Session 11 - Basic molecular pathology

Question 1

Lung - how can this be investigated

Answer 1

• Broncoscopy - accessing the lung through the airway (espeically if cancer is central)
• CT guided biopsy (if tumour is more peripheral)
• If tumours are producing pluera effusion - can remove some of this

NOTE - When take samples from the tumour, also take samples from the nearest lymph nodes e.g. mediastinal lymph nodes if lung cancer

Question 2

Mediastinal lymph nodes EBUS

Answer 2

This allows the doc to takes a sample of lymph node.

This will help with cancer staging

Question 3

Aside - What cells surround the alveoli

A

B

C

Answer 3

Pneumocytes

A - Arterial supply

B - Bronchioles

C - pneumocytes surrounding the alveoli

Question 4

What are the most common types of lung cancer?

What are other types of lung cancer?

Answer 4

Squamous-cell carcinoma
Large-cell carcinoma
Adenocarcinoma

These three are Non-small cell lung cancers (80-85% of all lung cancers)

Another type of lung cancer:
Small cell lung cancer

Question 5

What does adenocarcinima look like?

Answer 5

Question 6

List some lung molecular markers for non-small cell lung carcninoma

How could you detect them?

Answer 6

EGFR

ALK

ROS1

KRAS

BRAF

RET

RB1

PDL1

FISH could be used to detect these mutations

Question 7

EGFR (Lung molecular marker)

• what is this? What does this mean for the cell cycle?
• group of people?
• which group of cancers?
• medications?

Answer 7

• Oncogene
• Transmembrane RTK (Receptor tyrosine kinase) - a mutation, or damage, in a gene causes the EGFR to remain stuck in the “on” position. This “drives” abnormal cell growth.
  Leads to constant activation of the RAS pathway, leading to generation and proliferation
• EGFR-positive non small cell lung cancer (NSCLC)
• Medications: Anti EGFR TKI (tyrosine kinase inhibitor) drugs e.g. Gefitinib
• Group: 10-15% white, 60% asian
• Pitfall - Drug resistance, not all mutations respond to this drug

Question 8

ALK (Lung molecular marker)

• what is this
• which group of people
• medication
• type of lung cancer

Answer 8

• Anaplastic Lymphoma Kinase (receptor tyrosine kinase)
• Activation of downstream signals and cell proliferation and survival etc
• Type of lung cancer: NSCLC
• Common to see in: YOUNG and NEVER SMOKED
• ATP kinase inhibitors e.g. Crizotinib
  (but pitful - drug resistance, tumour evolve and not all cell mutations respond to this drug)

Question 9

ROS1

• Type of mutation
• Type of lung cancer
• Medications

Answer 9

Oncogene
RTK insulin receptor

2% of NSCLC - adenocarcinomas

ATP Kinase inhibitor e.g. Crizotinib

Question 10

KRAS

• Type of mutation
• Type of lung cancer
• Group of people
• Medications

Answer 10

Oncogene

25% of adenocarcinoma

SMOKERS

No specific meds yet - clinical trials ongoing

Question 11

Tumour suppressor genes - which cancers is p53 mutated in?

Answer 11

• 50% of NSCLC (especially Squamous cell carcinomas)
• 80% Small cell carcinomas

Question 12

Tumour suppressor genes - RB1 and myc mutated in…

Answer 12

RB1 and myc mutated in:
Small Cell carcinomas

Question 13

Immunotherapy

• How does this work?
• Medication?
• Problems with med?

Answer 13

Tumour cells can express PDL1 receptors. T cells produce PD1 as the receptor, then a complex of PDL1 (tumour) and PD1 (T cell) forms. This leads to the T cells not recognising the tumour cell as being foreign/bad.
Note – if the tumour didn’t have PDL1, the T cell would recognise it as foreign and the Tc would kill the tumour cell.

Medication – To inhibit the PDL (programmed death ligand) or its receptor with a monoclonal antibody
E.g. Nivolumab/Pembrolizumab against PD1 receptor
e.g. Atezolizumab and Duralumba against PDL1 (ligand)
This recereves T cell exhaustion and results in activation of host anti-tumour immune response – cancer cells then die.

Pitfalls: Inability to predict treatment efficacy and side effects

Question 14

Bit of an overlap here, but…

Growth factors

• examples
• there receptors?

Answer 14

Cancer cells produce growth factors to stay alive and proliferate
Low requirement for growth factors (i.e. don’t need much)
E.g.:
PDGF (Platelet derived growth factor) - angiogenesis, stromal proliferation
TGF beta (Transforming growth factor) - angiogenesis, interaction with lymphocytes and macrophages (suppress immune response) and production of extracellular matrix

Tyrosine kinase receptors:
EGFR, etc…

EGFR expressed on epithelial cells: amplified and overexpressed in lung SqCC and adenocarcinoma and breast cancer (anti EGFR drugs are afatinib, gefitinib, Erlotinib

Question 15

MELANOMA…

Question 16

Look at the pic, what type of primary cancer is this likely to be?

Answer 16

Melanoma - can see the brown pigment (melanin)

Question 17

What mutations are very common in melanoma?

Answer 17

BRAF mutations - look for V600E mutation (45% of melanomas have BRAF mutations)
NRAS (15% of melanomas have NRAS mutations)

-> This mutation leads to the Activation of MAPK (mitogen activated protein pathway)

Question 18

What treatments are really good for melanoma?

• overall name
• when are each used?
• then go into specifics i.e. names of drugs…

Answer 18

- Target therapies e.g. anti-BRAF
Anti-BRAF drugs - Dabrafenib and Trametinib
— but tumour can develop resistance in approx. 6 months

- Immunotherapies e.g. PDL1
First line treatment in patients with stage IV disease lacking BRAF mutation
The treatment blocks the PDL1 ligand from binding to receptor or blocks the PD1 receptors, this allows the T cells to restore its normal immune function = increase in cytokine production and cytolysis
e.g. Nivolumab and Pembrolizumab

Question 19

Future cancer treatment

Answer 19

Personalising treatments further - combination of drug targetting specific mutations…

• including immunotherapies
  e.g. Metastatic urothelial carcinoma - PDL1
  Head and neck cancers mets - PDL1
  Colorectal cancer