Pharmacogenomics

The Pharmacogenetics Roll Out – Gauging Response to Service [PROGRESS] programmee  is an NHS England (NHS-E) Funded transformation project led by researchers at the NHS Manchester University NHS Foundation Trust (MFT) and the NHS NW Genomic Medicine Service Alliance (NWGMSA), to investigate the feasibility of delivering pre-emptive pharmacogenetic panel testing in primary care in the NHS

It has been split into three distinct work packages, each of which deals with a different aspect of the programme.

Pharmacogenetics describes how we can leverage the knowledge of an individual’s genetic information to support medicines optimisation, better-informing medicine selection, and dosing.  

Work Package 1  has focussed on the validation of the pharmacogenetic testing technology, involving a lab scientist at the NHS NW Genomic Laboratory Hub (NWGLH) assessing a number of commercially available pharmacogenetic panels to determine the appropriate choice for the clinical trial, based on factors including the robustness of testing, cost and turnaround time.

In Work Package 2 we have worked with health informaticians and digital experts to run a series of workshops with primary care doctors and pharmacists to develop an informatic solution that can communicate the results of the pharmacogenetic testing from the NWGLH to the primary care team. Initially, this will be through a standalone interface that will need to be logged in to, when informed that patients’ results are back, but later we aim to deliver that result directly into the EPR system used in the practice, e.g., EMIS or System One.

Work Package 3 is the PROGRESS Clinical Trial, a portfolio-adopted study, which will test the feasibility of delivering these pharmacogenetic results for real patients in primary care in the NHS and provide genotype-guided prescribing. Phase 1 of the PROGRESS Clinical Trial will initially begin at five primary care networks (PCNs) in the North West of England. Recruitment will open in Spring 2023.

Patients who are being seen for a new prescription of one of the following classes of medicines will be invited to participate in the study: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), statins or proton pump inhibitors (PPIs). They would then provide a blood sample which is sent to the NWGLH for testing and the results will be returned to the primary care team in 7 to 10 working days. The patient’s own primary care team will then be able to incorporate this guidance to inform the patient’s prescription.

For example, the patient may have attended with low mood and a prescription of citalopram was considered. If their pharmacogenetic results show that they are a CYP2C19 ultrarapid metabolsior, the system would recommend an alternative antidepressant which is more likely to be efficacious.

This will generate some useful evidence around the feasibility of delivery in primary care and the aim is to scale during 2023 to an extended national pilot with additional practices from other GMSA regions across England. Ultimately this will feed into national commissioning decisions about how we implement pharmacogenetics in the NHS

For further information, contact the team at: contactus@nw-gmsa.nhs.uk

In each newsletter, we use this section to highlight the role of a North West pharmacy professional who uses genomics in their practice, for the benefit of their patients.  In this issue, two specialist oncology pharmacists, Ollie Williams and Joe Williams from the Christie NHS Foundation Trust explain how they use genomics to guide the treatment of patients with colorectal cancer.

Colorectal cancer is the fourth most common cancer in the UK. All patients diagnosed with colorectal cancer should undergo genomic testing of their blood and tumour tissue samples to inform the most appropriate treatment options. Identification of genomic variants can help to determine whether a patient is more or less likely to respond to certain drug treatments or whether they are at increased risk of adverse drug reactions. Most colorectal cancers are adenocarcinomas though rarely they may be squamous cell carcinomas or neuroendocrine tumours (NET) [1]. The below table provides a summary of the commonly screened genomic tests and relevant medicines available depending on the outcome of these tests.

Many patients with colorectal cancers will, at some point in their treatment, receive a fluoropyrimidine based chemotherapy such as capecitabine or 5-fluorouracil. These agents are a class of chemotherapeutics which are widely used in the treatment of solid tumours, such as breast, colorectal and gastric cancers. Between 5% and 10% of patients receiving this treatment may experience neutropenia, coronary artery vasospasm, severe diarrhoea, mucositis and hand-foot syndrome [1]. 5-fluorouracil is broken down by dihydropyrimidine dehydrogenase and genetic variants in the gene encoding this enzyme (DPYD), are linked to an increase in likelihood of a patient experiencing potentially life-threatening toxicities. Patients found to have a heterozygous genotype for the DPYD gene should start therapy at a reduced dose until tolerance is assessed or use an alternative agent.

