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Cancer Genetics > Lung and Colon Cancers > Flashcards

Lung and Colon Cancers Flashcards

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1
Q

What is neo-adjuvant treatment?

A

Neo-adjuvent - treatment given before definitive (curative) treatment.

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2
Q

What is concurrent treatment?

A

Concurrent - given along side definitive treatment.

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3
Q

What is adjuvant therapy?

A

Adjuvant - treatment given after attempt at cure to reduce the changes of incurable recurrence.

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4
Q

What cancer treatments are available?

A
  • Radiotherapy - can be used to treat/cure localised cancers.
  • Chemotherapy - often used for more disseminated disease - can be curative in lymphoman and germ cell cancers.
  • Surgery - used as mainstay of treatment for many tumours - will be curative as long as the tumour hasn’t spread. Will essentially be curative in all the cases where radiotherapy is used - surgery used more because deeper tissues are harder to treat with radiotherapy.
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5
Q

What is cancer staging and what is it used for? Outline the TNM scheme for defining tumour stage.

A

Defines prognosis:
- maps out local, regional and distant spread

  • Varies by tumour site
  • TNM scheme used a lot
  • T-size / depth of invasion - will be variations in how T-stage will be measured for different cancers.
  • N- presence or absence of lymph node invasion.
  • M- presence or absence of metastases
  • Staging informs management - e.g. spread usually indicative of poor prognosis and may choose not to treat.
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6
Q

What methods/tools can be used for staging tumours?

A
  • CT scanning
  • Positron Emission Technology (PET) - needs tumour to be metabolically more active - inflammation can give false signal.
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7
Q

Overview of Lung Cancer:

A
  • 2nd most common cancer in the UK (after breast cancer).
  • Most common cause of cancer related death.
  • Heterogeneous disease - most common types are squamous cell carcinoma, small cell carcinoma, adenocarcinoma.
  • Usually presents with advanced disease (stage IV) - few pain receptors in lungs so tumours can grow locally - often coughing up blood is the first sign.
  • Poor prognosis - median survival is approximately 10 months.
  • Standard chemo - OS-12 months, RR 30-25%. Given over 3 months and adds about 2 months.
  • Newer agents - interest in identifying sub-groups more likely to benefit by predictive markers.
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8
Q

What is the prognosis for lung cancer in general and how is it treated?

A
  • Usually presents with advanced disease (stage IV) - few pain receptors in lungs so tumours can grow locally - often coughing up blood is the first sign.
  • Poor prognosis - median survival is approximately 10 months.
  • Standard chemo - OS-12 months, RR 30-25%. Given over 3 months and adds about 2 months.
  • Newer agents - interest in identifying sub-groups more likely to benefit by predictive markers.
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9
Q

What is the difference between predictive and prognostic markers?

A

Predictive markers indicate whether a tumour is likely to be responsive to a treatment.

Prognostic markers indicate the likely outcome for the patient.

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10
Q

What is a good pathway for targeting in Lung cancers?

A

EGFR pathway

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11
Q

Overview the EGFR pathway in treatment of lung cancer.

A

EGFR pathway:

  • Over-expressed/mutated in multiple tumours.
  • Who might benefit from therapies?
  • Biologics can be used - Cetuximab (chimeric antibody),
    Panitumimab (fully humanised antibody) - both targeted to the extracellular portion of the EGF receptor. Identify different epitopes of EGFR.
  • As EGFR is a TK it can be targetted by Tyrosine Kinase inhibitors such as Erlotinib / Gefitinib.
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12
Q

What therapies can be used to specifically target cancers with mutations in the EGFR pathway?

A
  • Biologics can be used - Cetuximab (chimeric antibody),
    Panitumimab (fully humanised antibody) - both targeted to the extracellular portion of the EGF receptor. Identify different epitopes of EGFR.
  • As EGFR is a TK it can be targetted by Tyrosine Kinase inhibitors such as Erlotinib / Gefitinib.
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13
Q

What pathways does EGFR primarily signal through?

A
  • EGFR signals primarily through the RAS/RAF signalling pathway - activates the MAPK pathway downstream = results in signals that lead to proliferation and inhibit apoptosis.
  • Small proportion of RGFR signalling also goes through the PI3K pathway which culminates in the activation of mTOR which then translocates to the nucleus and activates the downstream targets.
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14
Q

Outline the mutations of interest in the EGFR pathway which may be seen in lung cancers.

