2.1 Definition and Examples2.1.1 Definition

An MTB is a regular interdisciplinary meeting held by experts from various clinical fields to discuss challenging, individual cases of patients with cancer that are not responding to standard-of-care therapies. The main aim of an MTB is to assist in providing accurate and timely clinical interpretations of complex genomic results for each patient. All potential therapeutic strategies based on genetic analysis, molecular drivers of carcinogenesis, and actionable therapeutic targets from somatic variants of the tumor in question are identified. Involved individuals such as molecular pathologists, genetic counselors, oncologists, and others confer in a multidisciplinary manner to derive recommendations based on multiple factors including specific molecular modifications and the features of a patient (performance, status, comorbidities, etc). The recommendations are used as a basis for trial screenings and cost coverage applications. Moreover, MTBs are used to clarify conflicting interpretations of clinical variants, and as educational tools in teaching hospitals and university clinics [7]. Furthermore, the composition of the board can be adaptive, accommodating additional specialists tailored to the specific disease under consideration, all with a singular focus: devising the most optimal treatment strategy for the patient at hand based on all available evidence. This embodies the convergence of expertise and technological advancements in the pursuit of individualized patient care.

The establishment of MTBs in an increasing number of medical institutions has garnered attention for their pivotal role in optimizing patient care [8]. Defined by Rao et al. in [9] as a mechanism designed to "aid in the delivery of accurate and timely clinical interpretations of complex genomic results for each patient, within an institution or hospital network," MTBs serve a critical function by amalgamating diverse expertise to dissect intricate patient cases, leveraging genetic insights gleaned from sequencing data [6].

2.1.2 MTB Examples in Germany and Worldwide

MTBs are becoming more adapted in all regions of the world. However, each institution uses different approaches, processes, and methods. The reimbursement structures for MTBs are dependent on the specific framework conditions of the healthcare systems and the regulations of the health insurance companies. In Germany, MTBs are reimbursed by statutory health insurers through case-based flat rates and additional payments using billing codes for MTB specific services varying by service scope and complexity. Furthermore, MTBs receive funding from research projects to support the development of new diagnostics and therapies. [10, 11]

The reimbursement structure of the MTB in Japan differs depending on the institution and the type of services provided. Large and university hospitals receive fixed fees from the national health insurance, ranging from 5000 to 10,000 yen (35 to 70 euros) per session [12]. Specialized hospitals receive around 30,000 yen (210 euros) per patient for comprehensive genetic testing and 50,000–100,000 yen (350–700 euros) for advanced molecular profiling respectively [12, 13].

Compensation structures for MTBs in the USA are complex and vary by region, institution, and the specific set-up of the board (Table 1). MTB members are compensated for their participation (100–500 US dollars [USD] per session) depending on the location. Genomic testing often costs thousands of dollars, with partial coverage provided by health insurance. Additional funding from the state and pharmaceutical companies through research and clinical trial grants further supports the development of new diagnostics and treatment options [14, 15].

Table 1 Differences between the individual MTBs in terms of structure and remuneration in the USA, Japan, Germany, Finland, Denmark and Italy

In the following sections we list examples of a selection of MTBs in Germany and worldwide. Both the MTB Freiburg and Heidelberg have already been established for many years, with the former being one of the few to have published specific evidence numbers to date similar to the MTB at the Tohoku University Hospital in Japan. The latter initiated the MASTER program as a central program for patient stratification across different institutions. Augsburg represents a smaller MTB currently transitioning to a fully digitalized workflow while evaluating support tools mentioned in Sect. 5. The MTBs from Italy were selected because of their network approach between regional MTBs including virtual components. Further, MTBs in Finland and Denmark showcase the workflow in smaller countries, with their specialized approaches targeting specific cancer types and different organizational structures respectively. In contrast to Germany, Japan, and Europe, the MTB at UCSF represents the focus on innovation and private funding of most MTBs in the USA.

