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. 2021 Jul 3;77(3):258–265. doi: 10.1016/j.mjafi.2021.06.020

Precision medicine: Uses and challenges

Nardeep Naithani a, Amar Tej Atal b, TVSVGK Tilak c, Biju Vasudevan d,∗, Pratibha Misra e, Sharmila Sinha f
PMCID: PMC8282516  PMID: 34305277

Abstract

Precision medicine has brought in many changes to the practise of medicine. The omics-based development of biomarkers and pharmaco-omics-based drug development programmes are evidences for the advancement. However, the field where it has proved to be most useful is in the development of various modalities of treatment in oncology. Various drugs targeting vascular endothelial growth factor, epidermal growth factor, tyrosine kinase receptor and rat sarcoma mutations have come to the forefront proving to be beneficial in many cancers. Some of the classic drugs developed using this concept include trastuzumab, bevacizumab, cetuximab and panitumumab among others. Precision medicine has been put to best use in the COVID-19 pandemic through use of various biomarkers such as IL-6 and c-reactive protein in assessing severity of disease, for development of various therapies and also to judge efficacy of vaccines. Precision medicine is also finding its place in management of infectious diseases, chronic diseases such as asthma, connective tissue diseases, cardiovascular diseases, diabetes and obesity. India has also made its presence felt in the field by launching various initiatives such as the Indian genome project and Indian cancer genome atlas. Numerous challenges still exist to the future of precision medicine such as cost involved, ethics, security of the Big data, merger of various platforms to integrate data and also availability of trained manpower to manage the data and algorithms. This new age medicine is a big step forward for mankind and hopefully it will bring more benefits for both patients and the caregivers in the near future.

Keywords: Precision medicine, Oncology, Emergency Medicine, Challenges

Introduction

Precision medicine promotes improvements in healthcare, medical decisions, treatments, practices and products customized to a subgroup of patients based on understanding of individual genes, environment and lifestyle.1,2 It aims at attaining optimal therapeutics with minimal iatrogenic damage and medical expenses.2 The ultimate goal is to provide rational pharmacotherapy i.e. to prescribe the right drug to the right patient in the right dose at the right time avoiding harm to the patient.3 With recent developments in the fields of genetics, molecular biology and biochemistry, the scope of precision medicine has increased greatly. During the COVID-19 pandemic, the requirement of early and targeted decisions has been highlighted further, and the development of therapies and vaccine against the corona virus has been a good platform which has further emboldened the precision medicine processes. Precision medicine has a wide range of applications in both diagnostic and therapeutic fields and includes the following section headings:

Development of new omics signature-based biomarkers

Omics technology has helped in discovering omics-based biomarkers with enhanced precision. The definition of biomarker can be translated in context of omics data by evaluating the association of the features of the omics profile or signature with particular medical conditions and building computational models with the features selected. The omics signature can be utilized as a potential biomarker for screening, diagnosis, prognosis, drug development, drug targeting and drug response.4

Some omics derived molecular signatures have successfully reached from bench to bedside. On top of the list is the MammaPrint, a 70-gene expression signature diagnostic test to predict breast cancer prognosis and to guide targeted therapy.5 Sept9 promoter methylation is an epigenetic diagnostic marker for colorectal cancer launched recently.6 OVA1 protein biomarkers to assess the likelihood of malignancy in women presenting with an ovarian adnexal mass prior to planned surgery is another successful omics signature-based biomarker.7

Because of the highly sensitive techniques, omics allows analysis of miniscule number of biological molecules in non-invasive samples such as blood and urine, called as liquid biopsy.8 The circulating tumour cells and cell-free DNA can be analysed for any of the omics with same specificity as from the corresponding tissue of the organ. Cancer management at various stages, and prenatal screening for inborn or inherited disorders are well established omics-based practices of precision medicine.9 On the other hand, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)–associated protein (CRISPR-Cas) system, a gene editing tool which has promising future in precision medicine, would do wonders based on the information provided by multi-omics. It would have a role in not just gene editing, but editing of epigenetic modifications thus allowing the switching ‘on and off’ of genes.10,11

Development of pharmacotherapy based on pharmaco-omics

Pharmaco-omics has helped in changing the focus from ‘one size fits all’ to individualized and targeted therapeutics. Pharmacogenetic guided dosing is especially important where there is an established drug-gene relationship and in drugs with narrow therapeutic window.