Lynch syndrome is a rare, hereditary condition which can predispose an individual to developing certain cancers including colorectal cancer. Genomic testing has enabled those patients with Lynch syndrome, and as such a higher risk of developing colorectal cancer, to be identified and treated with appropriate medications. Lynch syndrome is caused by variation in mismatch repair genes, most commonly MLH-1 and MSH-2. Tumour tissue testing is employed looking for micro satellite instability (MSI), namely MSI high which is suggestive of Lynch syndrome. If a pathological sample is found to be microsatellite stable (MSS) there is a reduced likelihood of Lynch Syndrome [2]. Patient’s identified as MSI-H become eligible for newer targeted immunotherapies such as nivolumab and pembrolizumab.

As a pharmacist screening prescriptions for colorectal cancer, it is imperative we check for the molecular profile and genetic status of each patient to ensure the most effective and appropriate therapy is being offered. As highlighted in the KEYNOTE trial,  immunotherapy such as pembrolizumab confers significant increased progression free survival for patients, and with fewer adverse effects Vs conventional chemotherapy and should be offered to all patients where appropriate.

RAS and BRAF testing are completed for all patients to determine their eligibility for targeted therapies. Epidermal growth factor inhibitor (EGFRi) therapies cetuximab and panitumumab are available to those patients who show no mutation in the RAS gene (are RAS wildtype) [3]. Patients with a BRAF V600E mutation are predicted to be poor responders to EGFRi therapies [4] and so patients are generally only considered if they are also BRAF wild type. Those patients exhibiting a BRAFV600E mutation are then eligible in the second line for Encorafenib with cetuximab. In practice a delay in returning RAS/BRAF testing can impact on first line choice of chemotherapy, and we often see clinicians starting the patient on up front doublet chemotherapy in the form of irinotecan with 5-FU or oxaliplatin in combination with 5-FU, awaiting RAS/BRAF results. Once returned if the patient is found to be wild type, the EGFRi can then be added in.

Currently in practice we are seeing delays in the processing and availability of genomic testing results. Where DPYD results can be returned in less than 7 days, RAS and BRAF testing can take up to 8 weeks to complete. As per the NICE Blueteq criteria for the immunotherapy agents, the patient must be MSI-H/dMMR but we also must know the RAS status at the time of prescribing. Given the delays in returning these results it can cause a situation where a patient may not be able to have immunotherapy first line if there is a need to treat the disease without delay. Clinically there is no significant difference in outcomes for patients who are RAS wildtype or RAS mutant whilst treated with immunotherapy and because of this, discussions have taken place and a plan is pending to add a section to the Blueteq form for these drugs to state, ‘RAS status unknown’. This move will allow patients to commence immunotherapy whilst RAS results are still pending[5].

References:

1. Colorectal cancer, GeNotes – Genomic Notes for Clinicians: https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/colorectal-cancer/
2. British Society of Gastroenterology, 2022. Available: A brief guide to the management of Lynch Syndrome - The British Society of Gastroenterology (bsg.org.uk)
3. MHRA drug safety updates (2014), Cetuximab. Available:https://www.gov.uk/drug-safety-update/cetuximab-new-safety-information-available
4. Targeted Therapy for Colorectal Cancers With Non-V600 BRAF Mutations: Perspectives for Precision Oncology | JCO Precision Oncology (ascopubs.org)
5. NICE TA709 (2021)

https://www.macmillan.org.uk/cancer-information-and-support/worried-about-cancer/causes-and-risk-factors/lynch-syndrome-ls

https://www.ncbi.nlm.nih.gov/books/NBK1211/

In each newsletter we use this section to highlight the role of a North West pharmacist who uses genomics in their practice, for the benefit of their patients.  In this issue, Alice Binns the Senior Antimicrobials Pharmacist based at The Northern Care Alliance (NCA) tells us how genomic testing is used within their service.

