Case 7: Breast Cancer

Front 1

Cancer

Back 1

Many diseases that cause cells to divide and invade surrounding tissue. Most cancers form from a single cell

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Primary tumour

Back 2

First site where the abnormal cell divides

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Metastasis

Back 3

Development of secondary site and tumour through malignant growth.

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Malignancy

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Spreading and invasion of cancer into nearby tissue. Cancer breaks from primary tumour and spreads to distant places in the body through lymphatics or the blood system. Does sometimes grow back if removed.

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Natural selection reasoning for the existence of cancer

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Cellular proliferative advantage and cellular evolution within an organism. - natural and inevitable

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Myeloma

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Plasma/immune cell cancer

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Carcinoma

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Epithelial cell cancer - histology = nuclear enlargement, hyperchromasia and pleomorphism

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Sarcomas

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Connective tissue/muscle cancer

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Melanoma

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Melanocyte cancer

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Cancerous cell differences to normal cells

Back 10

- Doesn't respond to host signals such as death etc.

- Will proliferate uncontrollably

- Less specialised than normal cells

- Mutation that promotes selfish cell behaviour.

- Overcomes senescence and avoids apoptosis

- Uses immune system to grow and divide

- influences microenvironment

- Forms blood vessels to gain O2 and remove waste

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Cause of cancer

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4-7 genetic events that mutate genes that control the cell cycle. Such as tumour suppressor genes and proto oncogenes - very low chance

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Tumour suppressor genes

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Genes that slow down cell division, repair DNA/genome stability and induce apoptosis. Mutation causes a decrease in activity and induces cancer in a recessive manner.

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Proto oncogenes

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Regulate cell survival and normal cell growth. Mutation induces cancer in a dominant manner increasing activity in creating an oncogene.

Normal functions:

- growth factors

- Cell surface receptors

- transduction system components

- transcription factors

- Cyclins

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Different pathogenesis of cancers

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- Increased cell division

- Cell survival regulation altered

- Growth of cell dysregulated

Overall due to genetic changes of somatic cells

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Cyclins

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Regulate the transfer of a cell from one stage to another in the cell cycle. Accumulation --> bind with cdk1 to activate them --> phosphorylation of cyclin-cdk1 complex --> change cell structures to move cell to the next stage.

Front 16

CdK1

Back 16

Bind with cyclins when they accumulate

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Cell cycle

Back 17

Front 18

Typical apoptosis mechanisms

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Intrinsic - Bax forms pores in mitochondria --> cytochrome c escapes --> activates caspases

Extrinsic- tnf-alpha from other cells binds to and homotrimerises receptors --> forms death induced signalling complex --> caspases activated.

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Necrosis

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Cell injury inflammatory death response.

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Regulation of cell growth

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Myc (Proto-oncogene) accumulates in function to create bigger c lls

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Carcinogenesis

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May have genetic predisposition. Mutation that increases rate of cell proliferation or destabilising the genome causing proliferative mutation. Mutation is due to random chance, carcinogens etc. Resulting in microsatellite changes or chromosomal changes --> clonal evolution evolution (selective growth of clones with mutations) --> cancer formation and malignancy.

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Destabilising of the genome

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Carcinogens induce chromosomal karyotype changes as well as microsatellite sequence changes.

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Sporadic cancer

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Due to genetic errors in somatic cells (environmental factors). Common and later onset.

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Familial cancer

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Predisposition due to inherited germline present mutations. Typically tumour suppressor gene. Rare and early onset.

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Oncogene activation mechanisms

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- Receptor/signalling mutations --> increase in cell proliferation

- Chromosomal translocation to an overactive site

- Chromosomal translocation creating a chimeric gene --> overactive growth signalling.

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Tumour suppressor gene cancer causes

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- Mutations - Knudson's two hit hypothesis

- Chromosomal abnormalities

- Methylation of promoters

- Viral protein interactions with genes.

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Knudson's two-hit theorum

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Germ cells

Somatic cells

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Neoplasm

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New and abnormal mass of cells which are unco-ordinated and exceeds growth parameters.