Pharmaco-omics techniques can be applied for identification of new drug targets and also to accelerate clinical trials.12 Omics data can be used to select the patient sub-population in which the drug would be effective. This would reduce the time for approval of new drugs, reduce the percentage of failures and cost, lead to more effective drugs and lesser drug withdrawals after approval.12 The combination drug BiDilR (hydralazine + isosorbide dinitrate) was tried for heart failure but failed in 1997 as it was effective in only an insignificant number of patients, all of whom were of African descent.13 The drug underwent trials again in this sub-population and received approval in 2005 for use only in African descent patients.14 Companion diagnostics i.e., the diagnostic tests required to choose the patients or monitor them during therapy are sometimes developed along with the drug to ensure proper usage of drug and also to get faster drug approvals. The drug crizotinib for non–small-cell carcinoma lung was developed with companion diagnostics relating to Anaplastic lymphoma kinase (ALK) testing and received accelerated FDA approval in only 4.9 months after its New Drug Application (NDA) in August 2011.15 It received regular approval in 2013 with a trial in only 347 patients.

Precision medicine in oncology

Conventional chemotherapy and radiation utilize the rapid cell division property of cancer cells for their efficacy. This often leads to bystander effect on the normal rapidly dividing cells, hair follicles, blood cells and cells of the intestinal tract, causing adverse effects and toxicity.

Targeted therapy or precision oncology aims to mitigate the conventional adverse effects of chemotherapy, maintaining the effect on the cancer cell, utilizing target identification at extracellular level, cell membrane level, intracellular level and intranuclear level. The extracellular targets include the ligands which bind the receptors on the cell surface and guide cellular processes. Vascularization is essential for growing solid tumours and vascular endothelial growth factor-A (VEGF-A) plays an important role in the same. Bevacizumab is a monoclonal antibody which binds the soluble VEGF-A, thereby preventing the interaction of VEGF-A with VEGF receptor and preventing the neo-vascularization pathways. This drug has proven to be effective along with chemotherapy or as single-agent maintenance therapy in many cancers such as colorectal, lung, renal, glioblastoma multiforme, and ovarian cancers.16, 17, 18, 19, 20

The receptors on the cell surface assist the cell survival by activating downstream signalling pathways. Cancer cells having over expression or abnormal expression of receptors can be targeted by using receptor directed monoclonal antibodies, thereby reducing the toxicity of normal cells. The epidermal growth factor-receptor tyrosine kinase (EGF-RTK) family, also called ErbB receptor family, consists of four members: EGFR (ErbB1, HER1), ErbB2 (HER2, neu in rodents), ErbB3 (HER3) and ErbB4 (HER4) and is one of the most extensively studied receptors for precision therapy. Among these, the ErbB2 (Her2/neu) over expression drives tumorigenesis by homodimerizing with other HER receptors and activating the downstream signalling pathways.21 Her-2/neu is over expressed in nearly 20–25% of breast and gastric cancers.22, 23, 24 In addition, Her-2/neu over expression is detected in many other solid tumours such as lung, bladder, uterine, cervix, ovarian, head and neck and oesophageal.25, 26, 27 This over expression has been targeted using monoclonal antibodies such as trastuzumab and pertuzumab, which have shown survival benefit in advanced malignancies, as well as in the adjuvant setting. The Her-2 receptor can also be utilised for targeting using a combination of monoclonal antibody and a chemotherapeutic linked with it. This modality is called antibody-drug conjugate (ADC). Trastuzumab emtansine is an ADC which combines the antibody with a microtubule targeting agent. When the ADC binds the Her-2/neu receptor, it exerts its effect by way of trastuzumab, as well as internalising of the microtubule agent causes cell cytotoxicity, thereby achieving a dual effect. Targeting of the Her-2/neu by various modalities including monoclonal antibodies, ADC, and intracellular tyrosine kinase inhibitors (TKIs) is shown in Fig. 1.

Fig. 1.

Fig. 1

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The various anti-Her-2 therapies in clinical use and research. Shown are the monoclonal antibodies (A), tyrosine kinase inhibitors (B), antibody-drug conjugates (C) and other drugs such as Bi-specific monoclonal antibodies and so on (D). TCR, T-cell receptor 9.

