Session 10: Personalised Medicine I

Personalised medicine

uses information about each individual's genetic material to tailor therapy with best response and highest safety margin to ensure better patient care

Benefits of personalised medicine

- Earlier diagnosis

- Risk assessment

- Optimal treatment

- Improves healthcare

- Lowers costs

The P's of personalised medicine & brief description

1) Prediction & prevention of disease

Identification of high-risk people before onset of symptoms to better inform lifestyle changes and reduce burden of disease/costs. Preventative measures can be taken

2) Precise diagnoses

When paired with improved imaging technology, better knowlege of an individual's abnormality can inform better diagnoses which informs earlier and better treatment.

3) More participatory role for patients

Increased public awareness is the most powerful driver for personalised medicine

4) Prevent adverse side effects

Variants in the genetic code can be used to predict potential adverse drug reactions = significantly reduces burden on NHS and improves patient experience

An example of a disease in which preventative treatment exists for potential cardiovascular events in the future

Familial hypercholesterolemia (FH)

- An inexpensive medication can be given to people as preventative measure for cardiovascular events

Example of a new/improved imaging technique that (when paired with personalised medicine) can provide a more precise diagnosis

Multiparametric MRI

- PROSTATE CANCER = classification of tumours volume/size/dynamic of growth/typical markers for malignancy and invasion of other organs

Spectroscopy

- Used to differentiate between lesions and inflammation on a molecular level

Example of a drug used to treat HIV in which patients must now take genomic test prior to using the drug (prevent allergic reaction)

Abacavir

- First-line treatment for HIV that 1/17 people have fatal adverse reaction

- Patients have specific genomic test before taking this drug which identifies those who could be allergic

- Reduced pressure on NHS

Why is cost-effective healthcare (personalised medicine) important?

State three reasons

1) Reduced trial-and-error dosing of medicines

2) Reduced hospitalisations due to adverse drug reactions

3) Reduced late diagnoses

100,000 Genome Project sequenced DNA from ___ people

85,000 people

Genetic variants are classified on a five-point scale.

What are these classifications?

1) Pathogenic variant

2) Likely pathogenic variant

3) Variant of uncertain significance (VUS)

4) Likely benign variant

5) Benign variant

Cancer is a ___ disease (>200 types)

heterogeneous

Biomarker

Biological molecule found in blood, body fluids, or tissues that indicates a normal or abnormal process or condition/disease e.g., cancer

Give examples of bodily fluids in which biomarkers can be found

- Circulation = whole blood, serum, plasma

- Excretions/secretions = stool, urine, sputum, nipple discharge

- Tissue-derived = biopsy

Genetic biomarkers can be ___ or somatic

Inherited

Give an example of a cancer biomarker which is used to estimate the risk of developing a specific type of cancer

BRCA1 germline mutation for breast/ovarian cancer

Give example of a cancer biomarker used for screening for prostate cancer

Prostate Specific Antigen (PSA)

Give example of a technique used for differential diagnosis of cancer

Immunohistochemistry to identify the tissue of origin

Give an example of a cancer biomarker which is used to predict response to cancer therapy/treatment

- K-ras mutation and anti-EGFR antibody = colorectal cancer

- HER2 expression and anti-HER2 therapy = breast & gastric cancer

- ER (estrogen receptor) expression = breast cancer

Give an example of a cancer biomarker which monitors for disease recurrence in colorectal cancer

Carcinoembryonic antigen (CEA) test for colorectal cancer

Five main intrinsic/molecular subtypes of breast cancer

1) Luminal A (best prognosis)

2) Normal-like

3) Luminal-B

4) HER2-enriched

5) Triple negative (worst prognosis)

What is the breast cancer subtype with the best prognosis

Luminal A

HR+

ER+ and/or PR+

HER-

What is the breast cancer subtype with the worst prognosis

Triple Negative

HR-

ER-

PR-

HER2-

Which breast cancer subtypes respond to Tamoxifen

1) Luminal A

2) Normal-like

3) Luminal B

Which breast cancer subtype responds to Herceptin

HER2-enriched

Which breast cancer subtype has the highest association to BRCA1

Triple Negative

What is the standard approach for reducing risk of recurrence in women with estrogen receptor positive (ER+) early-stage breast cancer

Tamoxifen

How does Tamoxifen work in women with ER+ breast cancer

Tamoxifen → Edoxifen

Edoxifen (primary active metabolite) blocks estrogen receptors (ER)

What is the enzyme that metabolises Tamoxifen into primary active metabolite of Edoxifen?

