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year 4 CDM 2 > Case 15: chemo > Flashcards

Case 15: chemo Flashcards

1
Q

Ibrutinib, acalabrutinib (targeted chemo therapies)

A
  • B cell receptor inhibitor, Bruton tyrosine kinase inhibitor (BTKi)
  • Chronic lymphocytic leukaemia, mantle cell lymphoma
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2
Q

Imatinib, dasatinib, nilotinib, ponatinib (targeted chemo therapies)

A
  • Tyrosine kinase inhibitor
  • Stopped translocation of the Philadelphia chromosome
  • Chronic myeloid leukaemia, Philadelphia positive Acute lymphoblastic leukaemia
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3
Q

Venetoclax (targeted chemo therapies)

A
  • B cell 2 inhibitor: protein which maintains survival in cancer cells
  • Chronic lymphocytic leukaemia, acute myeloid leukaemia
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4
Q

Midostaurin

A

FLT3 inhibitor
Acute myeloid leukaemia

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5
Q

Other agents: cancer treatment

A
  • Proteosome inhibitors: Bortezomib (Velcade), ixazomib, carfilzomib
  • Immunomodulatory agents: Lenalidomide, thalidomide.
  • Used in Myeloma
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6
Q

Common chemo regimes for blood cancers

A
  • AML: DA
  • CLL: FCR
  • Non Hodgkins lymphoma: R-CHOP
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7
Q

Bone marrow transplant

A
  • HSCT = BMT (bone marrow transplant)
  • Can be Autologous (own cells) or Allogenic (Someone else’s cells)
  • An immune system transplant
  • Chemotherapy +/ Radiotherapy Conditioning beforehand
  • Only curative treatment for many Haematological diseases
  • <70 years old
  • Why do we do it: Haematological malignancies (normally ALL, AML, lymphoma, Myelodysplasia), Red cell disorders i.e. sickle cell, Immunodeficiencies i.e. SCID, other i.e. metabolic
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8
Q

What’s involved: bone marrow transplant

A
  • Identify a donor/harvest stem cells- if own cells frozen, if donor used fresh
  • Hospital admission
  • Chemo +/- radiotherapy (conditioning)
  • Stem cell return: returned like blood transfusion via Hickmann line
  • Await engraftment: for the stem cells to travel to the bone marrow (takes 2-3 weeks there will be a rise in WCC). Whilst waiting can give blood and platelet transfusion
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9
Q

What can be done to prepare for bone marrow transplant

A
  • discuss fertility
  • dental appointment to treat any issues prior to transplant (infection risk)
  • pre-transplant investigations (bone marrow biopsy, bloods, imaging)
  • central venous catheter insertion
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10
Q

Bone marrow transplant: major risks and side effects

A
  • Side effects as per chemotherapy: Nausea, vomiting, hair loss, infertility, organ toxicity
  • Infection
  • Graft versus host disease: for allogenic transplants
  • Relapse
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11
Q

GvHD

A
  • Donor immune system attacking recipient
  • HLA matching – not really a ‘perfect’ match
  • Have to balance immunosuppression as there is a graft versus tumour effects where the cancer is also being attacked
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12
Q

Acute and chronic GvHD

A
  • Acute (within 100 days of transplant) vs Chronic
  • Acute: Skin (erythematous maculopapular rash- itchy), GI tract (nausea/diarrhoea), liver
  • Chronic: major cause of morbidity and mortality. Clinical features resemble auto-immune disease (joint stiffness/swelling, dry eyes and mouth). Develops post acute GvHD
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13
Q

Targetable Enzyme mutations: Kinases

A
  • FLt-3 in AML (Midostaurin, Sorafenib)
  • C-kit in mastocytosis (Midostaurin)
  • B-Raf in hairy cell leukaemia and some histiocytosis (Vemurafenib)
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14
Q

Other targetable Enzyme Mutations

A
  • Dehydrogenases: IDH1 in AML (Ivosidenib) ot IDH2 in AML (Enasidinib)
  • Methyltransferases: EZH2 in follicular lymphoma (Tazemetostat)
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15
Q

PD-1 inhibition as treatment for cancers

A
  • Very good results in Hodgkin’s disease, used extensively in solid cancers
  • Stops cancer cells from hiding from T cells
  • Not as effective in haematological cancer
  • Significant side effects especially autoimmune disease: can be life threatening and affect any organ
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16
Q

PD-1 inhibitors MoA

A

T cells are very good at recognising and killing T cells. However, Cancer cells can hide from T cells through PD-1 upregulation. Antibodies can still attack cancer cells but don’t have the killing power of T cells

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17
Q

CAR-T cells

A
  • Fusing host T cells with a TCR which recognises targeted antigens i.e. cancer cells. Causes release of cytokines and inflammatory cell expansion
  • Promising class of ‘living drug’
  • Very expensive, given as an inpatient
  • Takes 3-5 weeks to get CAR-T cells manufactured. Infused after chemo conditioning
  • can typically be only given once
  • Still high proportion of patients will die of disease
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18
Q

