenic. The identification of this variant altered medical management for this patient as he was started on a calcium antagonist and has reported no further hemiplegic episodes. This case illustrates the value of implementing genomic medicine for precision therapy in underserved populations.

Hallazgos incidentales en medicina genómica / Incidental Findings in Genomic Medicine

Las técnicas de Biología Molecular de última generación, como es la secuenciación masiva en paralelo o NGS (Next Generation Sequencing), permite obtener gran cantidad de información genómica, la cual muchas veces va más allá de la detección de una variante patogénica en un gen que explique la patología (hallazgo primario). Es así como surgió desde hace años la discusión internacional respecto a la decisión a tomar frente a los hallazgos secundarios accionables, es decir, aquellos hallazgos de variantes clasificadas como patogénicas o probablemente patogénicas que no están relacionadas con el fenotipo del paciente, pero que tiene alguna medida preventiva o tratamiento posible y, por lo tanto, podría ser de utilidad para la salud del paciente. Luego de revisar la bibliografía internacional y debatir entre los expertos del Hospital de Pediatría Garrahan, se logró establecer una política institucional y reforzar el hecho de que se trata de una disciplina multidisciplinaria. Así, fue posible definir que solo se atenderá las cuestiones relacionadas con la edad pediátrica, dejando para un tratamiento posterior aquellas variantes detectadas en genes que sean accionables en edad adulta. En el Hospital Garrahan, ha sido posible definir claramente cómo proceder frente a los hallazgos secundarios, al adaptar el consentimiento informado a esta necesidad, definiendo cuándo serán informados, y sabiendo que serán buscados intencionalmente en los genes clínicamente accionables enlistados en la última publicación del American College of Medical Genetics and Genomics, siempre y cuando el paciente/padre/tutor lo consienta (AU)

The latest generation of molecular biology techniques, including massive parallel sequencing or NGS (Next Generation Sequencing), allows us to obtain a whealth of genomic information, which often goes beyond the detection of a pathogenic variant in a gene that explains the pathology (primary finding). As a result, an international discussion has arisen over the years regarding the decision-making concerning actionable secondary findings, it means, those findings of variants classified as pathogenic or probably pathogenic that are not related to the patient's phenotype, but which have some possible preventive measure or treatment and, therefore, could be useful for the patient's health. After reviewing the international literature and discussing among the experts of the Hospital de Pediatría Garrahan, an institutional policy was established and the concept that this is a multidisciplinary discipline was reinforced. Consequently, it has been defined that only issues related to children will be addressed, reserving those variants detected in genes that are actionable in adulthood for later treatment. At Garrahan Hospital, we were able to clearly define how to proceed with secondary findings by adapting the informed consent to this need, defining when they will be reported, and knowing that they will be intentionally searched for in the clinically actionable genes listed in the latest publication of the American College of Medical Genetics and Genomics, as long as the patient/parent/guardian consents (AU)

Implementación asistencial de estudios genómicos aplicados al diagnóstico molecular / Implementation of genomic studies applied to molecular diagnostics

El Hospital Garrahan ha sido pionero en el diagnóstico molecular de patologías pediátricas en Argentina. Los avances tecnológicos de las últimas décadas en el área de la biología molecular, sentaron las bases para la optimización y ampliación del diagnóstico molecular a partir de la secuenciación masiva en paralelo de múltiples genes. El presente trabajo describe el proceso de implementación de los estudios de secuenciación de nueva generación y el desarrollo de la Unidad de Genómica en un hospital público pediátrico de alta complejidad, así como su impacto en las capacidades diagnósticas de enfermedades poco frecuentes de origen genético. La creación del Grupo Interdisciplinario de Estudios Genómicos constituyó la vía institucional para la toma de decisiones que implican la implementación de nuevos estudios genómicos y el establecimiento de prioridades diagnósticas, extendiendo la disponibilidad del diagnóstico molecular a más disciplinas. La Unidad de Genómica trabaja en diseñar las estrategias que permitan la mayor optimización de los recursos con los que cuenta el hospital, teniendo en cuenta el equipamiento disponible, las prioridades establecidas y la frecuencia de las distintas patologías. Se demuestra el salto significativo operado en nuestras capacidades diagnósticas, tanto en la variedad de enfermedades como en el número de genes analizados, habiendo estudiado a la fecha alrededor de 2.000 pacientes, muchos de los cuales ven de este modo finalizada su odisea diagnóstica. Los estudios de NGS se han convertido en una herramienta de la práctica diaria para la atención de un número importante de pacientes de nuestro hospital. Continuaremos trabajando para ampliar su aplicación a la mayor cantidad de patologías, a través de los mecanismos institucionales ya existentes (AU)

