Introduction of genomics in cancer care

Genome UK- national genomics healthcare strategy

Three pillars: diagnosis & personalised medicine, prevention, research

• Incorporating the latest genomics advances into routine healthcare to

improve the diagnosis, stratification and treatment of disease

gene to protein

DNA contains the instructions for the creation of biological molecules, usually proteins.

Humans have around 20,000 genes, all containing the information needed to build one or more proteins.

genomics

is the study of an organisms genome (its DNA) and how that information is applied

genetics

is a study of genes and how they are inherited.

pharmacogenetics

how variation in one single gene influences the response to a single drug

Pharmacogenomics

study of how an individual’s genetic information determines how an

individual manages and responds to medicines

personalised medicine

individualising drug therapy in light of genomic, diagnostic and clinical information

variant

Any difference between the sequence of two individuals’ genomes, or a reference genome. Variants can be harmless or disease-causing (pathogenic)

genotype

The DNA sequence of an organism or individual, which determines (along with environmental influences) the specific characteristics (phenotype) of that organism or person.

allele

Alternate forms of a gene at the same position on a chromosome (locus)

phenotype

An organism’s observable physical and biochemical characteristics directly influenced by the genotype and/or environment.

gene therapies

Use cutting-edge technology to deliver tailor-made genetic material into a patient’s cells to treat disease

new targeted treatments

Based on an increased understanding of the genomic basis for disease & diagnosis

Pharmacogenomics

Guide treatment decisions and dosing using genomic data to predict drug response

repurposing

New indications for existing medicines

predicting

Drug resistance and pathogen resistance

cancer genomics in practice

• screening

• diagnosis

• treatment

variation

• Changes in the DNA sequence range from small

  (one base) to large (entire chromosome)

  • Not all variants are associated with disease, for example:

  • Benign

  • Natural variation

  • Drug effects (pharmacogenomics)

types of variants

Constitutional (germline): Occur in gametes (sperm and eggs)

and can be passed on to offspring

• Somatic: Arise in an individual and are not heritable. These type

of variants are the most common cause of cancer.

defining cancer genomics

Cancer is a group of heterogeneous disorders whereby the common

feature is uncontrolled cell growth and spread/invasion causing an

imbalance between cell proliferation and cell death

• Can be caused by germline or somatic gene changes

• But most often caused by somatic gene variation and often by more

than one somatic gene change

types of sequencing

• Targeted sequencing

  • Panel sequencing

  • Whole exome sequencing (WES)

  • Whole genome sequencing (WGS

single nucleotide polymorphism

• these are position in a genome where some individuals have one nucelotide and others have a different nucleotide

national genomic test directory

Defines the testing commissioned

by NHSE in England

• Commissioning is mirrored in Wales

by NHSWJCC

• Information includes the

description of the technology by

which it should be delivered

NSCLC

• Smoking is most strongly associated with SCLC

  • Adenocarcinoma is a type of NSCLC and is the most common

  histology in never smokers and associated more commonly

  with driver mutations such as EGFR mutations

  • EGFR mutations – most common in women and east Asian

  populations

why is testing important in lung cancer

• Studies have shown that patients with actionable variants who

  receive appropriate targeted therapy have improved

  outcomes

  • Important to consider molecular testing to select the correct

  treatment either immunotherapy or targeted treatments

when are patients tested

• at diagnosis

• at disease progression

at diagnosis

To determine if EGFR variant or PD-L1 overexpression detected

• Metastatic disease (need comprehensive panel test)

at disease progression

• To check for treatment resistance

  • E.g. targetable EGFR resistance mechanisms – T790M

  • For other biomarkers, mostly informational for clinical trials

  • Patient by patient basis

tissue testing

• Gold standard practice – taken from a surgical biopsy of tissue

  • May be unable to repeat biopsy due to difficult tumour

  location, procedural availability, and patient preference

  • Lung cancer biopsies are more heterogeneous/less cellular

  compared to other solid cancers

  • Bone biopsies less reliable – decalcification can degrade DNA

  • Turnaround time 2-3 weeks and can be longer

liquid biopsy

Circulating tumour DNA (ctDNA)

