Contributing lab leader: Michael Vogeser, Christa M. Cobbaert and Esa Hämäläinen
Contributing lab leader: Michael Vogeser, Christa M. Cobbaert and Esa Hämäläinen
Mass spectrometry (mass spec) is offering labs an unbiased, consistent method to evaluate a vast number of substances, such as proteins and therapeutic drugs with typically better specificity and sensitivity compared to traditional immunoassays. Specific use cases such as proteomics, steroid hormone analysis, and therapeutic drug monitoring, offer a glimpse into how mass spec-based approaches could empower the development of safe and effective clinical diagnostics and precision medicines.
At this year’s annual European Congress of Clinical Chemistry and Laboratory Medicine (EuroMedLab), Prof. Dr. Esa Hämäläinen, Prof. Dr. Christa M. Cobbaert, and Prof. Dr. Michael Vogeser, shared their insights into how mass spectrometry (mass spec) can push the boundaries of clinical diagnostics.
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Unraveling the proteome, which is the complete set of proteins produced by an organism, can help better define the molecular basis of health and disease. Through proteomics, there is an opportunity to unlock breakthrough insights into protein and proteoform composition and tissue distribution longitudinally. While immunochemistry analysis has been at the forefront of understanding protein biology, mass spec has the potential to measure the vast number of proteoforms with better accuracy and reliability.1
A review by Forgrave and colleagues points to the use of mass spec applications for studying proteomics, with higher molecular sensitivity, detection, and characterization than other methods.2 Clinical applications that lend themselves to mass spec for protein evaluation include phenotyping of pathogenic variants, along with analysis of proteolytic processing and degradation, and endogenous vs. exogenous proteoforms.
To that end, developing quantitative mass spec-based protein tests that can be used in routine clinical care could enable more direct identification of proteoforms and their correlation to disease and outcomes. Taking this approach to studying proteins could uncover the next generation of biomarkers and targeted therapies. However, before these breakthroughs can take place, there is a need for better mass spec automation, cost-effectiveness, implementation, and training of lab personnel.3 By addressing these challenges, lab leaders are more likely to widely adopt mass spec-based proteomics to fulfill unmet clinical needs in current clinical care pathways.
Clinical evaluation of steroid hormones is critical for diagnosing a wide range of conditions and understanding treatment responses. Over the last two decades, the life sciences community has published over 3,000 studies of mass spec analysis for clinically relevant hormones, including testosterone, cortisol, aldosterone, estradiol, and progesterone, demonstrating the importance of the technology for steroid hormone-based disease diagnostics.
Researchers are pushing mass spec for steroid hormone analysis due to some of the limitations with the more common and widely used method of direct immunoassays to evaluate the endocrine system. These challenges include:
With better specificity, sensitivity, and accuracy, mass spec is helping to mitigate these challenges. For example, Wang and colleagues compared several immunoassays with liquid chromatography-tandem mass spec for the measurement of total serum testosterone in adult men.4 By comparison, direct immunological testosterone immunoassays showed a significant lack of precision, accuracy, and bias.
Furthermore, global professional organizations, like the Endocrine Society are pushing for the use of mass spec to measure testosterone levels in hypogonadal men. Similarly, the U.S. Centers for Disease Control and Prevention created the Hormone Standardization Program for Testosterone and Estradiol supporting the use of mass spec to enhance accuracy and precision of steroid hormone measurement.5
In the future, mass spec could potentially be utilized in several diagnostic clinical labs, enabling better analytical quality and multiple steroid profiling with automated analyzers, better isotope internal standards, and improved certified calibration standards for steroid analysis.
Therapeutic drug monitoring (TDM) aims to allow clinicians to evaluate the pharmacodynamics (PD) and pharmacokinetics (PK) of drug therapy for individualized dose adjustment. While PD determines what the drug does within the body, PK determines what the body does with a drug. In general, TDM can help to verify patient compliance by measuring drug concentration in blood and to exclude relevant PD abnormalities. Evidence-based target concentration ranges can then guide individual dosing for a safe and effective treatment.
One area where TDM will be useful is determining the PK of antibiotics in life-threatening infections. For example, Zander and colleagues developed a multi-analyte ultra-high-performance liquid chromatography-tandem mass spec to quantify several antibiotics in critically ill patients who have a high incidence of sub-therapeutic treatment levels.6 The results of the study suggested that mass spec could be used as part of a reliable and optimized workflow to improve TDM in this patient population.
In this context, experts are pointing to TDM as one element to advance antibiotic stewardship, which aims to help improve outcomes and allow clinicians to correctly apply and select doses of antibiotics in a multidisciplinary approach.7 The goal of this concept is to better utilize and preserve antibiotics for life-threatening infections. From all analytical aspects, mass spectrometry represents the most powerful technology for TDM of small molecule pharmaceuticals.
Another area merging TDM and mass spec is the quantification of small molecule drugs, specifically for cystic fibrosis transmembrane conductance regulator (CFTR)-modulators for cystic fibrosis and oral tumor therapeutics, such as cyclin-dependent kinases (CDK) 4/6 inhibitors for breast cancer. For these medicines too, mass spec can help pinpoint issues that arise such as drug-drug interactions, absorption, patient adherence, and genetic background.
Compared to traditional immunoassays and other technologies, mass spec for small molecule quantification boasts several advantages, including:
With these fundamental advantages over immunoassays, mass spec will be crucial pushing the field of TDM away from focusing on solely the safety of medication, and enabling clinicians to shift efforts towards both safety and efficiency of medication.
Today, the healthcare industry is focused on mass spec to empower clinical laboratory medicine diagnostics, opening new avenues for personalized medicines. Mass spec-based clinical approaches are allowing the field to study vast numbers of substances such as proteoforms, steroids, and drug metabolites for antibiotics and TDM with better sensitivity and specificity than the conventional immunoassays. While mass spec has not yet become routine in clinical practice, addressing barriers such as costs, personnel training, and workflow automation could bring the technology into more labs, expanding its use to address patient needs faster with better reliability and consistency.
If you want to hear more from Prof. Dr. Michael Vogeser, Prof. Dr. Christa M. Cobbaert, and Prof. Dr. Esa Hämäläinen and how mass spectrometry is influencing clinical diagnostics, then click here to register to watch their full presentation.