Harnessing Genomics to drive a step change in personalized medicine
A Cancer Genomics Project Manager perspective
Cancer Genomics is an area of life science focusing on cancer-associated genomics, epigenomics and transcriptomic alterations, enabling gene-guided diagnosis, prognosis, and identifying eligibility for increased surveillance or personalized therapies, in patients with inherited or acquired cancers.
Genomics mainstreaming in the NHS
The National Genomic Medicine Service (GMS) has evolved from the world-renowned 100,000 Genomes Project, and is the organization responsible for the detection of cancer-relevant genes. The GMS is divided in to 7 regional Genomic Laboratory Hubs (GLHs). Each GLH delivers Genomic testing that has clear and proven clinical benefit. Providing equitable access to Genomic analysis with an option for Genomic data to be accessed by approved researchers, expanding the genetic diversity of the clinical database, and increasing the discovery of drug-gene pairs of significance in cancer management.
Predicting cancer risk
Germline Genomics can also be used in the assessment of familial cancer risk. Patients undergo personalized genetic education and counselling prior to testing to determine the likelihood of future cancer development. If there is a genetic diagnosis, this testing is cascaded to blood relatives. When pathogenic BRCA gene variants are detected for example, clinical management can be tailored, with increased breast awareness, annual surveillance by mammogram or MRI, chemoprevention, or risk-reducing surgery before cancer presents.
Identifying tumour susceptibility
Some patients with locally advanced or metastatic solid tumours, cannot be resected, however NTRK gene fusions detected by Genomic analysis in such tumours, are important targets of larotrectinib. Providing a treatment option when previously there was none, larotrectinib now improves overall and progression-free survival.
Similarly patients with ovarian cancer are now eligible for olaparib immunotherapy if their tumours test positive for HRD, a marker of genomic instability and genetic cancer predisposition.
DNA mismatch repair (MMR) leads to microsatellite instability (MSI), a genetic predisposition to mutation. DNA replication errors are seen in tumours such as colorectal cancer. However MSI-high expressing tumours are highly responsive to immunotherapies such as nivolumab, and are associated with a better prognosis than MSI-low or stable tumours.
Pan-genome analysis
Molecular investigation of a particular sequence by NGS, whole exome or whole genome sequencing, detects many mutations in different cancer types. Melanoma, non small cell lung cancer (NSCLC), squamous carcinomas and metastatic tumours have the highest tumour mutation burden (TMB). Lung cancer patients with high TMB levels can access pembrolizumab treatment.
Tumours harbor distinct mutational patterns which can be used to stratify treatments or also indicate resistance to therapies, for example tamoxifen resistance in breast cancer. Some mutational signatures are observed in diverse tumour types, whilst others are associated with specific tumours only.
Liquid biopsies
Liquid biopsies are less invasive than other tumour sampling methods. Free circulating tumour DNA (ctDNA) and cells can be analyzed from blood samples using next generation sequencing (NGS), to determine the effectiveness of anti-cancer therapies, or monitor minimal residual disease thus providing early indication of relapse, sometimes years in advance of clinical presentation and enabling earlier intervention. The clinical utility of ctDNA is demonstrated in lung cancer for example, with EGFR-positive tumours identified as sensitive to Gefitinib immunotherapy.
Reducing risk of harm with Pharmacogenomics
Some people carry inherited variants in single genes, placing them at increased risk of adverse drug reactions which can be life-threatening. Knowing about these gene variants that affect drug metabolizer status in advance of prescribing anti-cancer therapies, means that lower doses can be administered with closer monitoring, or alternative treatments selected, for example DPYD gene variants and the anti-cancer drug capecitabine. This personalized medicine approach removes the significant morbidity or mortality from anticipated toxic effects in affected individuals, reducing harm and hospital admissions.
A global effort in a Genomic generation
Worldwide collaboration between the triad of academia, healthcare and life science industry, is driving the Genomics culture in the UK. There is widespread acknowledgement that personalized medicine has great clinical utility, for improving both overall survival and progression-free survival in cancer care.
Identification of clinically significant or desirable genes in the research domain quickly translates in to routine practice. Gene profiling recommended by national policies and guidelines is rapidly becoming the new standard of care, presenting potential clinical risk when not adopted.
Change in healthcare is both inevitable and necessary, to keep pace with Genomic advancement, and drive improvement in cancer management.
Thankyou for reading. Have you seen the other topics discussed in my blog?
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