Molecular Pathology of Lung Cancer

Question 1

Lung cancer is how common and how deadly compared to other cancers?

Answer 1

The third most common cancer, but the cause of most cancer deaths (21%)

Question 2

What is Stage I lung cancer?

Answer 2

1 nodule in one place, <3cm

Question 3

What is Stage II lung cancer?

Answer 3

3-5cm tumour. Some affected lymph nodes from metastatic cells

Question 4

What is Stage III lung cancer?

Answer 4

More metastasis, both sides of lung affected. Tumour >5cm.

Question 5

What is Stage IV lung cancer?

Answer 5

Tumour metastasis to distant site. Tumour >7cm.

Question 6

Most lung cancer is diagnosed when?

Answer 6

At stage IV

Question 7

What is the 1 year survival of Stage IV cancer when detected?

Answer 7

20%

Question 8

How do you sample lung cancers?

Answer 8

Resections in early stages.
Core biopsy or cytology for stage 3 and 4 diagnosis and staging…

Question 9

What do we want to maximise in lung cancer patients?

Answer 9

The use of their tissue/cores/blocks.

Question 10

What is the most common type of lung cancer?

Answer 10

NSCLC 80%

Question 11

What is the less common type of lung cancer?

Answer 11

Small Cell carcinomas 20%

Question 12

What are the histo features of small cell LC?

Answer 12

Big nuclei, staining blue from the DNA replicating

Question 13

How is SCLC treated typically?

Answer 13

chemotherapy

Question 14

What are the main two types of NSCLC?

Answer 14

50% Adenocarcinoma.
30% Squamous cell carcinoma (appears pinker, produces keratin).

Question 15

How is NSCLC treated typically?

Answer 15

Lobectmy surgery if early enough. Otherwise chemo or radiotherapy.

Question 16

In 2004 a subset of lung adenocarcinomas were found to have what type of mutation where?

Answer 16

Activating mutations in the TK domain of EGFR transmembrane receptor.

Question 17

What do EGFR mutations in lung cancers typically do?

Answer 17

Causes abnormal dimerisation so they don’t need EGFR

Question 18

What makes EGFR mutations able to be targeted?

Answer 18

Mutant EGFR can have increased binding affinity for TKIs over ATP when compared to WT protein. Treatment increases progression free survival.

Question 19

What mutations are very high in an Asian never smoker population?

Answer 19

EGFR

Question 20

Which mutations seems particularly associated with smoking?

Answer 20

KRAS mutations

Question 21

EGFR mutations tend to occur in which type of adenocarcinomas?

Answer 21

Well differentiated adenocarcinomas with a lepidic pattern of growth (on surfaces, not penetrating deeper)

Question 22

How does ALK typically get affected in LC?

Answer 22

Get’s rearranged forming a chimeric protein. The TK domain of ALK is given an N terminal partner, often EML4. It leads to an activated TK with transforming abilities that drives carcinogenesis

Question 23

What is the TKI that treats ALK fusion LC with a response rate of 65%?

Answer 23

Crizotinib

Question 24

Who do we test for ALK fusions?

Answer 24

All advanced adenocarcinomas and any not otherwise specified

Question 25

Who usually has ALK fusions?

Answer 25

Young never smokers

Question 26

What can normally be seen by Histo for ALK fusion LC?

Answer 26

Signet ring/goblet mucin cells. Mucin fills cells, pushes nucleus to the side

Question 27

What's the ALK fusion rate between UK and Asia?

Answer 27

2% for UK, 11% for Asia

Question 28

How do you normally detect the EML4 inversion on chr2 that fuses in the middle of ALK?

Answer 28

FISH with breakapart probes

Question 29

What used to be the first screen for ALK fusions?

Answer 29

ALK IHC with a sensitivity of 99%. Any weak staining would be checked with FISH or NGS. If negative results on IHC, normally confident it would be true.

Question 30

What's on the pansolid NGS panel at Manchester?

Answer 30

ALK, BRAF, EGFR, KRAS, MET

Question 31

EGFR variants, and ALK and ROS1 rearrangements tend to be in...?

Answer 31

Adenocarcinomas

Question 32

How do you test for ROS1?

Answer 32

NGS, FISH, or IHC strongly positive

Question 33

BRAF mutations are in lung cancer but are mainly in what other cancer?

Answer 33

Melanoma

Question 34

Which BRAF mutation is most common in LC and why is it a good thing?

Answer 34

V600E, it is treatable.

Question 35

What is V600E associated with morphologically and survival wise in Lung cancer?

Answer 35

Micropapillary features in 80% of patients. Shortest disease free and lowest survival rates.

Question 36

KRAS mutations are associated with smoking. Which is the most common in NSCLC which can be treated with sotorasib?

Answer 36

G12C in 13% of NSCLC.

Question 37

Which histology pattern has the best prognosis?

Answer 37

Lepidic, just on surface (tends to be well differentiated)

Question 38

Which histology pattern has an intermediate prognosis?

Answer 38

Acinar

Question 39

What are the 5 listed histology patterns?

Answer 39

Lepidic, Acinar, Solid, Papillary and Micropapillary

Question 40

TRK receptors A, B and C (NTRK) signal to cause what?

Answer 40

Proliferation, survival, invasion and angiogenesis

Question 41

What drugs are used against NTRK fusions?

Answer 41

Larotrectinib and Antrectinib

Question 42

NTRK fusion rates are rare. But they are more common in rare cancers. name which rare cancers.

Answer 42

Infantile fibrosarcoma, secretory breast cancer, congenital mesoblastic nephroma

Question 43

IHC staining is good for detecting NTRK fusions, yes or not?

Answer 43

Good at 1 and 2, not good at 3 so much.

Question 44

MET is mutated in what percentage of squamous LC and adenocarcinomas?

Answer 44

3% of squamous LC. 8% of adenocarcinomas

Question 45

What changes are relevant in MET in LC?

Answer 45

Exon 14 splicing alterations that lead to skipping. Or gene amplification.

Question 46

So NSCLC is gradually classified based on:

Answer 46

Histology then molecular pathology.

Question 47

What are the two ways a tumour might become drug resistant?

Answer 47

Small subclone with an alteration already hangs around and grows once other cells are killed (can be mono or polyclonal). Gain of new mutations over time.

Question 48

How can ALK positive lung cancers sometimes be mechanically resistant?

Answer 48

Drugs unable to reach brain metastases

Question 49

How do LCs get EGFR treatment resistance?

Answer 49

After a year many get resistance that can be from MET, HER2, BRAF or PIK3CA mutations. OR T790M in EGFR itself half the time.

Question 50

Which EGFR mutations have the best treatment response?

Answer 50

Exon 19 deletion and L858R in exon 21

Question 51

What does the EGFR T790M variant do?

Answer 51

Reduces the binding affinity of TKIs so EGFR binds ATP more, leading to more proliferation

Question 52

We're now on 3rd and 4th gene EGFRi. Which one works well against T790M?

Answer 52

Osimertinib.

Question 53

What does C797S in TK domain of EGFR fo?

Answer 53

Prevents Osimertinib and other TKIs from working

Question 54

How is PD-L1 testing also important?

Answer 54

Might need to use a drug in combination with one targeting PD-L1 if highly expressed.