At The NCA a proportion of our positive influenza samples are sent for viral DNA sequencing. This information is shared with UKHSA who collate and publish weekly national surveillance reports detailing numbers and proportion of positive results for each of the current Influenza subtypes; A(H3N2), A(H1N1)pdm09 and B. Surveillance monitoring can allow us to adjust influenza treatment if the dominant circulating strain shows resistance to oseltamivir (Tamiflu).  If this was found to be the case, we would use zanamivir first line instead. In the past A(H1N1)pdm09 has shown resistance to oseltamivir however so far this season in the UK we have not found any reduced susceptibility which is reassuring.

In a recent C Diff. RCA Scrutiny Panel at The Royal Oldham, we had a case which involved someone who had been nursed in a side room which had previously been used by another patient who had also tested positive for CDT. In a scenario like this it is important to question whether cross transmission between two patients could have occurred. In this case we were able to send both patients’ isolates for ribotyping using the enhanced fingerprinting service to determine the C Diff strain causing the infection. It was found that both isolates were in fact the same strain which led the panel to deduce that the second case had almost certainly been a result of cross-transmission and should have been avoidable.

A recent topic of discussion at our NCA weekly microbiology Journal Club was the R65 genomic test for the m.1555A>G variant which is associated with an increased risk of aminoglycoside-associated ototoxicity. This started some interesting conversations around the evidence for the increased risk, available national guidance, accessibility and feasibility of the test and potential cohorts of patients who might benefit from being offered this. We also began to discuss what a positive test result might mean for patients in terms of treatment options. These discussions are now ongoing!

In each newsletter, we will use the Genomics in Practice section to highlight the role of a North West pharmacist who uses genomics in their practice to the benefit of their patients.

In the September 2022 edition,  Michael Dooney, the Adult Cystic Fibrosis (CF) Pharmacist based in Blackpool, tells us how genomic testing is used within their service.

Nowadays people are typically, although not exclusively, diagnosed with CF via the NHS new-born screening programme. Before the inception of the national screening programme failure to thrive, loose oily stools and recurrent chest infections in children were presentations that were potentially indicative of CF and resulted in referral for testing. Those who screen as potentially having CF through the immunoreactive trypsin test have their blood spot sent for genetic testing to look for variants in the CFTR gene and are referred for a sweat test. The CFTR protein is responsible for chloride and bicarbonate transport across epithelial surfaces in the airway, gastrointestinal and reproductive tracts, pancreas, and sweat glands. Genetic changes in the CFTR protein can lead to an absence or reduction in the quantity or function of CFTR, or both. This dysfunctional anion transport results in viscous mucus secretions, that are characteristic of CF, and multiorgan dysfunction, including pancreatic insufficiency and airway infection and obstruction. Chronic airway infection leads to progressive lung damage and eventually respiratory failure.

Traditionally medical management has been based on the treatment of the downstream effects of CF, i.e., symptom management. This resulted in a high burden of care which included: high use of oral and nebulised antibiotics, nebulised mucolytics, bronchodilators, daily airway clearance therapy, pancreatic enzymes, fat soluble vitamin supplements amongst many others and multiple admissions for rescue treatment with IV antibiotics. Whilst great strides have been made in the medical management of CF over the years it was reported in 2018 that approximately half of those born with CF born that year were expected to live into at least their mid-40s.  

In 2013 a new, first of its kind, treatment for CF was made available through the NHS called ivacaftor (Kalydeco®). This treatment, a CFTR modulator, was revolutionary in that it was the first treatment that targeted the genetic problem of CF at a protein level rather than the sequelae of CF. It helped to restore CFTR protein functionality to enough of a degree to produce some dramatic results. In trials participants saw significant improvements in lung function, the need for both oral and IV antibiotics reduced due to reductions in pulmonary exacerbations, as well as improvements in quality-of-life scores. It is a truly life changing drug. Sadly, it was only effective for approximately 4.5% of the CF population of the UK due to the prevalence of the mutations it was effective for in the country. Therefore, it was only prescribed for individuals with one copy of the following mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R

New CFTR modulators, tezacaftor/ivacaftor (Symkevi®) and lumacaftor/ivacaftor (Orkambi®), became available in 2019 that were targeted at a wider range of the CF population. These were approved for use in those with CF who were homozygous for the F508del mutation, which is the most common CF genotype. This meant that it could be prescribed for approximately 50% of the CF population in the UK. It also provided similar health benefits to ivacaftor in that it improved lung function, reduced need for antibiotics due to pulmonary exacerbations of CF and improved quality of life scores but the improvements were not as drastic as they were for ivacaftor in those with the gating mutations listed earlier. However, it represented a significant step forward in the care of those with 2 copies of the F508del mutation.