• Molecules released into circulation actively or passively which

originate from tumour cells due to apoptosis or necrosis

• ctDNA can be measured most commonly in the plasma but

can also be measured in other bodily fluids such as urine, saliva,

pleural or CS

when should you use a liquid biopsy

• cancer diagnosis/ plasma first approach

• cancer diagnosis/ sequential approach

• cancer diagnosis/ complementary approach

cancer diagnosis/ plasma first approach

for inadequate or no tissue biopsy possible or available – advice if negative to re- biopsy for tumour tissue

cancer diagnosis/ sequential approach

tumour tissue adequate for genotyping – follow with liquid biopsy only when results from tissue incomplete

cancer diagnosis/ complementary approach

• increased rate of biomarker detection

molecular tumour board

MDT meeting to understand and utilise molecular reports

• e.g. oncologists, geneticist, clinical scientists, pharmacists, pathologists, bioinformaticians, clinical nurse specialists

• Aim is to interpret molecular tumour reports and make treatment decisions based on genomic results and other clinically relevant details

• More complex treatment decisions – e.g. unlicensed medicine use, decision on further genetic testing or clinical trial implications.

summary of cancer genomics

Somatic tumour testing guides drug-gene matches which is

resulting in greater understanding of cancer and how we can

sub-categorise even common cancers due to gene variations

• Patients need to be screened up front for many genetic tumour

variants to ensure the patient receives the right treatment first

• Where the biopsy is taking from and when the testing takes

place is very important

pharmacogenomics

the study of how an individual’s genetic information can help predict their response to medicines"

types of metabolisers

Poor metaboliser

● Intermediate

metaboliser

● Extensive (normal)

metaboliser

● Ultra rapid

metaboliser

Slide taken from Uni of Exeter lecture slides for Pharmacogenomics module

drug metabolism

• prodrugs

  • codeine

  • clopidogrel

  • tamoxifen

• active drugs

  • warfarin

  • omeprazole

  • phenytoin

single nucleotide polymorphism

most common type of genetic variation among people

haplotype

A haplotype is a group of genetic variants inherited

together on the same copy of a gene

• Star alleles are often shorthand labels for haplotypes

where do recommendations come from

PGx recommendations should come from validated

sources.

• Examples include:

o Clinical Pharmacogenetics Implementation Consortium (CPIC)

guidelines

o Dutch Pharmacogenetics Working Group (DPWG) PGx guidelines

o National guidance e.g. NICE

o Local NHS pathways

DPYD testing

DPYD pharmacogenomic test offered to all patients prior to

starting fluoropyrimidine chemotherapy (5-fluorouracil, capecitabine)

DPYD testing project at Velindre Cancer

Centre (pilot site) Early 2020

Implemented DPYD testing for all patients

commencing fluoropyrimidines

Developed clinical pathways and addressed

various challenges

Later rolled out across Wales by AWMGS

MediWales award winners for scaling up &

collaborative approach

benefits of personalised medicines

Improve patient care and compliance

• Reduce medicine wastage

• Reduced impact on healthcare

services

• Improve drug safety

• Test result required once per lifetime

• To ‘personalise’ patient treatment

potential challenges

Access to testing

• Data management

• Interpreting test results

• Consent

• Research

• Population diversity

• Up-skilling the workforce

• Education

personalised medicine

Ensuring medicines are safe, appropriate

and work effectively for patients

• Embedding pharmacogenomics into

medicines optimisation

• Equitable access to genomic testing and

personalised medicine

• Responsible for the safe preparation,

storage and supply of medicines

advanced therapeutic medicinal product (ATMPs)

ATMPs are medicines for human use that are based on genes, tissues or cells. They offer groundbreaking new opportunities for the treatment

of disease and injury.

ATMP classification

• Gene therapy medicines

  • Somatic-cell therapy medicines

  • Tissue engineered medicines

gene therapy medicines

these contain genes that lead to a therapeutic,

prophylactic or diagnostic effect. They work by inserting 'recombinant' genes into

the body, usually to treat a variety of diseases, including genetic disorders, cancer

or long-term diseases. A recombinant gene is a stretch of DNA that is created in

the laboratory, bringing together DNA from different sources;

somatic cell therapy medicines

these contain cells or tissues that have been manipulated to change their biological characteristics or cells or tissues not intended to be used for the same essential functions in the body. They can be used to cure, diagnose or prevent diseases;

tissue engineered medicines

these contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue;

• In addition, some ATMPs may contain one or more medical devices as an integral part of the medicine, which are referred to as combined ATMPs. An example of this is cells embedded in a biodegradable matrix or scaffold.

challenges of ATMPs

• regulatory

• financial

• technical

• scientific