In colorectal cancer, EGFR directed therapy is based on a concept of mutated receptor or wild-type receptor. In the case of mutated EGFR receptor (rat sarcoma mutations), there is constitutive activation of the downstream signalling pathway, thereby negating the effect of surface receptor blockade. In clinical practice, anti-EGFR therapy (cetuximab, panitumumab) are used only in patients with wild-type status of EGFR.28

As seen previously, the intracellular targets for precision therapy include the TKIs. Phosphorylation of the tyrosine residues on the protein substrates by the RTK triggers the downstream signalling pathways. Mutations, translocations or amplifications of the RTK lead to abnormal signalling promoting tumorigenesis, invasion and metastases of malignant cells.29 Targeting the inhibition of RTK with TKI has been used as a modality in numerous malignancies based on the type and function of the RTK. The details of various TKI approved for clinical use is schematically depicted in Fig. 2.

Fig. 2.

Fig. 2

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Time-line of development and approvals for use of various small molecules (tyrosine kinase inhibitors) for various malignancies. NMPA, National Medical Products Administration (China); MHLW, Ministry of Health, Labour and Welfare (Japan); FDA, Food and Drug Administration (USA).

The other modality of precision therapy is harnessing the host immunity by use of immune checkpoint inhibitors (ICIs). The pioneering work of James Allison and Tasuko Honjo on immunotherapy has been declared as the fourth modality of therapy alongside surgery, chemotherapy and radiation therapy. The genetic and epigenetic changes in the cancer cell leads to expression of neoantigens on the cell surface. This triggers a T-cell immune response in the body. However, as a protective mechanism of the body to prevent autoimmunity and inflammatory state, the immune checkpoints regulate the T-cell response. The cancer cell expresses the ligands of these immune checkpoints, successfully evading the host immunity. Use of ICIs directs the T-cell response of the body toward the tumour in selected cases. Although biomarkers for optimizing the ICI in clinical use are still being studied, the expression of the programmed death ligand (PD-L1), high tumour mutational burden and deficiency of mismatch repair genes are commonly utilized for initiating ICI therapy. The indications of ICI, as a result, are tumour agnostic, and many of the solid tumours have received approval for use of ICI.30

Chimeric antigen receptor T-cells (CAR-T cells) are engineered cells which have tumour-associated antigen binding domain, an extracellular hinge domain, a transmembrane domain, as well as an intracellular domain along with a costimulatory molecule.31 This produces a chimeric molecule-a T-cell with an added specificity of an antibody. The effect is specific tumour antigen directed T-cells in a non-MHC restricted manner for precision killing of the cells. The FDA approved indications for CAR-T cell therapy include relapsed/refractory acute lymphoblastic lymphoma and diffuse large B-cell lymphoma.32 The process of CAR-T cell therapy is depicted in Fig. 3.

Fig. 3.

Fig. 3

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Figure depicting the process of CAR-T cell therapy. CAR, chimeric antigen receptor. CRISPR- Clustered Regularly Interspaced Short Palindromic Repeats; cas9- CRISPR associated protein9.

Over the years, molecular understanding of the pathogenesis of cancer has led to discovery of numerous targeted agents which are actively used in clinical practice of precision medicine in oncology.

Precision medicine in chronic disorders

Chronic diseases, with their higher incidence and resultant frequent complications, attract a variety of pharmacologic interventions, thus providing a suitable substrate to apply a precision medicine approach. From disease risk prediction to targeted therapeutics, the multi-omics repertoire is ever increasing. As we better understand clinical implications of genes and biomarkers, patients stand to benefit from early accurate diagnosis, treatment and preventive strategies.

Personalised medicine and asthma

It is known that CD4 T helper cell subsets include, amongst others the Th1 and Th2 population. Activity of Th2 cells drives airway inflammation in Asthma by the production of IL-4 (IgE production), IL-5 (eosinophil activation) and IL-13 (mucus secretion and IgE production). This, and the recent discovery of type 2 innate lymphoid cells as potent producers of cytokines IL-5 and IL-13, characterizes a ‘type 2 (T2) high’ endotype. The ‘type-2 (T2) low’ endotype is characterized by IL-1 and IL-17 secretion. Each endotype is thus defined by a distinct biological mechanism linking clinical characteristics with a molecular pathway. These two diverse groups fall under the umbrella diagnosis of the asthma syndrome.

The precision medicine approach enables identifying specific therapy for refractory type 2 high asthmatics in the form of monoclonal antibodies. Omalizumab binds circulating IgE and mepolizumab and reslizumab block IL-5; benralizumab blocks IL-5 receptor, and dupilumab, an IL-4RA antagonist, blocks IL-4 and IL-13 signals. Chemokine receptor (CXCR2) antagonism and dual CXCR1/CXCR2 antagonism is a therapeutic option in type 2 low or ‘neutrophilic’ asthma (Fig. 4).33

Fig. 4.