A
  • EGFR is expressed in about 65% of all lung cancers.
  • EGFR mutated in cancers via a number of different mechanisms and these are important in deciding how the pathways should be targeted.
  • EGFR copy number changes leading to up-regulation of receptor in about 35% lung cancers - number or receptor molecules on cancer cell increased but they are still normal wt molecules that can be targeted using the appropriate biologics.
  • EGFR activating mutations in TK domain of EGFR seen in 15% - can become targets of TKIs - may or may not be good targets for biologics.
  • 20% of lung cancers have a KRAS mutation - no point in targettng EGFR as the activation of the pathway is downstream. KRAS and EGFR mutations are mutually exclusive.
  • PTEN mutations in about 65% of lung cancers - probably driven by activation of PI3K signalling pathway.
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15
Q

Outline some trials that have been undertaken to ascertain the benefits of targeted treatments for lung cancers.

A
  • As a first line therapy - FLEX-EGFR expressing NSCLC - used chemo + cetuximab/chemo - 1 month survival benefit using cetuximab (11 months compared to 10 months).
  • As a second line therapy - Erlotinib was found to give better results when used as a second line therapy. Erlotinib vs BSC - 6 vs 4 months. May be more pronounced in adenocarcinoma cases in non-smokers, cases of Asian origin.
  • NICE - recommended that cetuximab is not used in first line setting because the benefit is very minor. Generally NICE won’t recommend drugs unless they give at least 3 months survival benefit. NICE does support using erlotinib as a second line treatment.
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16
Q

Are any bologics or TKIs recommended by NICE to be used in the case of lung cancers?

A
  • Biologics can be used - Cetuximab (chimeric antibody),
    Panitumimab (fully humanised antibody) - both targeted to the extracellular portion of the EGF receptor. Identify different epitopes of EGFR.
  • As EGFR is a TK it can be targetted by Tyrosine Kinase inhibitors such as Erlotinib / Gefitinib.
  • As a first line therapy - FLEX-EGFR expressing NSCLC - used chemo + cetuximab/chemo - 1 month survival benefit using cetuximab (11 months compared to 10 months).
  • As a second line therapy - Erlotinib was found to give better results when used as a second line therapy. Erlotinib vs BSC - 6 vs 4 months. May be more pronounced in adenocarcinoma cases in non-smokers, cases of Asian origin.
  • NICE - recommended that cetuximab is not used in first line setting because the benefit is very minor. Generally NICE won’t recommend drugs unless they give at least 3 months survival benefit. NICE does support using erlotinib as a second line treatment.
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17
Q

What can we test to try and establish what biologics/TKIs are likely to best treat a certain lung cancer (if any)?

A
  • Interested in identifying EGFR sub groups who will benefit from therapy.
  • Activating mutations in exon 19 and 21 of EGFR receptor.
  • Occurs in 30% asian and 8% caucasians.
  • Mutually exclusive with KRAS mutations.
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18
Q

What is the other major targetable mutation found in lung cancers other than those in EGFR?

A

ALK (Anaplastic Lymphoma Kinase).

ALK is a recently discovered kinase whose aberration is important in:

  • Anaplastic lymphoma
  • Neuroblastoma

In lung cancer it has been described with a different mechanism of activation - usually a fusion with the ELM4 gene to make ELM-ALK. Results due to an inversion within the short arm of chromosome 2.

ALK is a potent oncogene.

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19
Q

In what types of cancer do ALK mutations occur?

A

ALK is a recently discovered kinase whose aberration is important in:

  • Anaplastic lymphoma
  • Neuroblastoma

In lung cancer it has been described with a different mechanism of activation - usually a fusion with the ELM4 gene to make ELM-ALK. Results due to an inversion within the short arm of chromosome 2.

ALK is a potent oncogene.

20
Q

What type of ALK mutations are seen in lung cancer?

A

In lung cancer ALK has been described with a different mechanism of activation - usually a fusion with the ELM4 gene to make ELM-ALK. Results due to an inversion within the short arm of chromosome 2.

ALK is a potent oncogene.

21
Q

Outline ELM4-ALK mutations seen in lung cancers and what lung cancers they are specifically associated with.

A
  • Present in 4-7% of lung cancers.
  • Specific phenotype.
  • Mainly seen in adenocarcinomas in younger patients and light/non-smokers.
  • The ELM4-ALK mutation can be inhibited by crizotinib which is a TKI.
22
Q

What % of lung cancers are the ELM4-ALK mutations present in?

A
  • Present in 4-7% of lung cancers.
23
Q

What can the ELM4-ALK mutation seen in 4-7% of lung cancers be inhibited by?

A
  • The ELM4-ALK mutation can be inhibited by crizotinib which is a TKI.
  • Very effective drug.
  • Only a small % of lung cancers have the ELM4-ALK mutations - is it worth the cost of testing for it?
24
Q

Lung Conclusions:

A
  • EGFR-activating mutations can be targeted with TKIs - role of biologics less certain.
  • ELM4-ALK fusion protein tumour patients live substantially longer with TKI treatment. Only took 4 years from discovery to clinical use for the ELM4-ALK TKI.
25
Q

What are the 3 main uses of genetic testing in CRC?

