Stratified medicine

Question 1

What is stratified medicine?

Answer 1

Targeting treatments according to characteristics shared by a group of patients (use markers)

Question 2

What is Companion Diagnostics?

Answer 2

Determine patient eligibility prior to treatment stratification

Question 3

What is HER2 and involved in what cancer?

Answer 3

Receptor TK in EGF family

Amplified in 20-30% early breast cancer

Question 4

What prognosis does HER2 amplification have?

Answer 4

Poor with increased risk of recurrence

Question 5

HER2+ targeted treatment

Side effect

Answer 5

Trastuzumab (Herceptin)

1 in 20 have heart damage so important to ID pts most likely to benefit

Question 6

Example of synthetic lethal drug effect

Answer 6

PARP inhibitors (Olaparib) for BRCA-null cancers

Ovarian, breast & prostate

Question 7

How does Olaparib work?

Answer 7

PARP facilitates repair of ssDNA breaks by base excision repair

PARP inhibition = accumulation of SSB = conversion to DSB for homologous recombination repair

BRCA-null = HR deficient, so accumulation of DSB from PARPi = apoptosis of tumor cells

Normal cells are protected by 1x BRCA-WT

Question 8

What is EGFR and implicated cancer?

Answer 8

Transmembrane glycoprotein receptor with extracellular protein ligands

Non small cell lung cancer

Question 9

How is EGFR mutated in NSCLC?

Prognosis?

Answer 9

GOF variants = constitutive activation of downstream signalling pathways critical for cancer e.g. proliferation, differentiation, migration

Better prognosis than WT

Question 10

How can EGFR GOF muts be targeted?

Answer 10

100x increased sensitivity to TKI e.g. Gefitinib that blocks ATP binding site

Question 11

TKI resistant mut in EGFR

Answer 11

T790M in tyrosine kinase domain = altered confirmation for increased affinity to ATP

Treat with Osimertinib

Question 12

Treatment for ALK and ROS1 rearrangements in NSCLC

Answer 12

TKI e.g. Crizotinib

Question 13

Companion Dx testing for metastatic colorectal cancer

Answer 13

RAS/RAF testing

Ras activating mutation confers resistance to EGFR monoclonal antibody e.g. Cetuximab (counteracts inhibition of upstream EGFR)

Question 14

KRAS hotspots

Answer 14

Exons 12, 13, 59, 61, 117, 146

Question 15

What is CLL?

Answer 15

B lymphocytosis preventing function of normal haematopoiesis

Indolent v aggressive clinical course

Question 16

Importance of TP53 testing at diagnosis of CLL

Answer 16

Mutated in 10% of pre-treated CLL

SNV or 17p13 deletion

Predicts refractory to traditional treatment = poor prognosis

Question 17

How is TP53-mutant CLL treated?

Answer 17

Ibrutinib bypasses TP53 and targets B cell receptors to prevent B cell proliferation

Question 18

How is CML treated?

Answer 18

Target the diagnostic t(9;22)(q34;q11) with tyrosine kinase inhibitors that target ATP binding site preventing phosophorylation of substrates and activation of downstream pathways

Question 19

Example TKIs for CML

Answer 19

1st line - Imatinib
2nd line - Dasatinib
3rd line - Ponatinib

Question 20

Example TKI resistance mut in BCR-ABL1

Answer 20

T315I

Question 21

What other haem malignancy is t(9;22) found in and prognosis?

Answer 21

B-ALL (adults and older children)

Good prognosis with TKI+intensive chemo

Question 22

Example trial looking at discontinuing TKI and effect on MRD

Answer 22

DESTINY

Found initial de escalation required before complete stop