Breast Cancer Flashcards
Biggest risk factor for breast cancer?
Older Age
Breast cancer risk factors?
RF in order of decreasing risk:
Older age
Genetic factors
Chest radiotherapy <30 years old
Dense breast tissue
Previous atypical DCIS/LCIS
Family Hx breast cancer
Hormonal factors
Lifestyle factors
What types of cancer are BRCA1/2 mutations associated with?
Breast and ovarian cancers
Prostate cancer in men (15% lifetime risk)
Pancreatic cancer (2% lifetime risk)
Slight increase in gastric and H&N cancers
Is BRCA1 or BRCA 2 associated with a higher risk of breast and ovarian cancer?
BRCA1
What scoring system is used to determine if a patient with breast cancer warrants genetics testing?
Manchester scoring system
- Score of 15 or more corresponds to a 10% risk of BRCA mutation carrier
Breast cancer modifiable risk factors?
Stop HRT
Lose weight
Exersise
Stop smkoing
reduce eoth
Bilateral risk reducing mastectomy
- recommended as a risk reduction strategy for women at high risk of breast cancer however most decline
Which pts should ideally undergo bilateral risk reducing salpingoopherectomy?
BRRSO in pts at high risk of ovarian cancer (ie BRCA1 or 2 mutation)
- should be performed between ages of 35-40 once child bearign completed
Nil benefit from additional hysterectomy however may be considered given tamoxifen may be used down the line
What forms of chemoprevention are there for breast cancer (excluding BRCA mutation carriers)?
Aromatase inhibitors
- Anastrazole halves risk of breast cancer in high risk pts
SERMS
- Tamoxifen reduced risk of breast cancers, however increased risk of VTE and increased risk of breast cancer
- No significant data for BRCA1/2 mutations
Which tests are used for breast cancer screening in the general population?
Mammogram +/- ultrasound
- results in a 23% reduction in the relative risk of breast cancer mortality in the 50-69yrs group
- Some data suggests benefit extends to 74yrs
- Nil evidence to support utility in 40-49yrs group (breast tissue too dense)
- No evidence of consensus on the use of Ultrasound but is performed widely
MRI screening only for those with familial breast cancer (identified gene mutation or not) or prior radiotherapy for hodgkins lymphoma
- Annual MRI
Use of MRI in pts with extremely dense breast tissue on MRI is unclear
- greater detection of in situ cancers, unclear if would have threatened pts survival
Histological subtypes of breast cancer?
Ductal (70-80% of breast cancers)
- Tend to respond to both endocrine and chemo therapy
Lobular (10-15% of cancers)
- Tend to be low grade, ER+
- Respond much better to endocrine therapy than chemo
Early breast cancer syndromes and the associated ER, PR and HER status? (ie luminal A and B)
Order of increasing aggressiveness:
Luminal A
- ER+, PR+, HER2-, Low Ki67, low grade
Luminal B HER2 neg
- HER2-, ER+, PR-/Low Ki67 OR PR+/high Ki67
Luminal B HER 2 pos
- HER2+, ER+, any PR, any Ki67, Any grade
Non luminal HER2+
- HER2+, ER-, PR-, any Ki67, any grade
Basal like
- Tipple negative (HER2-, PR-, ER-, any Ki67)
What is regarded as early stage breast cancer?
Early stage breast cancer is non-metastatic, resectable disease (ie confined to the breast and local LN such as axiliary or intramammary LN)
- It is treated with curative intent
Overview of treatment for early stage HER2+ disease?
- Neoadjuvant therapy - usually chemo and HER2 mab
- Surgery
-Radiotherapy if indicated - Adj Therapy - usually HER2 mab, endocrine therapy (if receptor positive), can include chemo
Overview of treatment of early stage Large disease?
- Neoadj therapy - usually chemo based, but can use endocrie therapy in older / lower ECOG pts
- Surgery
- Radio if indicated
- Adj therapy - usually endo therapy if receptor pos, can include chemo
How is large disease breast cancer defined?
Large disease is 2cm or more (depending on the size of the breast) or clinically node positive disease
Overview of treatment of early stage small disease breast cancer?
- Surgery
- radio if indicated
- Adj therapy - usually endo therapy but may include chemo
What surgery is performed in early state breast cancer (ie curative intent surgery)?
Wide local excision OR mastectomy +/- node sampling or disection
When is radiotherapy post surgery indicated in Early stage breast cancer (ie curative intent treatment)?
Consider radiotherapy if poor prognostic factors:
- <40yrs
- >4cm primary
- >4 LN
- positive surgical margins
Note radio must be used in all WLE to ensure appropriate control
Preferred Chemo regimes for early stage breast cancer?
AC-T (doxorubicin and cyclophosphamide followed by paclitaxel
TC (docetaxel and cyclophosphamide)
What is a dose dense chemo regime?
This is when the dame dose is given but over shorter periods of time
- it is more toxic but more effective
What two immunotherapy agents are preferred in early stage breast cancer?