MTB Freiburg (Germany) In the context of the Comprehensive Cancer Center Freiburg (CCCF), a total of 22 interdisciplinary tumor boards have been established, each playing a pivotal role in orchestrating the precise and tailored therapeutic interventions required for patients [16,17,18,19]. Presently, the MTB at the CCCF comprises a complement of 35 proficient physicians and scientists. The attending physician plays a pivotal role as the facilitator in this framework, determining the eligibility of a patient for inclusion within the MTB. For prospective participants, the sole requisite is the provision of informed consent, thereby permitting the utilization of their clinical data for deliberations.

Predominantly, patients who gain admission to the MTB at the CCCF either

have nearly exhausted conventional guideline-based therapies,

exhibit limited tolerance to standard therapeutic options,

or are afflicted by rare tumor entities, where established guideline-directed therapies are conspicuously absent.

In cases wherein patients are referred to the MTB, a comprehensive evaluation is undertaken by contributors within a span of 14 days, alongside an exploration of extant clinical options.

After this preliminary evaluation, the case is subjected to further assessment within the precincts of the MTB. Biomaterial samples are collected, and their molecular characteristics assessed. An incisive analysis is conducted to ascertain the congruence between the genetic mutations specific to the individual patient and the potential therapeutic modalities. The analysis workflow consists of many steps, starting with sequencing, a preprocessing phase, alignment, variant calling and annotation, analysis, and finalizing report generation and export to an external support tool (cBioPortal) [16, 19]. This process can extend over a period of up to 3 months.

Between 2015 and 2020, the MTB at CCCF has provided its guidance to a total of 1400 patients, encompassing almost 3000 distinct clinical cases over the 5-year period [20]. The multidisciplinary team of specialists has been able to provide 53% of the MTB patients with various personalized therapeutic recommendations, ranging from off-label therapy (61%), in-label (23%) to clinical studies (16%). Notably, these recommendations often venture into the realm of off-label usage, wherein approved pharmaceutical agents are repurposed within a divergent clinical context. An empirical analysis of patient outcomes from this approach has indicated a favorable response rate, with 8% of patients exhibiting positive responses to the recommendations [20].

MTB Heidelberg (Germany) The MTB Heidelberg is considered one of the most advanced in Germany. Two interdisciplinary tumor conferences are held on a weekly basis with experts from various medical disciplines, including thoracic surgery, pneumology, thoracic oncology, pathology, radiology, and radiotherapy [21,22,23,24,25]. These MTBs discuss various oncological disorders, such as dermatological, gastrointestinal, gynecological, and neurological tumors and many others [24]. Notably, Heidelberg features state-of-the-art molecular pathology methodologies, including next-generation sequencing (NGS), multiplex analysis, and liquid biopsy, with the aim to identify distinctive molecular alterations within patient samples. The identification of rare and unique genetic anomalies, on a case-by-case basis, presents an opportunity to furnish specialized therapeutic interventions either within the framework of clinical trials or through the off-label application procedure [23, 24].

At the National Center for Tumor Diseases (NCT) Heidelberg and Dresden, German Cancer Research Center (DKFZ), and the German Cancer Consortium (DKTK in Berlin, Essen/Düsseldorf, Frankfurt/Mainz, Freiburg, Munich, and Tübingen), the central program Molecularly Aided Stratification for Tumor Eradication Research (MASTER) was initiated. The main goal of this multidisciplinary platform is to stratify and classify patients with advanced rare cancers or incurable common tumors at early ages [22, 23]. An interdisciplinary team is involved, including physicians, biologists, study nurses, molecular oncologists, pathologists, documentalists, clinical, geneticists, investigators, and bioinformaticians. This team discusses registered patients’ cases to identify novel treatment approaches based on whole-genome or exome sequencing (WGS/WES), RNA sequencing (RNA-seq) and DNA methylation profiling.

The MASTER program [26,27,28,29,30,31] is structured modularly:

1.

Fundamentals of clinical research and evidence-based practice: This module introduces scientific methodologies, study designs, and the hierarchy of evidence.

2.

Systematic reviews and meta-analyses: It covers the methodology for conducting and interpreting systematic reviews and meta-analyses, providing insights into how to aggregate and assess evidence.

3.

Critical appraisal and evidence synthesis: Participants learn techniques for critically evaluating scientific literature and synthesizing findings to develop evidence-based guidelines.

4.

Special topics: These are in-depth studies focusing on specialized areas such as pharmacology, oncology, and cardiology offering a detailed exploration of specific fields.

