Breast Cancer 🎀 Flashcards
Risk Factors of Breast Cancer
- Age
- Inherited gene mutation BRCA1/2
- Overweight
- Alcohol
- Combined hormonal contraception
- Radiotherapy
- Smoking
- Food
- Race
- Age at first birth of first child
What does BRCA stand for?
BReast CANCER gene
BRCA1 and BRCA2 normal role…
Tumour suppressor genes
Ie. Encode proteins involved in DNA repair
Genetic mutations in BRCA1 or 2 cause…
- Germ-line mutations
- A lack of functional DNA repair protiens
- Breast cancer predisposing mutations
Luminal A …
HER2- / HR+
= Most favourable prognosis due to response of hormone therapy.
Luminal B…
HER+ / HR+
= Poorer prognosis than Luminal A.
HER2- enriched …
HER2+ / HR-
= Poorer prognosis than HR+ but improving after development of targeted therapies
Triple negative BC (TNBC) and
Basal Like BC (BLBC) ….
HER2- / HR-
=poorest prognosis, most aggressive
Cytotoxic Drugs for BC…
- Anthracyclines (doxorubicin, epirubicin)
- Alkylating agents (cyclophosphamide)
- Taxane (dovetail, paclitaxel)
- Platinums (carboplatin)
- Antimetabolites (flurouracil, methotrexate, capecitabine)
SERMS
Selective Estrogen Receptor Modulators… selectivity for?
Tissues
Objectives of SERMS (selective estrogen receptor modulators) … ×2
- Anti-estrogenic at breast &/or endometrium = inhibit tumour growth
- Estrogenic at other tissues (ie. Bone, liver, lipid, endrometriun)
Name SERMS drugs (×2) ….
- Tamoxifen
- Endoxifen
SERMS… Tamoxifen and endoxifen,
which drug has more affinity for ER?
Endoxifen
MOA of Aromatase inhibitors
Inhibit estrogen production,
By stopping conversion of androgens to estrogen.
Who are Aromatase Inhibitors indicated for?
Mainly POST- menopausal woman.
In PRE- menopausal, use WITH ovarian suppression (ie. GOSERELIN - Gonadotrophin- releasing hormone agonist).
Name AROMATASE INHIBITOR drugs…
- Anastrozole
- Letrozole
- Exemestane (steroidal AI)
Estrogen Receptor Antagonists MOA:
Competitively binds to ERs on cancer cells inhibiting Receptor dimerization = ER down-regulate.
Estrogen Receptor Antagonists, indicated for?
POST menopausal
… if disease progresses following use of SERMS
+ for ER+ advanced/metastatic.
Name Estrogen Receptor Antagonists…
Fulvestrant
(Fulvestrol)
ER Antagonist
Fulvestrant used in combo with?
Targeted therapies
CDK 4/6 Inhibitors
Why do we NOT dose Tamoxifen (SERM) based on CYP2D6?
No CYP2D6 guided dosing as…
Only 20-40% of variability in Endoxifen level is explained by CYP2D6 phenotype.
Drug switch in POST menopausal?
Use of AI’s in post-menopausal is favoured over Tamoxifen monotherapy.
*extended adjuvant endocrine therapy with AIs beyond 5 years =
Reduced secondary breast cancer occurrence
BUT MORE toxicity.
Targeted therapy
Name
Cyclin-dependant Kinase 4 & 6 (CDK4/6) Inhibitors ….
- Palbociclib
- Ribociclib
- Abemaciclib
TT:
Name
mTOR kinase …
Everolimus
TT: HER signalling pathway
Name
HER2 monoclonal antibody …
Trastuzumab
Pertuzumab
TT: HER signalling pathway
Name COMBO:
HER2 Receptor targeting with antibody-drug conjugate (ADC)…
- Trastuzumab - emtansine or T-DM1 (Kadcyla)
- Trastuzumab - deruxtecan (Enhertu)
Name Tyrosine kinase (TK) ….
Lapatinib (tykerb)
Neratinib (nerlynx)
MTOR kinase Inhibitors
Indicated for?
HR+ and HER2- adv. Breast cancer in POST menopausal after failure of treatment with letrozole abd anastrozole.
BOLERO-2 trial: everolimus + exemestane
HER signalling pathway and Tyrosine kinases - Receptor family?
ErbB family of Receptor Tyrosine kinases (RTKs) > ErbB2/HER2
HER2 activation results in cancer cell proliferation via… (×2)
- MAPK ( RAS, RAF, MEK, ERK) pathway
- PI3K / AKT / MORE pathways
HER2 monoclonal antibody: Trastuzumab MOA
Binds to HER2 extracellular domain, and inhibits kigand- independent HER2 signalling.
HER2 monoclonal antibody
Pertuzumab MOA?
HER2 Receptor dimerisation inhibitor.
Binds to the dimerisation site in the HER2 domain abd orients ligand- mediated pairing of HER2 with other HER2 Receptors (HER3) by steric hindrance.
Which drug has complementary action to trastuzumab? (Favourable combo)
Trastuzumab- taxane + PERTUZUMAB
Trastuzumab-emtasine (aka. T-DM1 or kadycla)
Indicated for?
2nd line for HER2+
And
1st line for HER2+ metastatic patients unsuitable for taxane based therapy
Trastuzumab deruxtecan (enhertu)
Indicated for?
Metastatic BC.
Who have recieved 2+ prior anti-HER2 based regimes.
**deruxtecan is 10× more potent thN SN-38
Targeted therapy:
Tyrosine Kinases (TKs) for HER2+
Name ×2
- Lapatinib (tykerb)
- Naratinib (nerlynx)
Tyrosine kinase
LAPATINIB
MOA
Dual tyrosine kinase inhibitor of HER2
Binds thr intracellular adenosine triphosphate binding domain of HER1 and HER2 and results in cell signalling inhibition.
Tyrosine kinase
Neratinib
MOA
Irreversible tyrosine kinase inhibitor that targets the human
HER1 (EGFR)
HER2
HER4
Targeted therapy
Trop2. Receptor
(Trophoblast Cell Surface Antigen 2 (Trop2) targeting with an ADC
NAME
Sacituzumab govitecan
(Trodelvy)
Trop2 Receptor
Sacituzumab govitecan
Indicated for?
Patients with unrepeatable locally advanced or metastatic triple-negative BC.
PARP proteins
(DNA damage repair)
Moa
Tumour collaboration with a mutated BRCA gene have trouble repairing damaged DNA -> blocking PARP proteins cancer cell death
TT with BRCA gene mutations
What is BRCA?
BRCA1 and BRCA2 genes protect against BC.
Name meds (2) for BRCA gene mutations patients
Olaparib
Tazoparib
Immune checkpoint Inhibitors PD-L1 blocked by
Atezolizumab + nab- paclitaxel
