Breast ca Flashcards
Risk factors for breast cancer
High to low risk
Genetic factors
Chest radiotherapy age <30 e.g. HL
Dense breast tissue
Previous atypical ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS)
FHx
Hormonal factors - HRT, nulliparity, menarche <12
Obesity, alcohol, smoking
Most common genetic mutation in breast ca
What conditions or demographic is this mutation associated with?
BRCA 1 and BRCA 2 mutations
Invasive breast ca <30 years Invasive breast ca in men Triple neg breast ca <60 years (BRCA 1) Ovarian or primary peritoneal ca (BRCA 1) Ashkenazi Jewish heritage
Which BRCA mutation is associated with higher risk of ovarian ca?
BRCA 1
Does breast ca need genetic testing?
Use Manchester scoring system
A score of 15 or greater = >10% risk of carrying BRCA 1 or 2 mutation
(Refer potential patients to familial cancer service –> calculate their pretest probability –> if pre-test probability >10% then they are funded for BRCA testing)
BRCA 1 mutation and hormonal status
More likely to be triple negative (ER, PR, HER2 neg)
More aggressive
BRCA 2 mutation and hormonal status
Associated with hormone receptive positive breast ca
More similar to the standard population
How to reduce cancer risk in BRCA1/2 mutation carriers?
- Bilateral mastectomy
- Bilateral salphingo-oophorectomy once childbearing is complete (before age 40 if possible); particularly BRCA1
- Increase surveillance - breast MRI from age 30
- Chemoprevention with tamoxifen, anastrazole or exemestane (rarely done)
Screening for breast ca
Mammography every 2 years from 50-74 years old
Women aged 40-49 or >74 are not invited but have access to free screening
MRI
- only for those with familial breast ca or radiotherapy for HL
Early stage breast cancer management
Consider HER2 positive, hormone receptor positive, node positive
Early = non-metastatic, resectable. Confined to breast +/- local lymph nodes
Large disease = 2cm or more
Small disease = <2cm
HER2 positive
- Neoadjuvant therapy with chemo and HER2 mab (trastuzumab) –> surgery
Large disease
- Neoadjuvant therapy with chemo +/- HER2 mab (depending on HER2 status) –> surgery
Smaller disease
- Surgery + radiotherapy
All the above will be followed adjuvant therapy (HER2 mab if HER2 pos or endocrine therapy if hormonal receptor pos)
Surgery
- WLE or mastectomy
- Radiotherapy MUST be performed after WLE
- If there is poor prognosis then will need radiotherapy post mastectomy - <40yo, >4cm primary, >4 LN, positive surgical margins
Breast ca main 2 histological subtypes
Ductal (80%)
Lobular (15%)
- Tend to be lower grade, ER+
Prognostic factors in early stage breast ca
Tumour grade Nodal status* HER2 status Tumour size ER/PR status Age at diagnosis Gene assay (e.g. Oncotype DX)
*Nodal status is most important prognostic factor
Chemotherapy used in early stage breast ca
AC-T (doxorubicin, cyclophosphamide, paclitaxel)
Immunotherapy used in early stage breast ca
new evidence in the triple negative (ER, PR, HER2) setting
Pembrolizumab (PD1 inhibitor) with chemotherapy
Endocrine therapy used in early stage breast ca
80% are ER+ or PR+
Aromatase inhibitor (post menopausal women only)
SERM (all women and men)
How do aromastase inhibitors work?
When is it used?
Stops testosterone –> oestradiol (in peripheral tissues e.g. fat, liver cells, myocytes)
Must be post-menopausal (if not the ovaries are still making oestrogen so this drug has no effect)
1st choice for postmenopausal women with ER+ or PR+ early breast cancer 5 years (can consider 10 years if high risk disease e.g. large tumour, node positive)
Better than tamoxifen. If they’re perimenopausal, can have 2 years of tamoxifen then switch to aromatase inhibitor
If used in pre-menopausal women must add ovarian function suppression with GnRH analogue. If not can cause paradoxical increase in estrogen levels.
AE aromatase inhibitor
Vasomotor symptoms Osteoporosis*** Myalgia, arthralgia weight gain Vaginal atrophy mood changes
How do SERMs work?
ER blocker in breast
ER agonist in bone thus osteoprotective (can be used in OP)
Tamoxifen
SERM AEs
Vasomotor symptoms
DVT
Endometrial cancer
How long to take tamoxifen for?
10 years better than 5 years
Management of in situ disease (has not crossed basement membrane, low potential for metastasis)
Surgery then adjuvant low dose SERM for 3 years reduces 4 year development of invasive breast ca
How do ovarian suppression work?
High dose GnRH agonists –> downregulate GnRH receptors in pituitary –> decreased FSH and LH release –> decreased estradiol production by ovary
When do you use ovarian suppresion?