Then in 2020 elexacaftor/tezacaftor/ivacaftor (Kaftrio®) was approved for use in the NHS for those with one copy of the F508del mutation, which represented approximately 90% of the CF population. This drug has truly revolutionised CF care as it has brought dramatic ivacaftor for gating mutations-like improvements in lung function, exacerbation reduction and improvements in quality of life to the masses. There are numerous life changing stories due to the effect Kaftrio® on the lives of those with CF who can benefit from his treatment and the outlook for the future has never looked so bright for those who fit these genetic criteria with life expectancy greatly improved, if yet unquantifiable due to the newness of these treatments resulting in this data not currently being available.

Genetic testing provided by the NW Genomic Laboratory Hub, as per criteria set out in the National Genomic Test Directory, gives information about the exact type of variant in the individual patient. This information was critical in helping us to identify those patients who are eligible for these life changing treatments. As the adult CF lead pharmacist, I have been responsible for checking all the genetic reports for our population to ensure they are on the most effective treatment available and rechecking eligibility for treatments as new combinations of CFTR modulators have been approved. The use of drugs informed by genomics has drastically improved the care of those with CF.

Without a doubt it has been one of the biggest steps forwards in the medical management in the history of CF, if not the biggest.

We are now looking to further incorporate genomics into our practice on the back of the success of the rollout of CFTR modulators by testing for genetic sensitivity to aminoglycoside-induced hearing loss by screening for the m.1555A>G mitochondrial mutation in our population.

Health Education England's Genomic Education Programme offers a comprehensive range of education and training materials for professionals across multiple areas of practice.

https://www.genomicseducation.hee.nhs.uk/

The Centre for Pharmacy Postgraduate Education (CPPE) is part of the Division of Pharmacy and Optometry, within the Faculty of Biology, Medicine and Health at the University of Manchester, and provides an introduction to genomics as a resource.

https://www.cppe.ac.uk

The CPPE has a Genomics landing page with an introductory programme and signposting to other useful resources. 

https://www.cppe.ac.uk/gateway/genomics

The Royal Pharmaceutical society have issued a position statement on the role of pharmacists in  the pharmacogenomics revolution. Read more here.

https://www.rpharms.com

The team regularly contributes and produce articles and reports which are published, primarily online.  Recent examples relating to pharmacogenomics and pharmacy practice will be available online, via links shared below:

DPYD genetic testing and the future of pharmacogenomic testing in routine care - The Pharmaceutical Journal (pharmaceutical-journal.com)

PRSB – Guidance for Using pharmacogenomic information in clinical practice Pharmacogenomics-Report_V1.0.pdf (theprsb.org)

British Pharmacological Society and Royal College of Physicians Personalised Prescribing | British Pharmacological Society (bps.ac.uk)

GeNotes is a  just in time resource to help healthcare professionals make the right genomic decisions at each stage of a clinical pathway- currently a beta test site for Health Education England’s GeNotes for Oncology.

This lecture-based course from Health Education England's Genomic Education Progamme forms part of the HEE Genomics Education Programme’s Master’s in Genomic Medicine framework.  It provides a comprehensive overview of the anlytical strategies and techniques used in pharmacogenomics and outlines how a patient's genetic make up can determine their response to medication.

https://www.genomicseducation.hee.nhs.uk/education/taught-courses/pharmacogenomics-and-stratified-healthcare/

The UK Network was set up (and is chaired) by Professor Sir Munir Pirmohamed in 2010 to develop research collaborations, between academics, clinicians, industry, and regulatory sectors.

The aim of these partnerships is to promote the use of stratified/personalised medicine in the clinic, to offer patients the most appropriate and safe drug, at the optimal dose, at the start of their treatment. Their website is a valuable resource providing information on how the field is progressing.

https://www.uk-pgx-stratmed.co.uk/