A

1) . The use of tests to decide whether to give adjuvant therapy in patients with Duke’s B CRC.
2) . Predicting response to chemo-radiation in rectal cancer.
3) . KRAS testing in predicting responsiveness to EGFR therapy and stratifying patients appropriately.

26
Q

Overview CRC.

A
  • CRC is the 3rd most common cancer in the UK and the 2nd most common cause of cancer death.
27
Q

What is the purpose of adjuvent therapy in CRC?

A
  • Adjuvant therapy is given in CRC cases to reduce the risk of incurable recurrence of the cancer.
  • Dukes’ B 5Yr Survival = 70%
  • Dukes’ C 5Yr Survival = 50%
  • Definite benefit of adjuvant therapy in Dukes’ C tumours as outlook is fairly poor. However, Dukes’ B tumours are a mixed bag. Some B’s have a very good outcome whereas others have a very poor outcome.
  • Prognostic factors for Dukes’ B tumours have been identified and can help us decide whether to give adjuvant therapies.
  • Prognostic factors include T3 vs T4, EMVI (vascular invasion), R1, inadequate LN harvest.
  • Benefit from adjuvant chemotherapy in Dukes’ B stage tumours is only about 3% overall - margin may be bigger in poor risk groups. Maybe molecular testing can help?
28
Q

What is the 5yr survival for Dukes’ B CRC?

A

Dukes’ B 5Yr Survival = 70%

29
Q

What is the 5yr survival for Dukes’ C CRC?

A

Dukes’ C 5Yr Survival = 50%

30
Q

What prognostic factors can be used to decide whether to give adjuvant therapy in in patients with Dukes’ B CRC tumours.

A
  • T4 vs T3
  • EMVI - vascular invasion
  • R1 - incomplete resection
  • Inadequate lymph node harvest - don’t usually stage the tumour properly and may end up with an inappropriately low staged tumour.
31
Q

What is the benefit from adjuvant chemotherapy in Dukes’ B stage tumours is only about 3% overall.

A
  • Benefit from adjuvant chemotherapy in Dukes’ B stage tumours is only about 3% overall - margin may be bigger in poor risk groups. Maybe molecular testing can help?
32
Q

What are the 2 main pathways along which CRC tumours develop?

A

1) . The chromosomal instability pathway (CIN tumours) - classical pathway involving a mutation of APC and ultimately P53 resulting in adenocarcinoma.
2) . A number of tumours also develop through the microsatellite instability pathway where they have slightly different features and have a slightly different spectrum of mutations to those seen in the CIN pathway. They are driven initially by the inactivation of MMR proteins (MLH1, MSH2, PMS2, MSH6)

33
Q

What is the function of MMR proteins? How do they work?

A
  • They are involved in removing mutations such as base mismatches and also insertion deletion loop mutations.
  • MLH1 and PMS2 form one dimer and MSH2 and MSH6 form another dimer.
  • On the formation of a mismatch the MSH2/MSH6 dimer binds onto the site of mismatch - the MLH1/OMS2 dimer is then recruited and it activates an excision pathway to remove the mismatch and repair the mutation.
  • Loss of function or expression of any of the 4 MMR proteins results in failure of mismatch repair and an increased mutation rate.
  • Mismatch repair deficiency results in microsatellite instability.
34
Q

What is the cause of microsatellite instability.

A
  • Mismatch repair deficiency results in microsatellite instability.
35
Q

What side of the colon do MMR deficient tumours tend to grow on?

A
  • The RHS of the colon
36
Q

What side of the colon do tumours with KRAS mutations tend to grow on?

A
  • Grow on both sides = fairly constant
37
Q

What side of the colon do tumours with BRAF mutations tend to grow on?

A
  • The RHS of the colon (commonly associated with MMR deficiency).
38
Q

Are MMR mutations always hereditary?

A
  • Abnormalities in MMR result in MSI - can be inherited or acquired.
  • Acquired defects occur in 10-15% of all CRC tumours - acquired (somatic) defect is usually methylation of the MLH1 promoter.
  • MMR status can be used as a prognostic (what is the likely outcome?) and predictive (will therapy x work?) marker.
  • Evidence that in Dukes’ B tumours deficiency in mismatch repair confers a good prognosis but it also indicates that 5-FU chemotherapy is likely to be poor (and have a negative consequence).
  • In Dukes’ C possibly no difference in survival with MMR status.
39
Q

In somatic CRC cancer what does the presence of defective MMR indicate?