CAR-T cells side effects

A

The cytokines released by CAR-T cells and other immune cells leads to a systemic inflammatory response and reversible organ dysfunction. Effects the whole body. Causes hypotension, SOB, fever and confusion. May need to be admitted to ICU

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19
Q

Biospecific antibodies

A
  • Specific antibody which links the T cell via the CD3 receptor with the target cell allowing the T cell to kill the cancer
  • Many in testing for different haematological cancers
  • T-cells get activated quickly and CRS occurs within few hours of administration
  • Good response but currently not licensed
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20
Q

Advantages to CAR-T cells

A

Cheaper, antibody infusion can be repeated multiple times. Can be given straight away (don’t need to manufacture) and toxicity is very predictable within few hours of infusion so dont need to be hospitalised for as long

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21
Q

NHS genetic services

A
  • Clinical geneticists (doctors) and genetic counsellors
  • Laboratory: Molecular genetics (DNA) and Cytogenetics (Chromosomes and increasingly DNA)
  • Highly specialised: for example, National limb girdle muscular dystrophy services
22
Q

What causes cancer

A
  • Due to a genetic mutation, most are acquired and some are inherited. Causes unregulated and uncontrolled growth.
  • Age prevents self from repairing damaged DNA
  • Exposure to toxins
  • Minority have inherited component
23
Q

Types of genetic alterations in cancer

A
  • DNA mutations (single genes): single base substitution
  • Chromosome number changes
  • Chromosomal translocation: Philadelphia chromosome (acquired 9:22)
  • Amplifications
24
Q

Why are genetic tests useful in cancer treatment

A
  • Pathology/radiology: determining treatment
  • Tumour DNA changes, can help with treatment: breast ca HER2 expression and Herceptin
  • Which are ‘driver mutations’ and can they be targeted?
  • As opposed to ‘passenger mutations
  • Allows for targeted therapy
25
Q

Questions to consider with geneticists when deciding about cancer treatment

A
  • Does this family have a higher (and how much higher) risk of certain cancers?
  • Is extra screening warranted?; are risk reducing options indicated?
  • How to advise other family members.
26
Q

Germline genetic testing: Tumour suppressor genes

A
  • Protective role in repairing cells during growth. Normally protect patient from cancer and genetic changes.
  • Mutation in tumour suppressor gene means we only have one normal working copy of the gene (the other is non functional)
  • Germline mutations need a ‘second hit’ in the working copy (Knudson’s hypothesis): will mean neither copy of the gene work
  • More complex than this
27
Q

Germline genetic testing: oncogenes

A
  • Promote growth
  • Often activate during early/embryonic life
  • If they acquire ‘gain-of-function’ (i.e. ‘activating’) mutations they are termed ‘proto-oncogenes’ and increase the chance of cancer- cause uncontrolled cell growth
  • E.g. activating mutations in MEN2 as a cause of Multiple Endocrine Neoplasia type 2
28
Q

Knudson’s two hit hypothesis

A
  • an individual is genetically predisposed **to cancer, but cancer is not inevitable
  • acquired mutations are still needed
  • penetrance may not be 100%
29
Q

Retinoblastoma- genetics

A
  • Bilateral Retinoblastoma or those with a family history are highly likely to have an inherited germline mutation in one copy of their RB1 gene
  • Have one faulty RB1 gene only get retinoblastoma if there is a mutation in the second one
  • Without inheritance would have to acquire a mutation in both genes
30
Q

Tumour suppressor genes

A
  • Retinoblastoma - RB1 - genes function is cell division, DNA replication and cell death
  • Li-Fraumeni syndrome (brain, tumours, sarcoma, leukemia) - TP53 - gene function in cell division, DNA repair and cell death
  • Familial adenomatous polyposis - APC - gene functions in cell division, DNA damage, cell migration, cell adhesion, cell death
  • Breast and/or ovarian cancer - BRCA1, BRCA2 - gene functions in repair of double stranded DNA breaks, cell division, cell death
31
Q

Germline testing

A
  • Need germline- generally blood DNA
  • Gene by gene – traditional approach e.g. test BRCA1/2 in breast/ovarian family; test CDH1 in diffuse gastric cancer family
  • Panel approach (often used now) e.g. in family with colorectal cancer/polyps test a panel of 15 relevant genes. Used in Melanoma/renal
  • ‘phenotype agnostic approach’ – large panel to test all known cancer predisposition genes or whole genome test
  • Enter cancer genome and germline genome in patient with cancer: in order to know which mutations are inherited and which are acquired. in order to give targeted treatment and discuss familial inheritance
32
Q

What tests may have already been done prior to a cancer genetics clinic appointment

A
  • tumour genetic testing
  • germline genetic tests in other family members
  • MSI or IHC testing for colorectal or endometrial cancer (esp in suspected Lynch syndrome)
  • histopathology on other lesions (e.g. benign skin tumours can be a clue to some rare inherited cancer predisposition syndromes)
  • investigations to explore phenotype
33
Q

What’s a genomic test

A
  • any test which analyses DNA whether a single nucleotide or an entire genome. Either:
  • Diagnostic- a test which seeks to confirm a clinical diagnosis
  • Predictive: a test offered to the relative of someone in whom diagnostic testing has confirmed a genetic disorder
34
Q