CYP-2D6

Tamoxifen is used to treat ___ positive early-stage breast-cancer

ER positive

Herceptin (trastuzumab) - what is it

Anti-HER2 monoclonal antibody used to treat women with HER2+ breast cancer

What is the Oncotype DX test?

Used to help determine the need for chemotherapy for women with stage I or II hormone receptor-positive cancer. Looks at 21 genes within the tumor to determine the likelihood of...

- Cancer recurrence

- Cancer response to treatment

The two functions of the Oncotype DX prognostic and predictive test for breast cancer

1) How likely breast cancer will reoccur

2) Predicts response to treatment (chemo/radiation)

Low-risk score of the Oncotype DX test means...

- Indolent (slow-growing)

- Hormone-therapy sensitive

- Minimal chemotherapy benefit

High-risk score of Oncotype DX test means...

- Aggressive (fast-growing)

- Less sensitive to hormone therapy

- Large chemotherapy benefit

What are some breast cancer prevention steps?

1) Lifestyle modifications

2) Early intervention with elective surgery (mastectomy)

3) Chemoprevention

4) Increased mammography frequency

What are some current barriers to personalised medicine?

1) Costs of tests/treatment

2) Guidelines = NICE (UK), FDA (USA)

3) Current knowledge and understanding

4) Massive amount of data to integrate (genomics, transcriptomics etc)

What is drug repurposing?

Identifying new therapeutic uses for old or already-existing drugs

Drug repurposing relies on two scientific bases

What are they?

1) The discovery (through human genome) that some diseases share common biological targets

2) The concept of pleiotropic drugs

Pleiotropic

A gene that influences many traits, rather than just one

Give three examples of drug repurposing

1) Aspirin

- Initially used as analgesic

- Repurposed as antiplatelet aggregation drug (prevent cardiovascular events)

2) Thalidomide

- Initially used for morning sickness - banned for teratogenicity

- Repurposed for leprosy (inhibition of TNF-a)

- Repurposed again as first-line drug for multiple myeloma

3) Sildenafil

- Initially used as anti-hypertensive drug (angina)

- Repurposed for vasodilation for erections (viagra)

- Second repurposing = treatment of idiopathic form of pulmonary arterial hypertension

Give an example of a drug that was repurposed before it even reached the market

Sildenafil

Direct-to-Consumer (DTC) Genetic Testing

Genetic testing that is offered directly to individuals. There is typically no input, recommendation, or follow-up by a genetics professional

e.g., 23-and-Me

23-and-Me (Direct-to-Consumer Genetic Testing) screens for ___ variants that predispose individuals to certain conditions

23-and-Me (Direct-to-Consumer Genetic Testing) screens for allelic variants that predispose individuals to certain conditions

Some benefits of Direct-to-Consumer (DTC) genetic testing

- Family planning

- Cheap and fast

- Increases autonomy

- Right to be informed (breaking paternalistic approach to healthcare)

- Active patient participation in their own medical management

- If true negative = avoids unnecessary anxiety and screening

Some cons to Direct-to-Consumer (DTC) genetic testing

- May not be entirely accurate results

- Ownership of DNA (privacy)

- Validity of risk

- Preventative treatments are invasive/not curative

- Potential economic harm e.g., life insurance

- Resource allocation = wasted healthcare money on low-risk individuals, provider time & access to genetic counselling services

- Psychological harm