Breast Cancer Flashcards
Breast screening programme in Australia
2 yearly mammogram for those between 50-74yo.
40-49, >75 are not invited, but have free access.
Features associated with BRCA1 or BRCA2 mutation
Invasive Ca <30 yo Triple -ve Br Ca <60 yo Invasive male Br Ca any age Ovarian/primary peritoneal Ca Ashkenazi Jew
What does BRCA 1 or BRCA2 do?
tumour suppressor genes. Codes for Ds DNA break repair. Mutation predisposes to homologous recombination deficiency
BRCA1 is associated with what kind of Ca?
Triple negative Br Ca
BRCA2 increases the risk of what kind of Ca?
Hormone Receptor + Br Ca
How do you minimise risk of Br Ca in patients w/ BRCA 1/BRCA2 mutations?
Bilateral mastectomy
Salpingo-oophorectomy post childbearing
Increase surveillance
Chemoprevention of Br Ca (before they get invasive cancer)
How does PARP inhibitor work with those with BRCA mutations?
PARP inhibition leads to tumour selective cell death via synthetic lethality
What does TAM01 study show?
Low dose tamoxifen is useful in preventing invasive breast Ca in patients with pre-malignant ER+ tumours.
When do you decide about curative intent vs. non curative intent?
Stage I-III disease that is resectable (or potentially resectable) is typically treated with curative
intent
• More intensive treatment regimens with higher rates of toxicity may be considered to be acceptable
• Stage IV disease is generally still considered to be incurable and treatment is typically with
palliative intent
• Intensive treatment regimens with high rates of toxicity are only considered acceptable under certain
conditions
Different subtypes of Breast Ca
HR+/HER- (65%) - best prognosis, late recurrence
HER2 + (20%) - poor prognosis, improved w/ target therapy
Triple -ve (15%) - poorest prognosis, late recurrence uncommon
Which type of breast Ca is associated with late recurrence?
HR+ breast Ca
General treatment principles of breast Ca
Primary tx: surgery + RT
Secondary: neoadjuvant or adjuvant therapy (hormonal tx, anti HER2 or chemotherapy)
If no distinct mets - then treatment intent is always curative.
Types of non invasive breast cancer
Ductal carcinoma in situ
Lobular neoplasm in situ
How do you decide treatment?
Prognostic factors ?rate of recurrence Predictive features ?will it work Anatomical features ?visual/physical findings If no physical features -> TNM status ER/PR status HER status
Precision oncology
Identifying gene expression pattern. This can help refine prognostic estimate.
What is Oncotype Dx?
a 21 gene expression assay that stratify HR+, node-ve early breast cancer by likelihood of benefit to adjuvant chemotherapy
Benefit of dose dense (neo) adjuvant chemotherapy
Most Node + BC will be treated with adjuvant chemotherapy (3rd generation anthracycline and taxane).
As per lancet 2019, Dose dense regimen can moderately reduce the risk of recurrence and death from breast Ca.
What is neoadjuvant treatment?
treatment given prior to surgery (chemotherapy, HER2 targeted therapy or endocrine therapy.
Rationale for neoadjuvant treatment
- refine prognostic estimate
- identify patient with complete pathological response (pCR)
- identify high risk population that may benefit from escalation/change of adjuvant treatment
- unresectable tumor more resectable
- understand disease biology
Mainstay adjuvant treatment for HR+, HER2- early breast Ca
endocrine therapy:
1st line: Aromatase inhibitor
2nd line: Tamoxifen
Tamoxifen
MOA, side effect, toxicities, clinical utility
MOA: selective estrogen receptor modulator
S/E: menopausal - hot flushes, myalgia, vaginal atrophy
Risk: VTE + endometrial cancer
Utility: pre or post menopausal
Aromatase inhibitor:
MOA, side effect, toxicities, clinical utility
MOA:
- block endogenous conversion of androgen to estrogen
- doesn’t inhibit ovarian estrogen
- e.g. anastrazole, letrozole, exemastane (steroidal)
S/E: menopausal symptoms - hot flushes, myalgia, vaginal atrophy
Toxicities: accelerated bone loss
Clinical use: post menopausal, pre menopausal (w/ GnRH) as can cause paradoxical rise in estrogen level
Benefit of ovarian function suppression (OFS)
- OFS + tamoxifen in pre-menopausal symptoms show superior disease free survival.
- OFS + exemestane is even greated DFS
- greater benefit in high risk disease patient (adjuvant chemo, very young <35)
Principle of combination chemotherapy treatment of metastatic disease
- combination vs. sequential single agent chemo
- single agent preferred in absence of rapid clinical progression, life threatening visceral mets, need for rapid symptom control.
Cyclin dependen kInase 4/6 inhibitor
Example, MOA, Clinical use, side effect
“ciclib” - e.g. ribociclib, palbociclib
CDK4/6+CyclinD phosphorylates Rb, releasing E2F and progression of cell cycle.
Inhibiting this reduce Rb phosphorylation and prevent cell cycle progression.
FOr luminal breat Ca (HR+), 1st line w/ aromatase inhibitor.
S/E: neutropenia, LFT derangement, QTC prolongatin
alpha P13K inhibitor
Example, MOA, Clinical use, side effect
e.g. alpelisib
MOA: P13K signaling pathway is complex and leads to proliferation. P1rK pathway is enriched in BrCa.
clinical use: endocrine resistant HR+ HER2- advance Br Ca
S/E: rash, hyperglycaemia, N+V/diarrhoea
T-DM1
Example, MOA, Clinical use, side effect
e.g. trastuzumab-emtansine
MOA: antibody drug conjugate, when binds to HER2R, DM1 is internalised and is cytotoxic.
clinical use: 2nd line for advanced HER2+ Br Ca
S/E: thrombocytopenia, liver toxicity
Immune check point blockade
Example, MOA, Clinical use, side effect
e.g. atezolizumab, pembrolizumab
MOA: Cancer upregulate PDL1 to promote immune escape. block PD1/PDL1 interaction between tumour cell+ cytotoxic T cell. so immune system can block this.
Clinical use: Atezolizumab+paclitaxel as first line therapy in triple negative breast Ca.
S/E: immune related - rash, colitis, etc
Treatment of brain mets
common in triple negative + HER2+ breast Ca
whole brain radiotherapy only if surgery or sterotactic RT unsuitable.