Fig. 4

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Precision medicine in asthma.

Precision medicine and diabetes

Monogenic diabetes mellitus with its multiple subtypes offers scope for precision medicine targeting therapeutic choices based on identified gene defects. Gene disorders related to glucokinase in maturity-onset diabetes of young (MODY-2) are characterized by mild non-progressive diabetes with high fasting glucose responding to diet and exercise. Genes coding for hepatic nuclear factor 1α (HNF-1α) in MODY-3 and HNF-4α in MODY-1 cause progressively deteriorating diabetes that is responsive to low dose sulphonylureas. Neonatal diabetes characterized by mutations in gene KCNJ11 (potassium voltage-gated channel subfamily 11) is seen to respond to high dose sulphonylureas. Numerous GWAS-based approaches are finding newer candidate genes that may affect response to insulin sensitisers, sulphonylureas, or incretin therapy.34

Precision medicine and systemic auto-immune connective tissue diseases

Systemic auto-immune connective tissue diseases (AICTDs) have myriad presentations with considerable overlap, variable course and remissions and relapses with time. There has been an effort of late to categorise them into subgroups based on measuring quantifiable molecular signatures using genomic technology i.e., ‘Inflammatory’, ‘Lymphoid’, ‘Interferon’, and ‘Undefined Normal like’. This would enable specific therapeutic targeting, as well, by using existing or experimental treatment tailored to a specified group. Analysis of gene expression, methylation and genetic data to create a molecular taxonomy of AICTDs could be the new treatment paradigm, using the precision medicine approach.35

Precision medicine in emergency care

As opposed to chronic disorders, emergency care settings allow for a limited time to take decisions with a narrow margin for error. The need for action prevails over need for analysis. The stressful setting, tests both the experienced physician and the greenhorn clinician. Precision medicine technology integrated with Clinical Medicine would be invaluable in such a high stakes situation.

A patient with dyspnoea could be triaged using a biomarker score (e.g., Manchester Triage Score). An ‘urgent’ score along with clinical, epidemiologic, sociodemographic parameters would prompt the use of a diagnostic biomarker panel as below to differentiate causes:

  • a)

    High sensitivity cardiac troponin T: a marker of cardiomyocyte injury, levels elevated in acute coronary syndrome prompting ECG, 2D ECHO, and revascularisation

  • b)

    d-Dimer: a value < 500 μg/dl would rule out venous thromboembolism as a cause, precluding the need for unnecessary imaging

  • c)

    Brain natriuretic peptide: elevated levels would indicate heart failure requiring a 2D ECHO and diuretics

  • d)

    C-Reactive protein: A universal inflammatory screening marker with levels guiding response to therapy in infection and inflammation

  • e)

    Procalcitonin: Elevated levels would prompt microbiological cultures and guide antimicrobial treatment. Unlike CRP, values are not affected by concomitant steroid use

  • f)

    Pro-adrenomedullin: a newer biomarker with prognostication value considered superior to CRP and procalcitonin (PCT), especially in a setting of community acquired pneumonia and other respiratory tract infections.

Other acute care settings too, stand to benefit. GWAS have identified vasculopathic changes associated with APOE ε2 allele affecting severity and clinical course of intracerebral haemorrhage. This knowledge could guide treatment and enable goals of care discussions. Genomic studies in stroke patients have identified three SNPs associated with recanalization in r-tPA treated stroke patients that would help guide treatment decisions. Transcriptomics in heart failure have identified miRNAs modulated differentially in ischaemic and non-ischaemic cardiomyopathy patients, helping guide decisions concerning coronary imaging and transplant options.36

Severe COVID-19 has been associated with ApoE ε4 homozygous genotype, loss of function variants of Toll-like receptor-7 and gene variations on chromosomes 3 and 9. We are already witness to the role of CRP, IL-6 and procalcitonin as predictors of poor outcome in COVID-19.