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How neoplasms are classified

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- Site

- Histology (tissue resemblance)

- Behaviour

- Histiogenesis (cell of origin)

- Aetiology (inheritance vs environmental)

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Benign tumours

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Mass of cells that grow to push normal cells out the way.

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Routes of cancer spread

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- Lymphatics

- Within epithelium

- Blood

- Transcoelomic (abdominal cavities)

- Along epithelial lined spaces

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How individual lesions are named

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- Site

- Histology

- Behaviour

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Adenoma

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Gland forming benign tumour

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Papilloma

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Outward growth of benign tumour

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Cystadenoma

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Benign tumour that is filled with mucus like material

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Polyp

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Mass that is attached to a surface which has an unknown cause

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Mesenchymal tumour

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Cancer of the connective tissue.

-oma = benign

-sarcoma = malignant

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Leukemia

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Haemopoetic stem cells of the blood; always malignant.

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Teratoma

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Germ totipotent cell cancer

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Lymphoid tissue cancer types

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Hodgkins and non-Hodgkins lymophoma. Depending on specific cell presence.

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Pre-malignant conditions

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Conditions that increase the risk of malignant cancer development. Neoplastic: familial or intra-epithelial and non-neoplastic: chronic inflammation

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Tumour effects

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Benign: Mechanical pressure, obstruction, infection, ulceration

Malignant: (all benign +) Tissue destruction, haemorrhage, anemia, pain

Para-neoplastic (not due to local presence) e.g. finger clubbing, hormone production changes

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TNM Cancer stages

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T = Primary tumour size (X, 0-4)

N = Number of lymph nodes dispersed to (X, 0-3)

M = Metastasis or not (X, 0-1)

Defined at diagnosis to determine the best treatment, prognosis and clinical trials.

Front 44

Cancer grading

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"How bad it looks" - Cell differentiation - Higher differentiation = more aggressive. (Only in malignant tumours)

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Cancer stage X meanings

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0 - Abnormal cells present but not in nearby tissue

1-3 - increasing degrees of tumour size and spread.

4 - Cancer has spread to distant parts of the body.

Front 46

Breast Cancer biopsy types

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Apply local anesthetic. -->

- Guided needle

- Vaccum assisted

- Gentle suction tube

Depending on type of cancer and what the doctor wants to find out.

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Pathologist role in biopsy

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Examine biopsy under microscope to identify cancerous cells --> immunocyto and histochemistry to classify and characterise breast cancer --> estimate prognosis and determine most appropriate therapy.

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Breast cancer Screening

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- Self check (Pain, lump, nipple discharge, skin changes)

- Mammogram every 3 years for 47-73 year olds. Also mri

Front 49

Diagnostic triple assessment in a ??breast cancer

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Every women who has a breast lump:

- Clinical examination + lymph nodes

- Imaging (Mammogram, Ultrasound or MRI) - sometimes use more than one die to dense breast tissue and more effective at identification

- Biopsy

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Mammogram

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Uses low doses of X ray to determine if cancerous tissue is present. Used primarily as a screening tool to identify microcalcifications - early breast cancer indication.

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Ultrasound

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Uses high frequency sound waves. Identify if lump is solid or liquid.

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BRCA1 function

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Associates with BACH1 to act as a ubiquitin ligase. BRCT domains use homologous recombination double stranded repair to repair genes. Regulates G2/M checkpoint. Cytoplasmic function of mediating apoptotic and centrosome regulation. (TSG)

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BRCA1

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1. Ring domain

2. Coiled coil domain

3. BRCT domains

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Pathogenic mutation types of BRCA1, cancer locations and behaviour

Back 54

15-30% are due to large rearrangements. High proportion of breast cancer chance and moderate proportion of ovarian cancer chance throughout lifetime. High grade pathology and likely to be triple negative breast cancer

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BRCA2 function

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- Maintenance of telomeres - RAD51

- Prevention of R loops

- Control g2/m checkpoint - PALB2

Homologous recombination repair pathway (TSG)

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BRCA2 structure

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1. BRC repeats

2. DNA binding domain

3.Nuclear localisation domain

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BRCA1 Cancer types/behaviour

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Typically high grade and atypical medullary type. high mitotic count and lymphocyte infiltration. Likely to be triple negative (ER, PR and HER2)

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BRCA2 cancer locations

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- High association with breast cancer (not tubular carcinomas)

- Lower association with ovarian cancer

- Association with pancreatic and prostate cancer. Not associated with tubular pathology

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BRCA2 Biallelic mutations cause what disease?