NCT derives treatment recommendations for the MTB discussions based on the tumor entity and four evidence levels as described in Table 2 to associate molecular biomarkers in patients’ samples to drug responses [23].

Table 2 This table shows the NCT evidence levels with m1 (in the same entity), m2 (in various entities), m3 (preclinical), and m4 (biological rationale).

During an MTB discussion, each patient case is presented individually and conferred in 8–10 min. The clinical history and the molecular alterations of the patient are first presented respectively by the handling physician as well as a clinical bioinformatician. Following the guidelines of the MASTER program, a level of evidence is assigned, a set of treatment options is concluded by the corresponding molecular oncologist, and the called variants are finally evaluated and classified by clinical geneticists taking into consideration the patient’s personal and family history. At the end of the discussion, a report is generated containing a summary of treatment recommendations, disease course and previous therapy, alongside all supporting and opposing evidence [23].

MTB Augsburg (Germany) The Comprehensive Cancer Center Augsburg (CCCA) comprises 29 clinics, institutes, and establishments of the University Hospital Augsburg (UKA). It constitutes one of six pillars of the Bayerisches Zentrum für Krebsforschung (BZKF; others are Erlangen, two locations in Munich, Regensburg and Würzburg), as well as one of the four pillars of CCC and NCT WERA (Würzburg, Erlangen, Regensburg, and Augsburg). The MTB in Augsburg was created in 2018, and its structure was conceptualized based on MTB Freiburg. The conference takes place weekly on Wednesday, in which a multidisciplinary team consisting originally of four to five, and currently 10 to 15 specialists (molecular pathology, presenting physician, oncologists, human genetics, documentation, IT) discuss registered patients with cancer. On average, 230 patients are admitted each year following these criteria:

malignant diseases (solid tumors and hematological neoplasms) with an absence of further standard therapeutic options,

malignant diseases with no established therapy options,

rare tumors or unusual tumor progress,

young patients with cancer.

The MTB in Augsburg uses the Knowledge Connector for collaborative case preparation and the identification of biomarkers and cBioPortal for data sharing for external partners. Further, both tools are currently in evaluation for future usage. The classification of the patients and the therapy recommendations follow the evidence level guideline set by the MASTER program (Table 2).

University of California (USA) The MTB assembly at the University of California, San Francisco (UCSF) involves a diverse selection of healthcare providers, with clinical practitioners, researchers, graduate students, postdoctoral fellows, clinical fellows, and residents [32]. Moreover, healthcare providers affiliated with UCSF-affiliated hospitals are accorded opportunities for active participation in regularly scheduled MTB meetings, thereby fostering a cross-institutional discourse.

Patients eligible for enrollment in the MTB must have received a cancer diagnosis, accompanied by molecular profiling of their tumor specimen. It is noteworthy that the MTB's purview extends to pediatric cases, inclusive of malignancies across all age cohorts and spanning a spectrum of tumor types, even those characterized by an elusive primary origin. UCSF uses NGS panels, comprising over 500 genes, which includes germline analysis, microsatellite instability testing, and the evaluation of tumor mutational burden.

Within the MTB’s operational framework, the UCSF tumor board convenes to deliberate upon a select subset of three to seven patient cases during each meeting. In preparation for these deliberations, the requesting physician generates a concise clinical summary employing a standardized slide template disseminated by the MTB team. Subsequently, the pertinent test results are subjected to oral examination; in cases involving UCSF500 [33] results, the molecular pathologist responsible for endorsing the patient's report offers insights into the findings. Subsequently, one of the MTB’s clinical experts expounds upon the clinical implications and utility of the findings, with a particular emphasis on addressing specific clinical queries. Following this presentation, the case is open for comprehensive discussion among the meeting attendees. Subsequently, a formal recommendation report is prepared and typically disseminated within a week of the MTB meeting.

Tohoku University Hospital (Japan) A retrospective observational study from September 2018 to January 2022 was conducted, focusing on Comprehensive Genomic Profiling (CGP) in patients afflicted with advanced solid tumors at Tohoku University Hospital and its affiliated medical institutions. The primary objective of this investigation was to extract comprehensive and granular data pertaining to patient demographics, a catalog of genetic alterations, and subsequent therapeutic recommendations. [13].

