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.