Stratified medicine Flashcards
What is stratified medicine?
Targeting treatments according to characteristics shared by a group of patients (use markers)
What is Companion Diagnostics?
Determine patient eligibility prior to treatment stratification
What is HER2 and involved in what cancer?
Receptor TK in EGF family
Amplified in 20-30% early breast cancer
What prognosis does HER2 amplification have?
Poor with increased risk of recurrence
HER2+ targeted treatment
Side effect
Trastuzumab (Herceptin)
1 in 20 have heart damage so important to ID pts most likely to benefit
Example of synthetic lethal drug effect
PARP inhibitors (Olaparib) for BRCA-null cancers
Ovarian, breast & prostate
How does Olaparib work?
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
What is EGFR and implicated cancer?
Transmembrane glycoprotein receptor with extracellular protein ligands
Non small cell lung cancer
How is EGFR mutated in NSCLC?
Prognosis?
GOF variants = constitutive activation of downstream signalling pathways critical for cancer e.g. proliferation, differentiation, migration
Better prognosis than WT
How can EGFR GOF muts be targeted?
100x increased sensitivity to TKI e.g. Gefitinib that blocks ATP binding site
TKI resistant mut in EGFR
T790M in tyrosine kinase domain = altered confirmation for increased affinity to ATP
Treat with Osimertinib
Treatment for ALK and ROS1 rearrangements in NSCLC
TKI e.g. Crizotinib
Companion Dx testing for metastatic colorectal cancer
RAS/RAF testing
Ras activating mutation confers resistance to EGFR monoclonal antibody e.g. Cetuximab (counteracts inhibition of upstream EGFR)
KRAS hotspots
Exons 12, 13, 59, 61, 117, 146
What is CLL?
B lymphocytosis preventing function of normal haematopoiesis
Indolent v aggressive clinical course
Importance of TP53 testing at diagnosis of CLL
Mutated in 10% of pre-treated CLL
SNV or 17p13 deletion
Predicts refractory to traditional treatment = poor prognosis
How is TP53-mutant CLL treated?
Ibrutinib bypasses TP53 and targets B cell receptors to prevent B cell proliferation
How is CML treated?
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
Example TKIs for CML
1st line - Imatinib
2nd line - Dasatinib
3rd line - Ponatinib
Example TKI resistance mut in BCR-ABL1
T315I
What other haem malignancy is t(9;22) found in and prognosis?
B-ALL (adults and older children)
Good prognosis with TKI+intensive chemo
Example trial looking at discontinuing TKI and effect on MRD
DESTINY
Found initial de escalation required before complete stop