20.06.11 Stratified medicine principles and examples

Question 1

What is stratified/ precision medicine

Answer 1

• Targeted treatment due to the characteristics shared by a group of patients.
• Uses biological markers to separate patients into specific groups and treating them by targeting a biological pathway.

Question 2

Benefits of stratified medicine

Answer 2

• Safer, more effective medicine (improved response rates, reduced side effects)
• drugs not administered to patients who won’t benefit, more cost effective.
• More refined disease prognosis
• Improved decision making
• Earlier approval of new therapies

Question 3

Review of stratified medicine in breast cancer- ERBB2

Answer 3

• ERBB2 (previously HER2) amplification or overexpression found in 20-30% early stage breast cancer
• HER2 is an EGFR (epidermal growth factor receptor)
• HER2 positive tumours are associated with more aggressive phenotype and higher disease recurrence
• Trastuzumab (Herceptin) is a monoclonal antibody specific for extracellular domain of HER2, given to patients with overexpression of HER2.
• ERBB2 testing is recommended for all new primary or metastatic BC.
• Can be done with IHC
• Confirmatory testing recommended: FISH, microarray or NGS.
• Side effect= cardiac related disease (heart failure). Benefit of treatment has to be weighed again adverse effects.
• Resistance to treatment due to cancer evolution and accumulation of genetic mutations. e.g PIK3CA and PTEN.

Question 4

Review of stratified medicine in breast cancer- BRCA1/2

Answer 4

• Patients with germline BRCA1/2 mutations at increased risk of breast and ovarian cancer.
• Absence of BRCA1/2 leads to predominantly NHEJ pathway rather than HR to repair double strand breaks, more error prone eventually leads to cancer.
• Poly(ADP-ribose) polymerase 1 (PARP1) binds to single strand breaks and involved in BER (base excision repair) and HR/ NHEJ repair of double strand breaks.
• Inhibition of PARP activity leads to synthetic lethality in mutated BRCA1/2 cancers. Inhibition causes replication fork to stall and dsDNA breaks to accumulate, leading to cell death.
• Olaparib is a PARP1 inhibitor.

Question 5

Review of stratified medicine in lung cancer- EGFR

Answer 5

-Lung cancer is 3rd most common cancer in UK and causes most cancer-related deaths worldwide.
-2 types:
small cell lung cancer (SCLC) 20-30% cases
non-small cell (NSCLC) 70-80% cases. Of which, adenocarcinoma is most common.
-Activating mutations in EGFR are in 10-30% NSCLC
-EGFR regulates cell proliferation, survival, differentiation and migration.
-Gefitinib: tyrosine kinase inhibitor directed against EGFR.
-EGFR mutations in exon 18, 19, 21 (encodes tyrosine kinase domain) are predictors for good response to gefitinib.
-Mutations in exon 20 confer resistance to gefitinib.
-NICE recommends sequencing tumour tissue prior to administration
-Acquired resistance= EGFR exon 20 mutation T790M most common.

Question 6

Review of stratified medicine in malignant melanoma- BRAF

Answer 6

• 6 most common malignancy in N. America. Cured by surgery in 80-90%. Becomes metastatic in remaining cases and often not curative.
• Often acquired mutations in BRAF.
• BRAF is a serine/threonine kinase and regulates MAPkinase/ERK signalling pathway. Affecting cell division, differentiation
• Most common BRAF activating mutation is V600E (80-90%), V600K (<20%)
• V600E indicates sensitivity to MEK inhibitors. Better response when BRAF inhibitors administered as well
• Screening for V600E by IHC, real time PCR, NGS, sanger