Patients enrolled in this study were those harboring advanced solid tumors or individuals anticipated to complete therapy after undergoing standard treatment regimens. Additionally, patients afflicted by rare neoplastic pathologies or those diagnosed with cancers of unknown primary origin (CUP), who had no recourse to established standard therapies, were deemed eligible for CGP testing before initiating treatment, thus rendering them suitable candidates for inclusion in this study.

The CGP tests administered were executed using approved in vitro diagnostic devices, grounded in NGS technology. By subjecting both normal and malignant tissues to the sequencing of 114 genes and discerning genetic variations, the NCC Oncopanel was conceived in Japan. This innovative panel allows for the concurrent identification of somatic gene mutations, while also facilitating the confirmation of germline mutations.

It is noteworthy that the Japanese healthcare regulatory framework necessitates those cases undergoing CGP testing be subjected to deliberation within an MTB forum prior to the treating physician communicating the results to the patient. This requirement is met through the convening of a weekly MTB meeting at the originating institution, wherein a diverse cohort of at least ten oncology specialists convene. The attendees are made up from different subspecialties, including gastroenterology, breast oncology, urology, gynecology, and pediatrics. Furthermore, geneticists, genetic counselors, bioinformaticians, and other experts contribute their insights to these sessions. Although the attendance of attending physicians is mandatory, it is noteworthy that more than 50 physicians from external institutions also actively participate in these deliberations.

Within the MTB meetings, the treating physicians expound upon the patients’ medical histories and general clinical conditions, paving the way for a comprehensive discourse regarding the potential therapeutic recommendations and the prospect of enrollment in clinical trials. Importantly, the MTB extends therapeutic recommendations to cases characterized by genetic alterations classified at level D or higher. Level D corresponds to cases wherein clinical reports have demonstrated therapeutic efficacy irrespective of the cancer type. Level E pertains to the preclinical stage of genetic alterations, whereas Level F denotes genetic variations with known implications in the realm of oncogenesis.

MTB Italy Italy currently hosts a total of 16 distinct active MTBs, representing a comprehensive network aimed at facilitating precision oncology initiatives. Notably, with a single exception, these MTBs have opted for a versatile approach, employing a mixed model that encompasses both virtual and face-to-face components, augmenting their accessibility and outreach [7].

Ciliberto et al. [34] published a commentary in 2022 summarizing a survey on different MTBs in Italy, conducted by the Alliance Against Cancer (ACC). It is evident that the ACC-MTB initiative is strategically evolving towards the establishment of a virtual MTB network characterized by a network topology akin to nodes and spokes. This network configuration mirrors non-redundant and cost-effective organizational paradigms commonly observed in healthcare management, optimizing resource utilization, and enhancing the dissemination of molecular oncology expertise.

More than half of the ACC members are engaged in the management of a diverse spectrum of solid and hematologic malignancies. Additionally, more than a third of these members are responsible for addressing neoplastic conditions manifesting at various anatomic sites. Notably, the average MTB is composed of 9 staff members, with the majority, precisely 13 MTBs, with an attendance of more than 10 staff members during their meetings with permanent presence from medical oncologists.. Their pivotal role encompasses the presentation of clinical cases, either following deliberations within organ-specific multidisciplinary panels or through direct clinical case presentations.

The scope of MTBs extends to cases undergoing NGS profiling as part of standard therapeutic regimens, thereby engendering a higher caseload. Consequently, the range of cases discussed within MTBs is broad and diverse. All MTBs undertake the administration of targeted NGS panels, with three MTBs further extending their diagnostic repertoire to encompass whole-exome sequencing and/or RNA sequencing methodologies.

In terms of diagnostic reporting and evidence-based frameworks, ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) [35] and/or OncoKB evidence levels assume prominence in the diagnostic reporting process. Notably, the majority of MTBs, specifically 11, offer a comprehensive written diagnostic report within a stringent time frame of 15 days conveyed to the patient by the attending oncologist.