Back 59

Fanconi's Anaemia - Short height, microcephaly, radial rau.

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Ductal breast cancer

Back 60

Milk ducts are origin of cancer. More common as invasive

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In situ cancer

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Is not invasive and cancer stays where it is

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lobular breast cancer

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Cancer originates at the milk lobules. Less common as invasive.

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Phyllodes tumours of the breast

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Typically benign tumours

Front 64

Paget's disease of the nipple

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Cancer of the nipple that then spreads throughout skin of breast

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Breast cancer molecular identifying receptors

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HER2, oestrogen, Ki67 and progesterone receptor subtypes.

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Oestrogen and progesterone receptors as cancer cause

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Overexpression --> overactivation --> promote growth. Protein levels are elevated in malignant and pre-malignant breast cancer

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Human epidermal growth factor receptor 2 and normal function

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Ligand is EGF that forms a heterodimer of HER1 and 2 which phosphorylate each other. --> signalling cascade --> cyclin activation.

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Personalised medicine of cancer

Back 68

Molecular classification of cancer subtypes (receptors etc.) to determine the most effective treatment. - Targeted therapies

Front 69

Assessing probability of cancer causing mutation of BRCA1/2

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Manchester score to determine, using family history. Assess cell surface markers and IDC grade. Results may show the cancer is pathogenic, variant of uncertainty (conflicting test results) or non-pathogenic. - IARC classification

Computer models can help.

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Management of women with BRCA1 or 2 mutation

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- Surveillance - mammography and/or MRI

- Prophylactic surgery.

- Preventative medication

- Therapeutic treatment

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Surveillence of those with BRCA 1 and 2 mutations

Back 71

Breast:

Mammogram - 30-69 yrs of age

MRI - 30-49 yrs of age(better identifying in this demographic

Ovarian:

Screening is not effective = surgery at 38/9?

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Chemoprevention of cancer in those with BRCA1/2 mutations

Back 72

Tamoxifen - inhibits oestrogen receptors = reduces proliferation mechanism in mammary tissue. However, endometrial cancer risk in pre-menopausal

Denosumab - monoclonal antibody that inhibits RANK L signalling. Treat bone metastases/

Front 73

Tamoxifen

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Inhibits oestrogen receptors in the mammary glands that are responsible for proliferation. Taken for 5 years and reduces risk by 40%.

Best for post menopausal women or those without a uterus due to endometrial cancer risk.

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Denosumab

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Monoclonal antibody that inhibits RANK L signalling which can cause breast cancer and bone metastases.

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Risk reducing surgery for women with BRCA 1/2

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- Bilateral Salpingo-oophectomy = Reduce in ovarian and breast cancer --> HRT needed for CV and bone

- Sentinel node biopsy - to identify spread

- Bilateral mastectomy = massive reduce in breast cancer

- Wide excision - best with radiotherapy.

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HER2 cancer pathogenesis

Back 76

HER2 overexpression --> spontaneous dimerization --> cells enter cell cycle all the time via cyclinD1 = cancer

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Breast reconstruction

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Important to consider body image and sexual relationship of the patient. Surgery uses tissue from abdominal wall, lattisimus dorsi and nipple tattoo. Delay = bigger scar.

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When is a mastectomy is needed?

Back 78

- large tumour in a small breast

- BRCA1 or 2 mutation

- Multifocaility.

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Therapeutic drug treatments of Breast cancer

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- Chemotherapy

- PARP inhibitors

- Platinum based therapies

- Herceptin

- Adjuvant therapy

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PARP inhibitors

Back 80

Normally used for people that relapse. PARP repairs single stranded breaks. The inhibitor therefore allows double stranded breaks to occur resulting in DNA error accumulation and the death of the cells.

Front 81

Platinum based therapies

Back 81

Mis-pairing of nucleotides and DNA damage --> death of cells

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Chemotherapies

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Target fast proliferating cells to kill them.

