Introduction

The molecular tumor board: Introduction for the proteomic researcher

Over the past few years, there have been tremendous developments and advancements in cancer diagnostics and treatment. Continuous research and technological progress allow early detection and targeted therapies for various malignancies. This has led to detailed clinical guidelines that entail treatment recommendations based on each patient’s tumor entity, mutational pattern, and other tumor characteristics. However, despite all efforts, there are still many patients suffering from malignancies that are either non-treatable or non-responsive to the available and recommended therapeutic options. Examples of these challenging cases include tumors that show particularly aggressive growth and progression that are atypical for the respective entities, rendering the recommended treatments based on clinical guidelines inadequate or ineffective. Other challenging cases are malignancies in young patients, which may indicate particularly aggressive tumor-promoting factors. Importantly, there are numerous examples of rare malignancies, for which clinical and molecular data is lacking, resulting in a limited understanding of the underlying molecular pathomechanisms and treatment guidelines. To address the urgent need for a more comprehensive molecular understanding and effective medical treatment of such challenging tumor entities, molecular tumor boards were initiated.
Molecular tumor boards (MTBs) are multidisciplinary committees that perform in-depth molecular diagnostics and subsequently discuss and advise on the medical treatment of particularly challenging tumor cases (Figure 1). Typically, the MTBs comprise experts from different fields, including physicians such as oncologists, pathologists, and radiologists as well as expert scientists in the field of genomics, transcriptomics, and bioinformatics1. The multidisciplinary panel allows expert-level analysis and interpretation of all the data involved, including large and complex data such as nucleic acid-based next-generation sequencing data. Furthermore, the frequent meetings stimulate and encourage scientific and medical exchange between the different scientists and physicians, promoting a thorough assessment of each MTB patient case. One of the earliest examples of successful implementation of an MTB has been shown by the University of California San Diego Moores Cancer Center since the end of 20122. In the following years, the concept and applicability of the initial MTBs have prompted the initiation of further MTBs across the United States and other countries3–7. In-depth molecular characterization and treatment recommendations by the MTBs have been linked to improved clinical outcomes in various medical centers and studies1,8–10.

Molecular diagnostics for personalized and precision medicine

Molecular diagnostics enables a comprehensive, sensitive, and accurate diagnosis of various diseases. In molecular diagnostics, biomolecules in a patient-derived sample (tissue or body fluid) are investigated aiming to confidently diagnose or classify a disease. An early and precise diagnosis is crucial for the identification of treatment options in tumor patients. Due to vast inter- and intra-heterogeneity in malignancies, there is an urgent need for specific stratification and classification of tumors. This heterogeneity calls for personalized and precision medicine, increasing the chances of therapy response and minimizing side effects11. One of the most popular examples and successes of precision medicine is the administration of Herceptin for the treatment of HER2-positive breast cancer patients12.
A fundamental approach in molecular diagnostics is the immunostaining of established protein biomarkers, such as HER2, PD-L1, and different types of keratins, or hormone receptors. This enables pathologists and clinicians to stratify and classify malignancies, estimate prognosis, and in some cases screen for potentially effective treatment options. However, this approach is often limited to established antibodies and staining protocols. Technological advancements have pushed molecular diagnostics towards high-throughput and in-depth nucleic acid-based screening approaches such as next-generation sequencing (NGS)11,13,14. The DNA-based NGS approaches are either targeted on individual genes, including small or large panels thereof, or on a larger scale such as whole exome/genome sequencing (WES/WGS)15–17. The primary focus of genomic approaches in oncology is the detection of mutations that can be associated with pathogenic, potentially pathogenic, or benign tumor development and progression. Further essential parameters of genomic approaches are the analysis of the tumor mutational burden, copy number variations as well as microsatellite stability. Additional methods that present an astonishing sensitivity due to the amplification of the respective analytes are RNA-based NGS approaches. The expression of RNA fusions and quantitative analyses of expressed mRNA levels can yield insights into the dynamic alterations during tumor development and progression. Due to continuous technological and methodological advancement as well as the high sensitivity there is a current trend towards NGS approaches in in-depth molecular diagnostics. This led to numerous clinical studies and vast knowledge databases that investigate and document the link between certain mutations and the occurrence of RNA fusions to respective clinical outcomes in different malignancies18,19. Current routine molecular diagnostics mainly comprise protein stainings (e.g. via immunohistochemistry) in combination with genomic and transcriptomic NGS approaches. The extent of the genomic and transcriptomic analyses depends on the clinical questions as well as the individual patient and the respective malignancy.
Molecular diagnostics paved the way towards personalized and individualized diagnostics and in consequence, targeted therapies20–22. The diagnostic, prognostic, and therapeutic implications of somatic variants and molecular biomarkers have been comprehensively analyzed and assessed, and assembled in different evidence classification systems10,23,24. Internationally recognized classification frameworks, such as the ”Joint Consensus Recommendation” (JCR) devised by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP), along with the ”ESMO Scale for Clinical Actionability of Molecular Targets” (ESCAT) introduced by the European Society for Medical Oncology (ESMO), provide robust guidelines25,26. Moreover, national-level classification systems exist, such as Germany’s widely adopted National Center for Tumor Diseases (NCT) and the German Consortium for Cancer Research (DKTK) classifications27. In the latter, evidence level 1 (m1A-C) recommendations are based on biomarkers and respective therapies that were described in the same entity; whereas evidence level 2 (m2A-C) recommendations are based on observations/studies in another tumor entity. Less substantial evidence level 3 (m3) implies a predictive value or clinical effectiveness of a biomarker based on preclinical data including in vitro / in vivo models and functional genomics. The weakest evidence level 4 (m4) is used for recommendations based on a biological rationale linking a biomarker to prognostic and therapeutic relevance (Table 1)24.
Several evidence-based classification systems are implemented within knowledge databases, clinical laboratories, and commercial applications, further augmenting their utility and accessibility. However, the different classification systems provide divergent evidence levels for some therapeutic variants, highlighting the importance of interdisciplinary discussions in the MTBs to assess and estimate the best therapeutic option for each individual patient. The divergent variant classifications demonstrate an urgent need for standardization and have caused the initiation of centers for personalized medicine (ZPM) in Germany28.