Finland tumor board A multidisciplinary functional precision medicine tumor board (FPMTB) approach was implemented for acute myeloid leukemia (AML) patients [36]. Meetings involved comprehensive assessments, incorporating clinical history, diagnostic workup, ex vivo drug-sensitivity testing, whole-exome sequencing, and transcriptomics. Treatment recommendations primarily relied on drug-sensitivity testing, supplemented by clinical history and routine molecular diagnostics. The diverse FPMTB team convened regularly to analyze clinical, molecular, and functional aspects of consecutive AML patients, assigning risk groups, evaluating treatment options, and making recommendations for clinical trials.

FPMTB meetings embraced a comprehensive strategy encompassing thorough clinical patient history, diagnostic workup involving laboratory values, cytogenetics, and clinical mutation data, ex vivo drug-sensitivity testing with a panel of 515 anticancer drugs, whole-exome sequencing, and transcriptomics sequencing data.

Treatment recommendations by the FPMTB were predominantly grounded in drug-sensitivity testing outcomes, complemented by clinical history and routine molecular diagnostics, including flow cytometry, cytogenetics, FLT3-ITD, NPM1, IDH1/2, and WT1 mutation status. Genomic and transcriptomic data were utilized when available to enhance precision.

The FPMTB comprised the AML tumor group chair, clinicians managing the patients, clinical laboratory specialists, translational scientists knowledgeable in functional assays and multiomics data, bioinformaticians, study nurses, and a genetic counselor for actionable germline variants, available by referral. Meetings were scheduled weekly, with ad hoc sessions as needed, ensuring timely discussions within one week of patient sampling.

The FPMTB’s primary objective was to comprehensively evaluate clinical, molecular, and functional characteristics of consecutively diagnosed or relapsed/refractory (R/R) patients with AML. This included risk stratification, assessment of standard-of-care options, initiation of relevant clinical trials, and ongoing analysis of treatment responses. For R/R AML cases, the board evaluated candidate drugs for on- or off-label treatment, based on drug sensitivity and resistance testing (DSRT) and other profiling data. The FPMTB also played a crucial role in recommending bridging to allogeneic hematopoietic stem cell transplantation (alloHSCT).

Danish MTB Established in the year 2013, the Danish National Molecular Tumor Board (DN-MTB) operates with the utilization of comprehensive molecular data, including information derived from whole exome/genome somatic DNA sequencing, copy number alterations (CAs), and RNA expression and sequencing. A minority of cases undergo analysis using expansive commercial gene panels, ranging from 161 to over 500 gene coverage [37].

The primary objective of the DN-MTB is to provide expert advice on tailored treatment strategies based on the unique molecular profiles of individual patients with cancer. Furthermore, the DN-MTB aims to propose supplementary molecular analyses deemed relevant for a comprehensive understanding of the patient’s condition, such as germline investigations. Also, the DN-MTB serves as a platform for the exchange of experiences among experts, fostering discussions on druggable genomic variants/profiles and targeted treatments. It is explicitly outside the scope of the DN-MTB to offer recommendations or priorities for standard treatments, recognizing the focus on personalized therapeutic approaches. Also, the DN-MTB does not engage in the conclusive decision-making process for individual patients’ treatment plans. Instead, it functions in an advisory capacity, leaving the final decisions to the treating medical professionals.

2.2 Members and Roles

Given the complexity of cancer diseases, fostering interprofessional exchange beyond the confines of individual medical specialties is imperative to gain fresh insights and offer patients the best possible care. Luchini et al. [7] describe the current state of MTBs globally through a systematic review-based approach using 40 studies with 6303 MTB cases. Using the gained information, they were able to provide a list of different professional figures that should contribute to MTB discussions. The evaluation showed that in any case oncologists and pathologists must participate in the MTB process. Further, geneticists make an important contribution to the discussion and result finding. Bioinformaticians can play an important role, especially if germline mutations are also to be considered. As soon as large amounts of molecular data are to be interpreted, the support of molecular biologists is useful. The expertise of oncology pharmacists, bioethicists, or scientists/physicians with a solid molecular background can also be supportive. If drugs are proposed or recommended for clinical trials at the end of the MTB process, the participation of a research/clinical trials coordinator may be beneficial [7].

