Since the turn of the century, when the term “personalised medicine” was first coined, the use of molecular diagnostic (or biomarker) testing in clinical trials has continued to grow in terms of complexity and importance. These tests have undergone a period of rapid development and growth in the last decade, with the implementation of new high complexity tests and technologies into the clinical molecular diagnostics laboratory serving as a critical step towards advancing precision medicine.1 Cindy Spittle, Vice President of Scientific Affairs, ICON Laboratory Services group, explains.
The discovery that cancer cells can harbour specific driver mutations led to the design and development of molecularly-targeted therapies. Since different tumours of the same histology (for instance, non-small cell lung cancer) may result from different genetic lesions, the development of companion diagnostic tests was also required giving rise to the “drug and diagnostic development” paradigm. The design and development of drugs that target specific genetic variants is now being applied to other disease areas outside of oncology.
A new wave of molecular diagnostic programmes
By definition, the development of targeted therapies in oncology requires molecular diagnostic testing. These tests are designed to identify patients who are most likely to respond to the therapy based on the pharmacogenomic profile of their tumour. The approval of Herceptin and the HercepTest in 1998 sparked a wave of drug and molecular diagnostic co-development programmes and was the first successful example of treating cancer with a targeted therapy rather than a one-size-fits-all approach.
Herceptin is a drug that targets the HER2 receptor. HER2+ tumors can be identified using several different molecular diagnostic tests, but the first to be approved as a CDx was the HercepTest, an IHC-based assay. Approximately 20% of all breast cancers are HER2+, so the approval of a molecular diagnostic test that could identify HER2+ tumours was a critical development for treatment selection.
In addition to guiding therapy decisions, molecular diagnostic tests are also beneficial for identifying patients with hereditary cancer syndromes (HCS). HCS are genetic defects that result in an elevated risk of cancers, often organ-specific, allowing physicians to arrange preventative interventions for germ-line mutation carriers, including chemoprevention. A variety of molecular methods are used for HCS testing. For example, genes that can harbour a variety of potentially pathogenic mutations, such as BRCA1 and BRCA2, are typically sequenced using Sanger or NGS methods. However, both PCR and/or IHC tests are used to aid in the diagnosis of Lynch syndrome, a disease that results from a deficiency in the function of mismatch repair genes. The full extent of the heritability of cancer risk is yet to be explored. Whole exome sequencing studies are expected to significantly increase the identification of known hereditary cancer genes.2
Minimal residual disease detection
Clinical studies of targeted therapies in a growing number of cancer indications have led to another important use of molecular diagnostic tests—monitoring efficacy and response, including minimal residual disease (MRD) detection. This detection is useful for cancer patients who need to see how well they’ve responded to treatment. MRD is a term most commonly used in hematological malignancies. MRD assessments can be conducted using PCR, NGS or flow cytometry-based methods. MRD testing canhelp find cancer recurrence sooner than other tests, identifying patients who may be at a higher risk of relapse or need to restart treatment, and identify patients who may benefit from other treatments such as stem cell transplantation.3 Recently, MRD testing is also being applied to the monitoring of solid tumor patients through the analysis of circulating free DNA (cfDNA) using highly sensitive digital PCR or NGS assays.
Personalised medicine – beyond oncology
Molecular diagnostic testing, however, is in no way limited to use in oncology. These tests have expanded to cover other therapeutic areas and applications.
One active and growing area of research is the identification of genetic and soluble biomarkers for neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Candidate biomarkers are being explored for use in earlier diagnosis of these diseases, thereby enabling earlier potential therapeutic intervention through participation in clinical trials. Biomarkers that could be used to monitor the efficacy of these therapies are also of great interest.
Imaging approaches continue to evolve and are making major contributions to target engagement and early diagnostic biomarkers. The incorporation of biomarkers into drug development and clinical trials for neurodegenerative diseases promises to aid in developing and demonstrating target engagement and drug efficacy for neurologic disorders.4
Drug dosing and safety
Additionally, advances in our understanding of the functional differences between absorption, distribution, metabolism, and excretion (ADME) gene variants have led to increased use of molecular diagnostic tests to ensure patient safety and optimal dosing. Pharmacogenetics or pharmacogenomics research focuses on identifying gene variants that impact the metabolism or response to drugs. A comprehensive list of drugs and corresponding pharmacogenomic information can be found on the following FDA website. Drugs that may require molecular diagnostic testing to identify an ADME gene variant span across many different therapeutic areas including oncology, psychiatry, hematology and infectious disease.
Detection of viruses and bacteria
Molecular diagnostic tests are not limited to the analysis of human genes in clinical trials. Vaccine trials utilise molecular diagnostic assays to screen and monitor patients for the presence of the targeted pathogen. Viral load assays are used to monitor response over the course of experimental treatment with anti-viral compounds. The emergence of the SARS-CoV-2 pandemic led to the rapid development and launch of both vaccine and therapeutic trials. Molecular diagnostic tests were also rapidly developed to detect novel coronavirus RNA, antigen or antibodies and continue to play a critical role in enrolling and/or monitoring patients in these studies. Molecular-based screening to determine whether a patient has an active or has had a prior viral infection such as HBV, HCV, and HIV is also routinely performed using PCR or immunoassays in a wide range of clinical development programmes.
Microbiome analysis is another rapidly growing area in drug development. The microbiome has been shown to play a role in cancer and other diseases. Molecular techniques such as metagenomic sequencing are used to identify signatures and detect new biomarkers based on the microbial composition of the stool, saliva and skin. These signatures may be used to develop microbiome-targeted drugs or to predict response to other therapies.
The future of molecular diagnostic testing
Molecular diagnostic testing has rapidly evolved to be an integral part of clinical drug development programmes. The field of molecular diagnostic assay development has expanded to cover a wide range of biomarker targets, diseases and applications. The data generated by molecular diagnostic tests can provide valuable insights into optimal drug dosing, patient selection and drug efficacy and facilitate more rapid development and approval of new therapies.
As the clinical drug development field continues to become more complex in terms of drug and clinical trial designs, the molecular diagnostics field will continue to grow and change as well. As more drug and disease-related biomarkers are identified, new technologies will be needed that enable “more with less” – for example, more data with less sample. As decentralised clinical trial designs become more mainstream, at-home sample collection and point-of-care molecular diagnostic tests will become more widely available.
The future of molecular diagnostic testing is bright and will continue to play a critical role in the development and approval of new therapies to treat a broad range of diseases.
About the author
Cindy Spittle, Vice President of Scientific Affairs, ICON Laboratory Services group. Spittle has over 30 years of experience in translational and clinical oncology biomarker research, diagnostic assay development and biomarker strategy for clinical drug development. She provides strategic scientific leadership related to the evaluation and implementation of new technologies and laboratory testing services. She holds a BS in Microbiology from The Pennsylvania State University, an ASCP Medical Technology Certification from Pennsylvania Hospital and a PhD in Molecular Biology from Lehigh Universit.