The Garrahan Hospital has been a pioneer in the molecular diagnosis of pediatric diseases in Argentina. The technological advances of the last decades in the area of molecular biology have laid the foundations for the optimization and expansion of molecular diagnostics through massive parallel sequencing of multiple genes. This study describes the process of implementation of next-generation sequencing studies and the development of the Genomics Unit in a public pediatric tertiary hospital, and its impact on the capacity to diagnose rare diseases of genetic origin. The creation of the Interdisciplinary Group of Genomic Studies constituted the institutional pathway for decision-making involving the implementation of new genomic studies and the establishment of diagnostic priorities, extending the availability of molecular diagnostics to additional disciplines. The Genomics Unit is working to design strategies that allow for optimization of the resources available to the hospital, taking into account the equipment available, the priorities established, and the frequency of the different diseases. It demonstrates the significant leap in our diagnostic capabilities, both in the variety of diseases and in the number of genes analyzed. To date, around 2,000 patients have been studies, many of whom have thus completed their diagnostic odyssey. NGS studies have become a tool in daily practice for the care of a significant number of patients in our hospital. We will continue working to expand its application to as many diseases as possible, through the existing institutional mechanisms (AU)

The evolution of cancer genomic medicine in Japan and the role of the National Cancer Center Japan.

The journey to implement cancer genomic medicine (CGM) in oncology practice began in the 1980s, which is considered the dawn of genetic and genomic cancer research. At the time, a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells, which led to the development of molecular targeted therapies in the 2000s and beyond. Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients, the National Cancer Center (NCC) of Japan has already contributed considerably to CGM advancement for the conquest of cancer. Looking back at these past achievements of the NCC, we predict that the future of CGM will involve the following: 1) A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed. The quantity and quality of these samples will be compatible with omics analyses. All biobank samples will be linked to longitudinal clinical information. 2) New technologies, such as whole-genome sequencing and artificial intelligence, will be introduced and new bioresources for functional and pharmacologic analyses (e.g., a patient-derived xenograft library) will be systematically deployed. 3) Fast and bidirectional translational research (bench-to-bedside and bedside-to-bench) performed by basic researchers and clinical investigators, preferably working alongside each other at the same institution, will be implemented; 4) Close collaborations between academia, industry, regulatory bodies, and funding agencies will be established. 5) There will be an investment in the other branch of CGM, personalized preventive medicine, based on the individual's genetic predisposition to cancer.

Industry involvement in evidence production for genomic medicine: A bibliometric and funding analysis of decision impact studies.

BACKGROUND: Decision impact studies have become increasingly prevalent in genomic medicine, particularly in cancer research. Such studies are designed to provide evidence of clinical utility for genomic tests by evaluating their impact on clinical decision-making. This paper offers insights into understanding of the origins and intentions of these studies through an analysis of the actors and institutions responsible for the production of this new type of evidence. METHODS: We conducted bibliometric and funding analyses of decision impact studies in genomic medicine research. We searched databases from inception to June 2022. The datasets used were primarily from Web of Science. Biblioshiny, additional R-based applications, and Microsoft Excel were used for publication, co-authorship and co-word analyses. RESULTS: 163 publications were included for the bibliometric analysis; a subset of 125 studies were included for the funding analysis. Included publications started in 2010 and increased steadily over time. Decision impact studies were primarily produced for proprietary genomic assays for use in cancer care. The author and affiliate analyses reveal that these studies were produced by 'invisible colleges' of researchers and industry actors with collaborations focused on producing evidence for proprietary assays. Most authors had an industry affiliation, and the majority of studies were funded by industry. While studies were conducted in 22 countries, the majority had at least one author from the USA. DISCUSSION: This study is a critical step in understanding the role of industry in the production of new types of research. Based on the data collected, we conclude that decision impact studies are industry-conceived and -produced evidence. The findings of this study demonstrate the depth of industry involvement and highlight a need for further research into the use of these studies in decision-making for coverage and reimbursement.

Guidelines for Handling of Cytological Specimens in Cancer Genomic Medicine.

Rapid advances are being made in cancer drug therapy. Since molecularly targeted therapy has been introduced, personalized medicine is being practiced, pathological tissue from malignant tumors obtained during routine practice is frequently used for genomic testing. Whereas cytological specimens fixed mainly in alcohol are considered to be more advantageous in terms of preservation of the nucleic acid quality and quantity. This article is aimed to share the information for the proper handling of cytological specimens in practice for genomic medicine based on the findings established in "Guidelines for Handling of Cytological Specimens in Cancer Genomic Medicine (in Japanese)" published by the Japanese Society of Clinical Cytology in 2021. The three-part practical guidelines are based on empirical data analyses; Part 1 describes general remarks on the use of cytological specimens in cancer genomic medicine, then Part 2 describes proper handling of cytological specimens, and Part 3 describes the empirical data related to handling of cytological specimens. The guidelines indicated proper handling of specimens in each fixation, preparation, and evaluation.

