Solid Tumours Flashcards
What are the genes and variant types which are targetable in Lung Cancer?
EGFR mutations ALK rearrangements RET rearrangements ROS1 rearrangements MET amplification
Response to what treatment is associated with EGFR mutations in lung cancer?
EGFR Tyrosine Kinase inhibitors
What types of EGFR variants are activating and associated with response to EGFR TKI’s in lung cancer and what are the most common variants?
- Point mutations (Missense), small insertions and small deletions
Most common (90%)
- In frame deletions in exon 19
- Point mutation (L858R) in exon 21
Other known sensitising variants
- Exon 19 insertions
- L861Q
- G719X
- S768I
What is the most common mechanism for resistance in EGFR activating mutation positive lung cancer patients hen treated with EGFR TKI’s?
The most common resistance mechanism is the T790M mutation in EGFR.
What type of EGFR variant is associated with a poor prognosis and lack of response to EGFR TKI’s
Exon 20 insertions
What is the clinical significance of BRAF variants (V600E and non-V600E) in lung cancer?
BRAF driver variants occur in 1-2% of lung cancer cases.
BRAF V600E typically occurs in current/former smokers and do not typically occur alongside EGFR, MET ex14, RET, ALK or ROS variants.
For patients with the BRAF V600E variant, combination therapy with dabrafenib and trametinib is recommended (BRAF inhibitor and MEK inhibitor)
Non-BRAF V600E variants impact on therapy is yet to be established.
What phenotype are KRAS variants associated with in lung cancer and what are there clinical significance?
KRAS variants are associated with cigarette smoking and are associated with a shorter survival than patients who are KRAS wildtype. Patients with KRAS driver variants do not respond to EGFR TKIs.
What types of variants can be found in MET in lung cancer and what is the function of MET
MET (C-MET), the hepatocyte growth factor (HGF) receptor is a tyrosine kinase receptor that is involved in cell survival and proliferation.
Driver variants in MET include exon14 skipping mutations, MET gene copy number gain/amplification and MET overexpression.
What is the clinical significance of MET variants in lung cancer?
Capmatinib (MET inhibitor) has been approved for treatment by the FDA but is still under review by NICE.
What is the function of RET/ALK/ROS1, what types of RET/ALK/ROS1 variants are identified in lung cancer and what is the clinical significance?
RET, ALK and ROS1 aretyrosine kinase receptors involved in cell proliferation.
RET, ALK and ROS1 rearrangements can be identified in lung cancer and may occur with a number of genes (e.g. KIF5B, CCDC6) which leads to overexpression of the RET, ALK or ROS1 protein.
Patients with rearrangements in these genes have been shown to respond to RET, ALK or ROS1 tyrosine kinase inhibitors.
Under what circumstances may a Lung patient be treated with immunotherapy.
Positive PD-L1 staining (>50%)
No approved targetable genetic mutations (EGFR / ALK/ ROS1 etc)
What are the tests which can be used to detect mismatch repair deficiency in colorectal cancer?
IHC for MLH1, MSH2, MSH6 and PMS2
or
Microsatellite Instability (MSI) analysis
What proportion of colorectal cancer patients have MMR defects and what proportion can be attributed to a germline cause?
15-20% are identified as having an MMR defect
3% have a germline cause
Describe the Lynch screening pathway with IHC as the starting test
IHC for MLH1, MSH2, MSH6 and PMS2
->
If MHS2, MSH6 or PMS2 IHC is abnormal proceed to Lynch germline analysis
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If MLH1 is abnormal continue to BRAF V600E analysis
->
If BRAF V600E detected -> Likely Sporadic
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If no BRAF V600E is detected proceed to MLH1 promoter hypermethylation analysis
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If MLH1 promoter is methylated -> Likely Sporadic
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If MLH1 promoter unmethylated -> Proceed to Lynch germline analysis
Describe the Lynch screening pathway with MSI as a starting test
MSI analysis
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If MSI is normal/low -> Likely somatic
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If MSI is high (unstable) proceed to BRAF V600E analysis
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If BRAF V600E detected -> Likely Sporadic
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If no BRAF V600E is detected proceed to MLH1 promoter hypermethylation analysis
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If MLH1 promoter is methylated -> Likely Sporadic
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If MLH1 promoter unmethylated -> Proceed to Lynch germline analysis
IHC uses antibodies to detect the expression of MMR proteins in Colorectal cancers. What does decreased or abnormal staining indicate?
Absent or reduced signaling of the proteins can indicate there may be a mutation (somatic or germline) in one of those genes.
What are microsatellites and why is the analysis of these regions used to test for MMR deficiency?
Microsatellites are repetitive sequences of DNA that are at increased risk of copying errors during replication.
In tumours with a defective MMR system, errors in copying microsatellite sequences cause them to vary in length - this is known as microsatellite instability.
What are the tests used following IHC or MMR to determine wether a colorectal is likely to be sporadic and why are they used?
MLH1 promoter hypermethylation - Sporadic CRC can show loss of MLH1 protein expression cause by mutations in the promoter.
BRAF V600E testing - BRAF V600E variants are associated with sporadic mutations in MLH1
What is the clinical significance for testing for KRAS and NRAS in Colorectal cancer?
KRAS or NRAS mutations are associated with a lack of response to EGFR inhibitors. This is because the proteins operate downstream from EGFR in the RAS/RAF/MEK/ERK pathway.
What are the hotspots for KRAS and NRAS?
Exon 2 - codon 12 & 13
Exon 3 - codon 59 & 61
Exon 4 - codon 117 & 146
In both genes
What is the clinical significance of BRAF V600E (therapy related) and non codon 600 BRAF variants in colorectal cancer?
BRAF V600E -associated with a worse prognosis and lack of response to EGFR inhibitors unless given with a BRAF inhibitor
Non-V600E - Currently uncertain significance
What treatment are colorectal patients who are MSI high eligible for?
MSI-H tumours or those with MMR deficiency have been shown to respond to the PD-1 inhibitor Pembroluzima (Immunotherapy)
What are the different classes of BRAF mutations?
Class I: Found at the V600 locus, defined as those with extremely strong kinase activity
Class II: Non-Codon 600 variants with intermediate to high activity
Class III: Lack of impaired kinase activity
What is the clinical significance of the occurrence of BRAF V600 and non V600 BRAF mutations in melanoma?
V600 - Approved use of BRAF inhibitors Non-V600 - Not approved but class II may respond to BRAF inhibitors
What is the clinical significance of KIT driver variants in melanoma?
KIT driver variants are more frequently identified in acural and mucosal melanoma. Patients with KIT variants have been shown to respond to the TKI imatinib but it is not currently approved.
What is the clinical significance of NRAS driver variants in melanoma?
NRAS driver variants are associated with poor survival in local and advanced melanoma. MEK inhibitors produce a response in a minority of patients.