Pre menopausal
Young
If no high risk disease
In conjunction with tamoxifen
Also in fertility preservation - reduces ovarian failure rate when used with chemotherapy
However only reduces the likelihood and is not the same as other methods such as embryo cryopreservation, oocyte cryopreservation etc
Early stage HER2 positive disease Rx
Trastuzumab (Herceptin)
1 year duration
Can also be given neoadjuvantly (pre-op) and the remainder of the 52 week regimen post operatively
In the event of residual disease being detected in the surgical specimen after neoadjuvant trastuzumab, switch to a drug-ab conjugate trastuzumab emtansine (ab drug conjugate) for the remainder of treatment
AE Trastuzumab
Very well tolerated
Mild like flu like symptoms
Cardiotoxicity
- Rare
- Asymptomatic LVEF decline in 13%. Reversible mostly
- Risk factor: prior anthracycline use, LVEF <55%, HTN, age >50, BMI >25
- 3 monthly ECHO
- Cease if LVEF has declined >15%. or <45% or symptomatic HF
- Add on ACEI +/- b blocker if drop in EF
Pertuzumab MOA
Also HER2 ab
$$$
Always added to trastuzumab not instead of
Slight improvement in recurrence by 1.5%
Olaparib - when is it used?
PARPi
Early stage
BRCA1/BRCA2
Used after surgery (adjuvant)
What’s oncotype Dx?
Prognostication biomarker (gene expression assay) $5000
In someone who is borderline suitable for chemotherapy, this can be done to determine recurrence score.
If low recurrence score, can get away with endocrine therapy alone.
If high recurrence score, benefit with chemotherapy.
Fulvestrant when is it used and MOA?
Selective estrogen receptor down regulator
In HR+ postmenopausal women with metastatic disease, 1st line is fulvestrant + aromatase inhibitor (much better than aromatase inhibitor alone)
CDK 4/6 inhibitors - MOA?
Palbociclib, ribociclib, ademaciclib
Inhibit a pathway (inhibits the binding of CDK4/6 to cyclin D and stops phosphorylation of Rb) that stops transition in cellular mitosis (G1 phase to S phase)
= stops cell proliferation/growth
When is CDK4/6 inhibitor used?
In HR+, HER2- women with metastatic breast cancer
Postmenopausal HR+ women with metastatic disease
When added to fulvestrant or aromatase inhibitor, improves OS and PFS
Premenopausal HR+ women with metastatic disease
When added to gosrelin (GnRH agonist) and aromatase inhibitor or tamoxifen, improves OS and PFS
PI3K inhibitor - when is it used?
Alpelisib
Use with fulvestrant
HR+ HER2- mBrCa after failure of CDK4/6i in those with activating PIK3CA mutations
Pertuzumab when is it used?
HER2+ metastatic breast ca
Pertuzumab + trastuzumab + docetaxel is standard of care now
Tucatinib when is it used?
Small molecules
Inhibit intracellular domain of HER2
3rd line setting in metastatic HER2+ disease
Sacituzumab govitecan when is it used?
Novel chemotherapy-ab conjugate
Metastatic
3rd line
Triple negative breast ca
Immunotherapy when is it used in breast ca?
Metastatic triple negative breast ca
Pembrolizumab/atezolizumab + chemo is first line
Breast cancer in men hormone status
Exclusively ER+
Less HER2+
Rx: tamoxifen is the only therapy used in the adjuvant setting
Ideal Duration of HRT in postmenopausal women
Attempt taper at 3-5 years
How does BRCA1/2 mutations increase your susceptibility to breast ca?
These genes are important for repair of double stranded DNA breaks via homologous recombination (error free repair).
If this is not working, you become over-reliant on non-homologous end joining (error prone repair) –> predispose to cancer
When do you use PARP inhibitors in breast ca?
BRCA1/2 mutations
How do PARP inhibitors work in breast ca?
BRCA mutation –> impaired homologous recombination (error free repair) –> become reliant on basic excision repair regulated by PARP –> by inhibiting PARP, you stop this kind of repair and overload the tumour with mutations –> genome becomes unstable and the cell becomes non-viable
Which type of breast ca is most likely to have late recurrence?
A) Hormone receptor positive, HER2 negative
B) HER2 positive
C) Triple negative
Hormone receptor positive, HER2 negative
Which type of breast ca has good prognosis?
A) Hormone receptor positive, HER2 negative
B) HER2 positive
C) Triple negative
Hormone receptor positive, HER2 negative has good prognosis but late recurrence (>5 years) can occur
HER2 positive has good prognosis due to effective targeted therapies
What’s Ki67?
Special stain
Indicates high turnover
What is trastuzumab-emtansine?
Ab-drug conjugate
Trastuzumab linked to a cytotoxic agent
On binding to HER2 on the cell surface, the cytotoxic agent is internalised
What type to breast ca are brain metastases common?
Triple negative
HER2 positive
Treatment of brain metastasis in breast cancer
Surgery or sterotactic radiotherapy preferred
If not possible, then whole brain radiotherapy
Treatment of HR+, HER2- metastatic breast cancer
Aromatase inhibitor/tamoxifen (depending on menopausal status)
PLUS
CDK4/6 inhibitor ribociclib
Treatment of HER2+ metastatic breast cancer
1st line
2nd line
Dual HER2 mab trastuzumab + perzutumab PLUS chemotherapy
2nd line: Trastuzumab-emtansine (ab-drug conjugate)
Treatment of triple negative metastatic breast cancer
Intense chemotherapy regimen (Nab-paclitaxel)
PLUS
PDL1 inhibitor pembrolizumab or atezolizumab
Treatment of BRCA1/2 early stage disease
Surgery + adjuvant PARPi (olaparib)
How often should we do MRI/mammogram after breast cancer treatment?
Every year
Does PR status influence treatment?
No - does not influence treatment
PR is just associated with better prognosis.