Genomic medicine in Africa: a need for molecular genetics and pharmacogenomics experts.

The large-scale implementation of genomic medicine in Africa has not been actualized. This overview describes how routine molecular genetics and advanced protein engineering/structural biotechnology could accelerate the implementation of genomic medicine. By using data-mining and analysis approaches, we analyzed relevant information obtained from public genomic databases on pharmacogenomics biomarkers and reviewed published studies to discuss the ideas. The results showed that only 68 very important pharmacogenes currently exist, while 867 drug label annotations, 201 curated functional pathways, and 746 annotated drugs have been catalogued on the largest pharmacogenomics database (PharmGKB). Only about 5009 variants of the reported ∼25,000 have been clinically annotated. Predominantly, the genetic variants were derived from 43 genes that contribute to 2318 clinically relevant variations in 57 diseases. Majority (∼60%) of the clinically relevant genetic variations in the pharmacogenes are missense variants (1390). The enrichment analysis showed that 15 pharmacogenes are connected biologically and are involved in the metabolism of cardiovascular and cancer drugs. The review of studies showed that cardiovascular diseases are the most frequent non-communicable diseases responsible for approximately 13% of all deaths in Africa. Also, warfarin pharmacogenomics is the most studied drug on the continent, while CYP2D6, CYP2C9, DPD, and TPMT are the most investigated pharmacogenes with allele activities indicated in African and considered to be intermediate metaboliser for DPD and TPMT (8.4% and 11%). In summary, we highlighted a framework for implementing genomic medicine starting from the available resources on ground.

Adjuvant Therapy in Node-Positive Endometrial Cancer: A Focus on Chemotherapy.

PURPOSE OF REVIEW: In advanced-stage and high-risk endometrial cancer, adjuvant treatment is the standard of care and typically includes chemotherapy with or without radiotherapy. Debate continues over the optimal use of these two treatment modalities together or separately. This review covers the historical literature leading to the current recommendation for adjuvant chemotherapy, in addition to looking forward to the relatively new field of targeted molecular treatment. RECENT FINDINGS: The review covers recent phase III trials comparing chemotherapy to radiotherapy in high-risk endometrial cancer. Additionally, the era of genomic medicine has a new foothold in endometrial cancer, and the review covers new discoveries on molecular classification and prognostic implications. Fortunately, the majority of endometrial cancer has a good prognosis. For advanced-stage and high-risk histologies, the prognosis can be guarded, with adjuvant treatment improving outcomes. Gynecologic oncologists continue to debate the optimal treatment modality/modalities, a debate which will likely become more robust as the field of molecular treatment in endometrial cancer evolves.

C-CAT: The National Datacenter for Cancer Genomic Medicine in Japan.

SUMMARY: Since June 2019, under the umbrella of the national health insurance system, Japan has started cancer genomic medicine (CGM) with comprehensive genomic profiling (CGP) tests. The Ministry of Health, Labour and Welfare (MHLW) of Japan constructed a network of CGM hospitals (a total of 233 institutes as of July 1, 2022) and established the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter for CGM. Clinical information and genomic data from the CGP tests are securely transferred to C-CAT, which then generates "C-CAT Findings" reports containing information of clinical annotation and matched clinical trials based on the CGP data. As of June 30, 2022, a total of 36,340 datapoints of clinical/genomic information are aggregated in C-CAT, and the number is expected to increase swiftly. The data are now open for sharing with not only the CGM hospitals but also other academic institutions and industries.

[The National Cancer Professional Council and the Cancer Genomic Medicine Subcommittee].

The Cancer Genomic Medicine Subcommittee of the National Cancer Professional Council held an online meeting on January 14, 2022. The meeting consisted of Part Ⅰ"Presentation of research activities by graduate school students", Part Ⅱ "Issues in Cancer Genomic Medicine"and Part Ⅲ"General Discussion". This special issue summarizes the contents of Parts Ⅱ and Ⅲ.

[Expert Panel Issues in Japan].

With the spread of cancer genomic medicine in Japan, the burden on expert panels is clearly increasing. Various factors, such as the conditions for calculation of reimbursement and the fact that the panels can only be conducted at core hospitals for cancer genomic medicine have contributed to this increase in the burden. This paper describes the challenges and future of expert panels in the implementation of cancer genomic medicine in Japan, based on the experience of our hospital.

[Multidisciplinary Collaboration and Education Program Required for Equalization of Cancer Genomic Medicine].

Precise understanding of cancer biology and molecular medicine is required for evaluation of genomic alterations in cancer. To promote cancer genomic medicine in increasing numbers of hospitals by multidisciplinary collaboration, researchers specialized in such fields of sciences are expected to have chances to participate in the expert panel. Furthermore, more efforts of biological research should be made in education programs for oncologists at graduate schools.