Companion Diagnostics

Question 1

Using the same medicines in everybody is how effective?

Answer 1

30-60%

Question 2

Tailoring drugs to the patient can have what benefits?

Answer 2

Improve response, minimise side effects, optimise dosage.

Question 3

What are companion diagnostics?

Answer 3

They are used to detect biomarkers that are prescriptive for a given therapy

Question 4

What advances are needed to personalised medicine on top of the development of different drugs?

Answer 4

Advances in diagnosis and classification. We need to be able to identify heterogeneity.

Question 5

How can personalised medicine also be used preventatively?

Answer 5

Identify those at highest risk of cancer, and help them lower their risk appropriately

Question 6

What’s a good case for needing precision medicine?

Answer 6

The mortality rate of certain cancers is so high, so many people are dying. We are saving so few with some treatments.

Question 7

WHO blue books are really useful for what?

Answer 7

They are for classification of different cancer types. Providing clear criteria in terms of histopathology, molecular pathology and genomic analysis

Question 8

We want to move away from trial-and-error prescribing to…

Answer 8

Optimal therapy first time round, with little gap

Question 9

To determine a patient’s optimal treatment, what sort of profile do we need to build up for them?

Answer 9

A pharmacogenomic / pharmacoproteomic profile

Question 10

You need therapeutics to be studied in who before using them?

Answer 10

The target population you’re hoping to use it in

Question 11

What are complementary diagnostics (which are not as refined as companion diagnostics)?

Answer 11

They measure biomarkers to define a subset of patients to determine if they will respond well to a drug. But these tests are NOT prerequisites for receiving the drug. Just guiding and informing a clinician.

Question 12

What are the criteria for a good companion diagnostic?

Answer 12

Assay should be specific. Sensitive and allow the prediction of therapy outcome.
Must be reproducible.
Should be easy to interpret.

Question 13

In older patients in particular what’s another key point to be considered when determining the medicine choice?

Answer 13

If they have other comorbidities. They need to be able to respond well in their current health.

Question 14

What a challenge with pharmacogenomics in cancer?

Answer 14

Being able to distinguish the clinically relevant aberrations amongst many changes. Which are drivers? Which are highly associated with this cancer subtype?

Question 15

What helps us to know if a mutation is an important one in cancer?

Answer 15

The functional prediction. The frequency of it in that cancer type. Knowing the molecular relations and pathways.

Question 16

What are some common genetic/genomic tests?

Answer 16

FISH, PCR, CGH, Gene Expression Profiling, Targeted NGS, WES, WGS.

Question 17

What topic do Manchester love that will aid pharmacogenomics and other companion diagnostics?

Answer 17

Liquid biopsies, ctDNA and the like

Question 18

What are the 2 most commonly affected genes in NSCLC adenocarcinomas?

Answer 18

EGFR and KRAS

Question 19

What histology is associated with mutated EGFR in NSCLC adenocarcinomas?

Answer 19

Micropapillary and lepidic

Question 20

What drug are EGFR positive NSCLC adenocarcinomas sensitive to?

Answer 20

Geftinib

Question 21

EGFR mutations have a higher rate in who and what?

Answer 21

Never smokers, women, asians, and adenocarcinomas

Question 22

What is geftinib an alternative to for treating newly diagnosed advanced NSCLC?

Answer 22

Doublet chemotherapy

Question 23

FISH is still routinely used, usually after morphology has suggested something might be the case. What is FISH sometimes used to find?

Answer 23

ALK rearrangements, and HER2

Question 24

Immune checkpoint inhibitors do against several tumour types?

Answer 24

Downregulates the response of Treg cells. Dissociates PD-1 and PD-L1 so that T cells (like CD8) can act to kill the tumour

Question 25

PD-L1 treatment was first introduced in lung cancers. But has now been used in?

Answer 25

Melanoma, glioblastoma, multiple myeloma and many more

Question 26

PD-L1 expression can be heterogenous, it’s not normally constitutive. Where does it tend to be restricted?

Answer 26

In the T cell rich areas of the tumour, particularly the invasive margin

Question 27

What is awkward about PD-L1 expression being heterogenous?

Answer 27

Biopsy may not be representative if its taken from the centre of the tumour

Question 28

There are different PD-L1 detection assays, what must be considered?

Answer 28

The type of antibody. The threshold for test to be classed as positive that has the max benefit.

Question 29

What are the technical requirements of a PD-L1 assay before the analysis?

Answer 29

Age of block, size of block, drying and fixing time etc.

Question 30

Based on the studied response rate of tumours to PD-L1 inhibitors, what is classed as high PD-L1 expression?

Answer 30

> 50% of the tissue

Question 31

What drug is used against PD-L1 positive advanced NSCLC?

Answer 31

Pembrolizumab

Question 32

For Lung cancers that are not NSCLC, is the PD-L1 assay of any use?

Answer 32

It is a complementary test and guides but doesn’t prescribe the use of other drugs

Question 33

What are some issues with PD-L1 IHC from a biological perspective (already stated heterogeneity of tumours)

Answer 33

Genomics alterations can edit PD-L1 expression.
PD-L1 expression can be modulated by other anti-cancer therapies (chemo, radio etc.)

Question 34

What are some technological issues with PD-L1 IHC?

Answer 34

Different anti-PDL1 antibodies have different PD-L1 affinity, some don’t recognise the same epitopes on PD-L1.

Question 35

When did Pembrolizumab become an option for treating NCLSC with >50% PDL1+?

Answer 35

2016 became available, 2017 became a NICE recommended first line treatment

Question 36

In a nutshell, what are the advantages of immunotherapy agents like anti-PD-L1?

Answer 36

Improved survival compared to platinum based chemotherapy.
Less toxicity and fewer side effects than platinum based chemotherapy.

Question 37

What are the disadvantages of anti-PD-L1 and other immunotherapies?

Answer 37

High cost.
Need a specific test before the drug can be prescribed.
In the case of lung cancer, each drug is linked to a specific assay that is not interchangeable with other assays on the market at the moment.

Question 38

What is emerging as a key biomarker of sensitivity to immune checkpoint inhibitors in lung cancer?

Answer 38

A high tumour mutational burden is associated with a better response to pembrolizumab.

Question 39

What are challenges with developing companion diagnostics?

Answer 39

Defining the diagnostic cut off.
Availability of samples for testing.
Time taken to generate results.
Diversity in methods across countries.
Testing reimbursement.

Question 40

We need what to be co-developed?

Answer 40

Drugs and diagnostics

Question 41

In the future, what will be the hopes for using tumour tissue for diagnostics?

Answer 41

Take the same amount of tissue, but use it more efficiently to do deep sequencing, RNA analysis, H&E, and protein expression. (Plus use blood and imaging for continuous monitoring)