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Flashcards in 18.06.11 Stratified medicine Deck (27):

Define stratified medicine.

The targeting of treatments according to the shared characteristics of a group.


What are some common, non-genetic, examples of stratified medicine?

Bisphosphonates to women over 60 at risk of vertebral fractures
Lipid-lowering therapy in patients at high risk of cardiovascular event


Why is cancer seen as a good target for stratified medicine?

Range of biological markers present in tumours to separate patients into specific group for targeted therapy e.g. hormone receptors, growth factor receptors.


Taking a stratified medicine approach has benefits for several key stakeholders in the NHS and private sector. What are some of the benefits to the patients?

1. Improved healthcare due to better matching of patients needs and therapeutic benefit.
2. Reduced likelihood of adverse events and thus greater incentive to remain of therapy (particualrly relevant to pre-morbid conditions e.g. FH)
3. More informed choice of therapy
4. More rapid access to new and innovative medicines that work for patients.
5. Access to broader range of therapies supported by the NHS
6. Greater person involvement in treatment decisions and thus greater likelihood to adhere to treatment.


Taking a stratified medicine approach has benefits for several key stakeholders in the NHS and private sector. What are some of the benefits to the payers and providers?

1. More cost effective healthcare resources due to:
- improved response rates for the treatment of disease
- avoidance of side effects and increased use of effective treatments
- avoidance of treatment for those who don't need it, or won't benefit from it.

2. Improved and more specific diagnosis of diseases and their prognosis leading to more accurate forecasting on healthcare resource requirements.


Taking a stratified medicine approach has benefits for several key stakeholders in the NHS and private sector. What are some of the benefits to the pharmaceutical industry?

1. Safer, more effective medicines
2. Focussed discovery and development programmes based on more refined disease diagnosis
3. Improved decision making and potentially lower attrition
4. Earlier approval of new therapies with improved confidence in post-marketing phamacovigilance systems
5. More accurate targeting of the marketing of medicines
6. Increased differentiation of new therapies from generic therapies leading to more valued patients and a greater likelihood to adhere to treatment.


Summarise some of the key benefits of stratified medicine.

1. Increased cost-effectiveness
2. Improved patient outcomes (?) - increased compliance rates, more targeted therapies, fewer adverse reactions, greater autonomy, greater access to broader range of drugs
3. Safer, more-effective medicines
4. Increased potential for collaboration between pharmaceutical industry and diagnostics (US?)


Give two examples of how stratified medicine can be applied to breast cancer patients.

1. ERBB2 (formerly HER2) amplification and/or overexpression and treatment with herceptin.

2. BRCA1/BRCA2 germline mutations and treatement with PARP inhibitors.


What are the benefits of testing breast cancer tumour tissues for HER2 expression? How is this performed?

Found in 20-30% of early-stage breast cancer. HER2 +ve tumours are associated with a more agressive phenotype, higher disease recurrence and poorer outcome.
HER2 +ve tumours can be targeted with herceptin (trastuzumab)
Testing performed at the same time as initial biopsy/surgery by IHC. HER2 graded
0-1 = Normal amount (HER2 -ve)
2+ = moderate HER2
3+ = higher than normal level of HER2 protein (HER2 +ve)

2+ tumours are confirmed by FISH targeting the HER2/neu gene. Gives a +ve/-ve result.


What are the clinical considerations/side-effects when deciding to administer herceptin therapy?

1 ) Benefits of treatment weighed against the risk of heart disease.
56.7 women need to be treated to save one extra life from breast cancer
however 1 in 20 women can get heart damage and 1 in 51 congestive heart failure

2) ~15% of treated patients will relapse. PIK3CA activating mutations and PTEN loss have been associated with resistance.


Which patient groups are more likely to benefit from PARP-inhibitors and how do these drugs work?

Patients with a germline BRCA1/BRCA2 mutation.

1. BRCA1 and BRCA2 are tumour suppressor genes, involved in the repair of dsDNA breaks through the homologous recombination pathway

2. PARP1 is required for ssDNA break repair through base excision repair.


Give three examples of how stratified medicine can be used in lung cancers?

1. Epidermal growth factor receptor (EGFR) activating mutations and gefitinib
2. KRAS mutations
3. Echinoderm microtubule assoicated protein-like (EML4)-ALK oncogenic gene fusion and crizotinib


Which patient group is more likely to benefit from gefitinib? How does this drug work?

Gefitinib (also erloinib and afatinib) is used to treat some patients with non-small cell lung cancer (NSCLC) shown to have a EGFR-activating mutation in EGFR TK domain (exons 18-21).