In general, due to the usage of NGS, the inclusion of participants from increasingly technical disciplines is required. Therefore, van der Velden et al. [38] recommend five groups of members of an MTB. Depending on the case and cancer type this comprises clinicians, e.g., oncologists, hematologists, from the appropriate various disciplines. Similar to the MTB study as described above, the second member group describes pathologists and molecular pathologists respectively. The third group includes clinical molecular biologists. It is stated that the corresponding gathered sequencing data determines the necessity of the fourth group, geneticists, and the fifth group, bioinformaticians. Both are usually required when conducting germline testing, their interpretation and subsequently developing experimental treatment options.

Further, additional training is recommended for involved parties regarding the usage of genetic and sequencing techniques. Schickhardt et al. and Merry et al. [39] state that an MTB meeting requires a predefined leader or moderator who acts as a supervisor, organizer, and spokesperson for third parties. The leader should be responsible for the selection of MTB members and their areas of responsibility while factoring in a level of trust in the results of each participant. The patient's physician is responsible for the inclusion of the patient in the MTB, e.g., through a presentation of the case in the MTB meeting. Yet, while communicating and staying informed about MTB meetings and their decisions, it is stated that they should not be a direct participant of the MTB, since their understanding of each discipline is limited and therefore dependent on the decision [39, 40]. Physicians interested in this collaborative approach can engage in individual interactions through the network's diverse service offerings or participate in a wide range of training and educational events.

Toward the culmination of the MTB process, wherein drug recommendations or clinical trial proposals are deliberated, the involvement of a research/clinical trials coordinator can be instrumental in facilitating seamless transitions from discussions to actionable plans. Luchini et al.’s comprehensive study emphasizes the indispensability of this multifaceted expertise, highlighting the intricate interplay of various specialized roles within MTBs, ultimately fostering comprehensive and informed decision-making in precision oncology [7].

2.3 Workflow

A simple MTB workflow (see Fig. 1). consists of the following steps [41]:

1.

Eligibility screening.

2.

Registration of a patient in the MTB, directly or through the handling physician. Patient’s personal and family history are shared with the MTB.

3.

A tumor biopsy is taken from the patient, and the DNA is extracted.

4.

An NGS method is used to identify characteristical modifications.

5.

Specific variants of the analyzed NGS data are called.

6.

Resulting information is interpreted and associated with potential treatments and clinical trials.

7.

A comprehensive clinical report containing all findings is created.

8.

MTB is held to discuss the case and suggest a specific treatment.

9.

The suggestion is exchanged with the handling physician and carried out.

10.

Follow-up

Fig. 1

The classic MTB workflow. A patient is first registered directly or through a handling physician to an MTB. A biopsy is taken from the patient, from which the DNA is extracted and sequenced. Results are analyzed, annotated, and presented alongside patient’s clinical data to the MTB board. A therapy is suggested to the handling physician. The presented tools and knowledge databases in Sects. 3 and 5 with their corresponding starting points in the workflow are shown in gray and light-blue respectively. The Knowledge Connector and the MIRACUM-Pipe aim to integrate the complete workflow, while the knowledge databases, cBioPortal, and the other tools are mainly used for interpretation and report generation, with the latter focusing on pipelines

The workflow delineated by Rao et al. in [9] elucidates the intricate process underlying MTBs and their virtual counterparts (VMTBs). Initially, following an initial eligibility screening, a tumor sample procured by the treating physician serves as the foundation for a clinical next-generation sequencing (NGS) assay conducted by the clinical laboratory. Subsequently, the results are shared and evaluated in conjunction with local expertise and available resources. Should local expertise prove insufficient for robust clinical recommendations, genomic variants of clinical significance are prioritized, and patient data undergo de-identification. This de-identified data is then shared among VMTB members from multiple institutions, who leverage their collective resources and expertise to collectively formulate recommendations tailored to the patient’s needs.

Nevertheless, the influx of information poses a significant challenge for stakeholders engaged in both the MTB and VMTB processes, impeding the ability to sift through and discern crucial insights. To address this challenge, supplementary methodologies, including natural language processing (NLP) and machine learning, are being employed to extract and summarize clinically relevant information from biomedical literature. Further, Hamamoto et al. and Rodriguez Ruiz et al. suggest models for the prediction of signifi