Pembrolizumab (PD1) and atezolizumab (PDL1)
What are the main forms of endocrine therapy for early stage breast cancer?
Aromatase inhibitors - Post meno only
- Anastrazole, letrozole
Selective estrogen receptor modulators (SERMs) - all women and men
- Tamoxifen
Ovarian suppression - GnRH agonist, Triptorelin
How do aromatase inhibitors work and why are they only used in post menopausal women?
Aromatase inhibitors black that actin of the aromatase enzyme which is responsible for the production of peripheral estrogen in fat tissue
Pre menopausal women has estrogen production from ovaries therefore aromatase inhibitors are ineffective (ie they will still have estrogen around)
What is the first line endocrine therapy for post menopausal women with PR or ER positive breast cancer?
How long are they used for adjuvantly?
Aromatase inhibtors
- usually continued for 5 years in adj setting
Does tamoxifen or anastrazole protect against OP?
Tamoxifen (SERMs) are osteoprotective. This is because they have ER antagonist effects in the breast, but ER agonist effect in the bone
Aromatase inhibitors increase risk of fracture, dose dependent
What is the only SERM that is used in the adj setting in early stage breast cancer?
What is the tox profile?
Tamoxifen
Can be used in both pre and post meno women, and men
SE inc:
- Vasomotor Sx
- DVT risk
- ENdometrial cancer risk
What are the three types of in situ breast cancer?
atypical ductal hyperplasia (ADH)
Lobular carcinoma in situ (LCIS)
Ductal carinoma in situ (DCIS)
How does ovarian suppression with GnRH work in breast cancer?
GnRH is usually secreted from hypothalamus in pulsitile fashion
Continuous high doses of GnRH (ie from exogenous agnoist) down regulates GnRH receptors in the anterior pituitary resulting in decreased LH and FSH secretion
After an initial spike in FSH and LH, this ultimately leads to reduced estrogen production by the ovaries
Can endocrine therapy be stopped to allow for pregancy in the adjuvant setting?
Yes
Can be stopped for up to two years then restarted
Nil significant increase in breast cancer rates
Given 2 examples of a HER2 Mab?
Trastuzumab
Pertuzumab
How does trastuzumab work?
HER2 receptor is part of the EGFR transmembrane tyrosine kinase receptors family
Trastuzumab stops the dimerisation with other HER2 receptors. THis induces antibody dependent cell mediated toxicity
Trastuzumab toxicity?
Usually very well tolerated
Can rarely cause cardiotoxcicity
- Asymptomatic LVEF decrease that is mostly reversible
- Monitor with 3 monthly TTE
How does pertuzumab work?
Stops dimerisation of HER2 and HER3 molecules
antibody depdnant cell mediated cell death same as trastuzumab
Provide some treatments that are used in metastatic breast cancer?
Endocrine therapies
Cell cycle inhibitors (eg mToR, CDK inhibitors)
MABs (ab-drug conjugates, immunotherapy)
TKIs
Chemo
BP/DMAB
treatment is very complex and individualized but takes into account the above
In which situation would the antibody drug conjugate trastuzumab deruxtecan be used?
HER2+ metastitic breast cancer
Name 2x Antibody drug conjugates that are used in breast cancer and a situation when they are used?
Trastuzumab emtansine ADC is better than trastuzumab alone in adj setting for HER2+ Ca if positive surgical margins
- this is less potent ADC than trastuzumab deruxtecan
Trastuzumab deruxtecan used in metastatic breast cancer HER2+
What are the two types of HER2 resistance mechanisms and two new drugs that target these resistance mechanisms?
Mutation of the intracellular kinase domain of the HER2 transcellular receptor results in increased constitutive signalling and downstream activation even if dimerisation is not allowed to occur (this is how activation usually happens)
- nernatinib
- Tucatinib
Co-occuring activating mutations in HER2 and HER3 can lead to enhanced downstream PI3K-AKT signaling pathways
- Alpelisib
What is Alpelisib and how does it work
Alpelisib is a PI3K inhibitor that is used in metastatic breast cancer after failure of CDK4/6i in those with an activating mutation in PI3K
Give some examples of CDK4/5i and explain how they work ?
Palbociclib, riociclib, abemaciclib
- these block the action of CDK4/5
- CKDs promote the pathway to transition from G1 to S phase of cell cycle
What is Fulvestrant and how when is it used?
Fulvestrant is a selective estrogen receptor down regulator
In hormone receptor positive post menopausal pts with metastatic disease, Fulvestrant + AI is better that AI alone
What of two molecules that block the kinase (intracellular) domain of HER2? and when are they used?
Nernatinib and Tucatinib
- Nernatinib is used in both early stage and advance / metastatic disease
- Tucatinib is used in advanced / metastatic disease only
What is an example of a chemotherapy- antibody conjugate that is used in metastitic triple negative breast cancer and how does it work?
Sacituzumab Govitecan
- Anti trophoblast cell surface antigen 2 (anti-Trop2)
- Trop 2 is upregulated in 90% of tiple negative Br Ca