1) EGFR is a cell-surface receptor for the EGF-family. EGFR controls two major cell-signalling pathways; a) cell proliferation and growth b) survival pathway.
2) EGFR is overexpressed in lung, breast, ovarian and brain tumours.
3) Gefitinib is a tyrosine kinase inhibitor that blocks the ATP-binding site of EGFR.
4) Cells with mutant EGFR are 100x more sensitive than wild-type


How is EGFR testing performed?

DNA extracted from formalin-fixed PETs. Pyrosequencing is often used to detect specific mutations in exons 18, 20 and 21 in EGFR.
Exon 19 dels and exon 20 dups can be detected using diplex fluorescent PCR and capillary electrophoresis


What is the effectiveness of gefitinib and some issues that patients may encounter following treatment with this drug?

Estimated to work in around 10% of patients with advanced NSCLC.
Secondary resistance mutations are proven to be the most common cause of acquired resistance. EGFT 7790M (ex 20) is the most common.
New drug developments targeted for this mutation.


What is the benefit of ALK testing in lung cancers?

Adult patients with lung adenocarcinoma/NSCLC and ALK-gene fusions can be treated with crizotinib, a tyrosine kinase inhibitor with a 50-60% response rate.


Which is the most common fusion partner of ALK? How does this fusion arise?

ALK most frequently pairs with EML4 and is the result of a paracentric inversion of chromosome 2 (2p21p23).
Rarer ALK fusion partners includ KIF5B and TFG.


How is ALK-gene fusion testing performed?

1. ALK over-expression can be performed by immunohistochemistry
2. FISH on FFPE tumour tissues using a break-apart probe, can be difficult as broken signals may still lay close together, appearing as a fusion.
3. RT-PCR under development but tricky due to many variant transcripts


Explain the use of KRAS, BRAF and NRAS testing in patients with colorectal cancer, in the context of stratified medicine and the use of cetuximab.

1. 50-70% of CRC are positive for a KRAS activating mutation and ~10% are positive for BRAF and/or NRAS mutations.
2. Cetuximab blocks EGFR inhibiting tumour growth
3. Patients with activating EGFR mutations do not benefit from this treatment (negative biomarker of response). i.e. only wild-type KRAS tumours will respond. KRAS treatment used in combination with chemotherpay for patients with metastatic CRC.
4.Patients with BRAF and NRAS mutations do also not benefit from these therapies.


What stratified medicine approaches can be used in treating patients with malignant melanoma?

1) BRAF mutation testing.
2) c-kit mutation testing.


What type of protein is BRAF and which signalling pathway is it found in?

BRAF is a member of the Raf kinase family of growth signal transduction protein kinases and has a role in the regulation of MAP kinase/ERK signalling pathway for cell division, differentiation and secretion (downstream of EGFR and KRAF)


For which patient groups in BRAF testing useful in? How is this performed?

Acquired BRAF activating mutations commonly occur in melanoma, CRC and lung tumours causing uncontrolled signalling. V600E is the most common (80%).

1. CRC patients with BRAF mutations do not respond to antibody based anti-EGFT therapies e.g. cetuximab.
2. Melanoma patients with metastatic disease (10-20%) with V600E mutations may benefit from BRAF inhibitors e.g. vemurafenib which has shown to shrink tumours and increase survival by a few months.

BRAF V600E mutation testing is usuallly by real-time PCR or pyrosequencing.


In which patient group is c-kit mutation testing useful?

Mucosal and acral melanoma patients with c-kit mutations may benefit from imatinib therapy. Response rates are 15-20%, lower than that for GIST.


How is a stratified medicine approach used in patients with CLL?

10% of pre-treated CLL patients has a TP53 mutation or deletion.
These patients have been shown to responds to therapies such as idelalisib, which bypasses the TP53 pathway and instead targets the B-cell receptor pathway to prevent B-cell proliferation.
TP53 mutation testing is recommended prior to testing.


What was the purpose of the CRUK Stratified Medicine Programme?

£18M partnership between government, NHS, pharma and CRUK to streamline and standardise genetic testing of tumour samples in the UK.


What did phase 1 of the the CRUK Stratified medicine programme involve?

Small scale pilot study involving 8 'Experimental Cancer Medicine Centres' recruiting patients with breast, CRC, lung, prostate, ovarian and advanced malignant melanoma.
>9000 samples taken from these patient (surplus sample from surgery) were sent to three lab hubs for molecular diagnosis.


What does phase 2 of the CRUK Stratified medicine programme involve?

Goal of advancing treatment for patients with late stage NSCLC through development of the National Lung Matrix Trial testing multiple drugs in multiple gourps of patients.
Collaboration between NHS, CRUK, AstraZenca and Pfizer,
Biopsies sent to technology hugs and result sent back to referring clinician who can recruit the patient in the arm of the clinical trial offering the drug that may most benefit them