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Herceptin

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Monoclonal antibodies inhibit EGF binding to HER2 = lack of proliferation

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Adjuvant therapy target

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Targets micrometastases in the blood.

Front 85

Postcode lottery problem of treatment

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Treatment available was dependent on how trusts spend their money = affect prognosis --> government initiative of multidisciplinary team --> standardized treatment.

Front 86

Molecular subtypes of breast cancer

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- Luminal A

- Luminal B

- Normal-like

- HER2 overexpression

- Triple negative

Front 87

What are the effects of cancer on social aspects of the person?

Back 87

Their relationships change with their friends and family - can be effected by coping strategies.

Front 88

Coping strategies purpose and types

Back 88

Purpose - to return to normal function.

Problem focused --> taking action

Emotion focused --> managing emotions

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How does a cancer diagnosis primarily affect:

Spouse

Family

Friends

Back 89

Spouse = grieving

Family - parents overprotective; siblings - varied

Friends - unsure how to support or cope.

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Valid consent

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Voluntary and with capacity

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Informed consent

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Patient is given all the information and understand it in regards to their potential treatment to give consent

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How to discuss obtaining consent for treatment with a patient

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Give as many options as you can. Discuss diagnosis, prognosis, treatment, share all required info and respect patients views and decisions.

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How to carry out shared decision making with a patient

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It is no longer a "Do what the dr. says" type affair. Give patient time to reflect before and after. Consider the patient's level of understanding. Try not to assume anything about the patients treatment.

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Genetics and consent conflict.

Back 94

Consent is required for a patient to allow a doctor to inform other family members about a potential genetic defect. Confidentiality of the patient comes first.

At risk relatives vs confidentiality of the patient - case by case basis.

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Additive consent

Back 95

Certain information is kept by hospitals when carrying out procedures e.g. genetic info, research, storage, human tissue samples.

Front 96

How do people respond to cancer diagnosis?

Back 96

- Increased chance of depression

- Body image negatives - e.g. loss of hair = perceived decreased femininity

- Coping strategies

- Cognitive adaption - changes in self perception

- Benefit finding - find meaning of life.

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Cognitive adaption to cancer diagnosis

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Fighting spirit vs fatalism. Patients want to feel in control, understand why they developed cancer and carry out self enhancement

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Diagnostic delays in cancer diagnosis

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- Primary care delays

- Secondary care delays

- Referral delays

- Public awareness to symptoms

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What factors impact a persons perception of illness?

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- Demographics (age, sex etc.)

- Moral dimension

- Internal and external views of health

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What triggers help-seeking in illness

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- It starts to impact social life

- Starts to impact work life

- Temporlising of symptomology - Change in symptoms

- interpersonal crisis

- Sanctioning - other people legitimising help

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Impact of depression on the health of cancer patients

Back 101

- Decreased Qol

- Decreased adherence

- Poor self-care

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Psychological impact of cancer

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Radical change and break --> losses, gains, they are still a person, self perception and social perception changes.

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What should be discussed as part of a consent process in regards to clinical process of identifying possible mutant DNA?

Back 103

- Family history

- communication with family members

- contacting at risk family members

- summary of genetic information to other HCPs

- timescale of test results

- Possibility of unexpected findings

- Predictive nature of genetic tests

- long term storage of data practice.

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solidarity and altruism in genetic information sharing

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Many people using genetic services --> partial aim of helping family members. Need to be explored with patient.

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Cachexia

Back 105

Severe weight loss

Increased metabolic rate

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Accurate family history required for determining susceptibility to cancer. Issues and confirming history

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Pt. are poor at recalling sites of malignancy in relatives. 3 generations of pedigree required. --> cancer registry, death certificates and hospital notes help.

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How to determine if a gene is cancer causing

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Compare panel of gene mutations with relative risk increase of cancer.

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Familial breast cancer causes

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BRCA 1 and 2 genes 10-20%; PALB2 - 1-2%

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Subphrenic abscess

Back 109

Causes: perforation of viscera: appendix/colon; inflammation, trauma, surgical operation complication, idiopathic

Symptoms: Fever, upper quadrant pain, chills and leucocytosis

Treatment: Abx and surgical drain