The Genome

A
  • Each nucleated cell contains two copies of the genome
  • Contains billions of nucleotides
35
Q

Chromosome analysis (Karyotype)

A
  • Use Giemsa due and analyse under a microscope
  • Karyotype analysis detects whole chromosome changes like trisomy, monosomy and translocation. Becoming outdated is being replaced by array CGH
  • FISH (fluorescent in situ hybridisation): detects microdeletions or microduplications. Used to detect Chromosome translocations and in cancer diagnostic i.e. to detect gene fusion
36
Q

Array comparative genome hybridisation (aCGH)

A
  • Is replacing karyotyping= as can detect detect duplications and absences in smaller chromosome regions
  • Allows high resolution chromosome analysis: done with DNA in solution rather than whole chromosome preparation
  • Can detect trisomy, CNVs, microdeletions and smaller ins/dels but it will not detect single nucleotide changes and cannot, at present, detect balanced translocations.
37
Q

When do you use CGH and when is it not useful

A
  • Not useful: cannot detect single nucleotide changes. Cannot detect balanced translocations (karyotyping can)
  • Clinical use of array CGH: pre-implantation diagnosis, for prenatal diagnosis after anomalies are detected by US
38
Q

aCGH MoA

A
  • DNA from patient and control are broken down into little pieces and are both labelled with different dyes
  • They then hybridise to a detector array
  • If the patient is missing some DNA it will go the control colour. If there is equal patient and sample DNA a fusion colour will form. If the patient has duplication of DNA it will give the patient colour signal.
  • If DNA is missing: red colour (control)
  • If DNA duplicated: green (patients)
39
Q

DNA sequencing

A
  • Originally used Sanger technique
  • Now use NGS (next generation sequencing): which can read fragments of DNA in solution very quickly and reliably. Sanger sequencing then confirms these mutations
  • Normally analyse a ‘panel of genes’
  • Can do ‘agnostic’ analysis where you see if there is anything of interesting
  • Standard genetic test: whole exome and whole genome sequencing, followed by focussed analysis of sequence data
40
Q

DNA sequencing: what can you read

A
  • Can read the whole exome (1% of the genome)
  • The ‘Clinical exome’ (18,000 genes associated with the disease)
  • The whole genome
41
Q

Questions to consider with sensitivity of genetic testing

A
  1. Sensitivity: This is the ability of the test to find the mutation
  2. Specificity: variation in a single gene can sometimes cause different diseases
  3. Technical: how good is a particular laboratory technique at identifying a genomic abnormality?
  4. Gene coverage: can we test all relevant parts of the genes associated with a particular phenotype?
  5. Phenocopy: the existence of non-genetic conditions that mimic a genetic disorder.
42
Q

The three results from a genetic test

A
  1. Normal
  2. Abnormal (a mutation, or ‘pathogenic variant’)
  3. Uncertain (a ‘variant of uncertain significance’, or VUS)
43
Q

Testing with high diagnostic specificity

A
  • testing CAG repeat in HTT for Huntington’s
  • high diagnostic specificity because negative genomic test can exclude the diagnosis
44
Q

Genetic test: tests with lower diagnostic specificity

A
  • Testing for mutations in genes associated with familial hypertrophic cardiomyopathy
  • lower diagnostic specificity because:
  • gene panel tests do not cover every possible gene associated with HCM
  • HCM is not the only cause of LV hypertrophy
  • mutation in a particular gene does not always cause HCM (may cause dilated cardiomyopathy or may have no consequence) - variable expressivity/ penetrance
45
Q

Pro’s and cons of genetic testing

A
  • Pros: such testing may clarify a genetic diagnosis, the cause of the patients cancer and other diseases risks for the patient and their family family
  • Cons: a lot to take in at a difficult time, worry about other cancer risks, worry about family
46
Q

Whole genome sequencing

A
  • Widespread germline genetic testing- will receive info on: other important single gene medical conditions (i.e. BRCA1), recessive disease carrier status and Pharmacogenomic information
  • Not generally offered on the NHS but might be in the future
47
Q

What is genomic variation

A
  • Anything that is not typically expected in a person
  • May be: benign, likely benign, uncertain clinical significance, likely pathogenic, pathogenic
48
Q

Types of inherited cancer

A
  • DNA mutations in single genes
  • amplifications/ over expressions of certain genes
  • chromosome number changes
  • chromosomal translocations
  • Cancer predisposition genes are often Tumour suppressor genes
49
Q

PARP inhibitors

A
  • A type of targeted cancer drug which treats ovarian cancer
  • Includes Olaparib, Niraparib and Rucaparib
50
Q

What tests are done before referral to a cancer Genetic testing clinic

A
  • Tumour genetic testing in patient
  • Germline genetic tests in other family members
  • MSI (Microsatellite instability)/IHC (Immunohisto chemical) testing – particularly on colorectal / endometrial tumours – particularly if suspect Lynch
  • Histopathology on other lesions e.g. benign skin tumours can be a clue into some rare inherited cancer predisposition syndromes (e.g. trichilemmomas in PTEN)

year 4 CDM 2 (39 decks)

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