Biomarkers such as MCP-1, CRP, procalcitonin, suPAR and NGAL have a role in differentiating sepsis from SIRS, predicting severe sepsis and septic shock and predicting mortality in sepsis.37

These and other encouraging indicators have inspired the concept of Emergency Precision Medicine which would, at its heart, include an efficient electronic health record system, receiving inputs concerning date of prior visits, baseline patient data, research updates and primary care screening data. This coupled with acute Omics (rapid turnaround testing and targeted testing) would assist in supporting complex decision making in an acute setting. The physician aided by vast number of inputs, including scores, clinical signs, biomarker levels and stands benefitted with respect to taking decisions and instituting treatments, as does the patient with better medical care.38 This process of applying precision medicine in emergency situations is also termed as systematic molecular phenotyping approach.

Precision Medicine in infectious diseases

The Medical Tricorder conceived in the 1960s was a machine with an additional hand-held scanner that could send life-sign information to the tricorder itself. It could check all vital organ functions and detect the presence of dangerous organisms. Its data banks also contained information on non-human races, thereby making it possible to treat other life-forms. Dr Mc Coy from the Science Fiction series Star Trek used it to good effect on his space craft. This seemingly impossible futuristic concept is, today, what metagenomics (the study of genomes recovered from environmental samples) aspires to achieve.

Metagenomic NGS (mNGS) involves running all nucleic acids in a sample, which may contain mixed populations of microorganisms. These are assigned to reference genomes to understand which microbes are present and in what proportions. Sequencing reads are usually first aligned to the human genome to eliminate reads of host origin by a method called digital subtraction. The remaining reads are then mapped to sequence databases to identify pathogens.39 This technique was used in 2008 to identify a new arena virus in a cluster of three transplant recipient deaths where culture, PCR and serological assays and oligonucleotide microarrays were ineffective.40

It is possible that in the near future, metagenomic sequencing would facilitate identification and surveillance of pathogens in chronic, as well as acute diseases and possibly replace culture of bacterial isolates. Identification of resistant organisms is also a precision medicine objective.

Neonatal screening for genetic disorders: the emergency medical genome

Rapid genome sequencing - STATseq is a breakthrough application of medical genomics which uses symptom and signs assisted genomic analysis correlation tool to map genetic disorders. It facilitates a 2-day genome analysis of acutely ill neonates with suspected genetic disorders (24-h whole-genome sequencing + 18-h bioinformatics analysis). This method facilitates a rapid diagnosis for applying treatment, if any exists, thus helping avoid futile intensive care in cases, where no treatment exists and offer genetic counselling instead.41 This tool is also critical for research and development of management guidelines in a rapidly advancing field. This has also motivated other specialities to develop direct to consumer tests for various disorders.

Developments in India

The Genome India Project has been introduced in India on 03 January 2020, and it aims to map genomes of the population through genome-wide sequencing in collaboration with 20 research institutes. The Indian Cancer genome atlas and Indian genome variation consortium are looking at the differences in genomes from the Indian population from the global genomes. The recent initiative of Unique Methods of Management and Treatment of Inherited Disorders initiative and NIDAN (National Inherited Disease Administration Kendra Network) launched in September 2019 are progressive steps in this field. The future looks bright for the field of precision medicine in the country with these important developments.

Challenges for precision medicine

Precision medicine as with every new initiative has to face a lot of challenges. The large amount of data required to be collected and analysed is not only an economic burden but also labour and technical knowhow intensive. The anonymisation of data and its security is a big issue. So, ethical challenges are paramount. Noise in data is another distraction. Turnaround time for data analysis is at the earliest 26 h which is still slow for decisions in acute care settings. The validity of such data is also difficult to calculate. Capacity building needs to be done at break neck speed especially with respect to training of healthcare workers and availability of high-quality artificial Intelligence (AI), machine learning (ML), and laboratory equipment. In search of precision-based treatments, population health may be undermined.

Conclusion

Given the scope of this field and pace of evolution, it seems a matter of time before omics technologies and precision medicine take over a dominant role in diagnostics and therapeutic decision making. So, the present physician needs to be resilient, resurgent, empathetic, with a patient ‘ear’, armed with a knowledge of omics, ability to apply big data, use AI and ML to the best of its abilities, analyse complex information, and present it to the patient in a cogent and convincing ‘capsule’. We need to build intelligent big data platforms, collect uniformly structured data, train healthcare workers in genomics, build infrastructure, and involve patient and community participation for the sustenance and success of precision medicine.

As aptly said by Sir Charles Darwin – ‘It is not the strongest of the species that survives nor the most intelligent, it is the one most adaptable to change’.

Disclosure of competing interest

The authors have none to declare.

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