A
  • MMR status can be used as a prognostic (what is the likely outcome?) and predictive (will therapy x work?) marker.
  • Evidence that in Dukes’ B tumours deficiency in mismatch repair confers a good prognosis but it also indicates that 5-FU chemotherapy is likely to be poor (and have a negative consequence).
  • In Dukes’ C possibly no difference in survival with MMR status.
40
Q

Overview rectal cancer.

A
  • Usually have neo-adjuvant chemo-radiation prior to surgery.
  • A proportion don’t respond to it whilst others show almost complete regression of tumour.
  • No-resonse = much less likely to have surgery = poorer survival.
  • Need predictive markers!
41
Q

What does the response to neo-adjuvant therapy indicate about prognosis in rectal cancer?

A
  • Usually have neo-adjuvant chemo-radiation prior to surgery.
  • A proportion don’t respond to it whilst others show almost complete regression of tumour.
  • No-resonse = much less likely to have surgery = poorer survival.
42
Q

Outline the potential markers that may indicate whether a rectal cancer is going to respond to additional chemo therapy.

A
  • Enhancement in the Thymidylate Synthetase gene.
  • Thymidylate Synthtase is a target of 5-FU - it is involved in the production of thymidine residues which allows the synthesis of DNA.
  • 5-FU inhibits TS and therefore prevents DNA synthesis - 5-FU also incorporates as a nucleotide analog into RNA and thus produces an abnormal RNA species which will then result in apoptosis because the proteins cannot be translated normally.
  • Overexpression of the TS gene (TYMS) is linked to poorer prognosis.
  • TYMS has a 28bp repeat in the 5’ UTR which acts as an enhancer (TS 5’ enhancer region - TSER). Usually 2 or 3 repeats (2R/3R) although can be up to 9. More repeats of enhancer associated with higher TS expression and poorer prognosis.
  • Studies found that good prognosis of rectal tumours associated with TSER *2 and bad prognosis associated with TSER *3 or *4. Good prognosis given standard chemo-RT, poor prognosis given chemo-RT and extra drug. Good and poor prognosis tumours then developed identical prognosis = clinical use of genetic tests in dictating management of tumours.
43
Q

How does 5-FU work?

A
  • Thymidylate Synthtase is a target of 5-FU - it is involved in the production of thymidine residues which allows the synthesis of DNA.
  • 5-FU inhibits Thymidylate Synthtase and therefore prevents DNA synthesis - 5-FU also incorporates as a nucleotide analog into RNA and thus produces an abnormal RNA species which will then result in apoptosis because the proteins cannot be translated normally.
44
Q

What relation do Thymidylate Synthase levels have on rectal cancer prognosis?

A
  • Enhancement in the Thymidylate Synthetase gene.
  • Thymidylate Synthtase is a target of 5-FU - it is involved in the production of thymidine residues which allows the synthesis of DNA.
  • 5-FU inhibits TS and therefore prevents DNA synthesis - 5-FU also incorporates as a nucleotide analog into RNA and thus produces an abnormal RNA species which will then result in apoptosis because the proteins cannot be translated normally.
  • Overexpression of the TS gene (TYMS) is linked to poorer prognosis.
  • TYMS has a 28bp repeat in the 5’ UTR which acts as an enhancer (TS 5’ enhancer region - TSER). Usually 2 or 3 repeats (2R/3R) although can be up to 9. More repeats of enhancer associated with higher TS expression and poorer prognosis.
  • Studies found that good prognosis of rectal tumours associated with TSER *2 and bad prognosis associated with TSER *3 or *4. Good prognosis given standard chemo-RT, poor prognosis given chemo-RT and extra drug. Good and poor prognosis tumours then developed identical prognosis = clinical use of genetic tests in dictating management of tumours.
45
Q

What KRAS and ant-EGFR therapies may be used to treat CRC? What is predictive of non-response to anti-EGFR therapies.

A
  • Almost all CRCs express EGFR
  • EGFFR amplifications and mutations also occur
  • EGFR would therefore seem to be a good target for therapy
  • However, some tumours found to respond but others didn’t
  • The discriminator was found to be KRAS mutation - not EGFR expression.
  • KRAS is downstream of EGFR so targeting EGFR in these cases is pointless.
  • Subsequently BRAD and possibly PIK3CA also found to confer resistance to EGFR therapies.
  • Thus the presence of KRAS mutation is predictive of non-response to anti-EGFR therapies.
46
Q

Overview: CRC

A
  • TNM for staging cancers and predicting overall survival still the most universal and widely applicable system.
  • Molecular genetic tests are beginning to influence the decision to treat a patient at all, as well as the choice of drugs.
  • We are in the early era of tailored treatment. The use of genetic testing is only going to increase.

Cancer Genetics (21 decks)

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