Breast cancer Lecture 20

Question 1

What are the risk factors for breast cancer and how is it detected?

Answer 1

Risk factors:

• Age (biggest)
• Obesity
• Alcohol / smoking
• Oestrogen exposure (early menarche/late menopause)

Detection:

• Mammography
• Symptoms (lump, nipple discharge, change in shape of breast)

Question 2

How can you classify breast cancer?

Answer 2

Histological types of breast carcinoma: In situ carcinoma Invasive carcinoma- Ductal NST, lobular, tubular, medullary-like, mucinous, metaplastic

Morphological factors- size, node involvement, tumour grade Nottingham prognostic index (NPI)- 5.41= poor

Question 3

Briefly summarise hormone involvement in breast cancer

Answer 3

Oestrogen has a major role in development and progression of disease

70% of cancers express oestrogen receptor (ER) and/or progesterone receptor

Question 4

Describe luminal A breast cancer

Answer 4

ER, PR positive- responsive to endocrine therapy

Mostly diploid, few copy number changes, low proliferation, recurrently mutated genes (PIK3CA, CDH1, MAP3K1, MAP2KA, FOXA1, TP53, RUNX1- less responsive to chemotherapy

Luminal A:

• ER and PgR +ve
• HER2 -ve
• Few mutated genes and low proliferation

Treatment:

Local disease (ductal carcinoma in situ)

• Exicsion
• Adjuvant radiotherapy

Invasive

-Surgery - wide local excisions

Question 5

Describe luminal B breast cancer

Answer 5

ER/PR positive, lower than Luminal A,

25% HER2+- not as responsive to endocrine therapy as Luminal A

Often aneuploid with many high level focal amplifications (cyclinD6 and EGFR1)

Recurrently mutated genes PIK3CA, GATA3, PTEN, TP53- more sensitive to chemotherapy

Question 6

Describe basal-like breast cancer

Answer 6

Triple -ve for ER, PR, HER2

High metastatic rate Y

oung age at presentation- motte common in African American

Associated with germline BRCA1 mutations

Question 7

Describe HER2 breast cancer

Answer 7

HER2:

• ER and PR -ve
• Responsive to herceptin

Question 8

Describe the oestrogen receptor (ER)

Answer 8

Associated with co-repressors in the nucleus, HSP90

E2 steriod passes through the membrane causes dimerization and phospohorylation and increases binding of coactivators and releases corepressors so it can bind to DNA and increase transcription

Transcriptional Activator Factor (TAF) 1&2 regions within receptor activated and increases gene transcription and tumour growth. INcreases the proliferation of tumour

Question 9

What are SERMs?

Answer 9

Selective oestrogen receptor modulators Eg Tamoxifen

Actively blocks TAF2 leaves TAF1 results in partially inactivated transcription and reduced rate of tumour growth

20mg of tamoxifen a day -no benefit to increase dose, Better than just chemo alone

Side Effects- menopausal symptoms like hot flushes and sweats, fatigue, painful joints, initial nausea

All Tumours eventually become resistant- mutation in ER- receptor activation in absence of ligand, E2 independent phosphorylation, hyper sensitivity to ligand, isoform variation, non-genomic effects of oestrogen

Question 10

Describe the non-genomic effects of oestrogen

Answer 10

Oestrogen can be present in the cytoplasm ➡SARC➡ PELP➡ PKC➡ MAPK

MAPK activates nuclear ER and AP1 transcription complex PELP is a ER co-activator, scaffolding protein coupling signalling complexes with ER

Assoiciages with chromatin and involved in histone function Couples ER to SRC and hence ERK Found in the cytoplasm of early and aggressive tumour cells- tamoxifen resistant

Question 11

What are aromatase inhibitors?

Answer 11

Prevent peripheral conversion of androgens to oestrogen in tissue by aromatase enzymes

-Decreases gene transcription and tumour growth in cancer cells

Treats breast cancer

Question 12

What is fulvesterant?

Answer 12

Pure antioestrogen

Mimics oestrogen ablation

Used as a 3rd line therapy

Question 13

Describe goserelin

Answer 13

One amino acid changes from the LHRH peptide

Binds to receptors in pituitary initially stimulating LH/FSH release but comntinous exposure leads to thee down regulation of the receptors and decreases FSH production within 2 weeks

Question 14

What is the significance of endometrial cancer in breast cancer?

Answer 14

Stimulates from high unopposed oestrogen levels

Usually in post menopausal women as they stop making progesterone

Tamoxifen has partial agonist properties particularly the uterus and increases the risk of endometrial cancer

Question 15

Describe the hereditary aspect of breast cancer

Answer 15

Family history most important factor 3 gens, primary sites, ages

Li Fraumeni syndrome- 80% breast cancer, young, HER+ve, adrenal cortical carcinomas, sarcomas, brain tumours

Other genes: NF1, RAD51C, PALB2, ATM, BRIP1

BRCA1/2 mutations have high penetrance - high risk of developoing cancer. Other DNA repair genes mutated have less chance.