Breast CA Molecular Profiling Flashcards
What are the 5 intrinsic breast cancer subtypes?
Liminal A, luminal B, Her2, normal-like and basal-like
What are luminal breast tumors?
They show expression patterns similar to normall luminal breast epithelial cells, including expression of low molecular wt cytokeratin 8/18, ER, and genes associated w/ an active ER signaling pathway.
What is the prognosis for luminal A tumors?
Excellent prognosis
Luminal A tumors usually have what histologic characteristics?
low grade, high amount of ER
Luminal A tumors have high or low ER expression?
High ER expression
What is the prognosis for luminal B tumors?
Poor prognonsis than luminal A
Luminal B tumors usually have what histologic characteristics?
Associated with a higher histologic grade and lower ER expression compared to luminal A
HER2 stands for
Human epidermal growth factor receptor-2
HER2 tumors are usually ER positive or negative?
Negative
HER2 tumors are associated with overexpression of the HER2 amplicon on what chromosome?
17q12
What breast cancer subtype does a HER2+ and ER+ cancer fall into?
Luminal B
What molecular profile do basal-like breast cancers have?
High molecular wt cytokeratins 5/6, 14 and 17; Her1; and smooth muscle actin
Basal-like cancers have what histologic characteristics?
High grade and poorly differentiated
Basal-like cancers have what prognosis?
Poor
What is the most common receptor status for basal-like breast cancers?
ER-/PR-/HER2-
What % of triple negative breast cancers display basal-like expression patterns?
70%
What % of basal-like breast cancers are triple negative?
77%
Basal-like tumors are more common in what demographic?
Younger women, women of African descent and typically in carriers of BRCA1
Luminal A accounts for what % of all breast cancers?
50%
Luminal B accounts for what % of all breast cancers?
10%
HER2 subtype accounts for what % of all breast cancers?
5-10%
Basal-like subtype accounts for what % of all breast cancers?
30%
What is the usual receptor status for Luminal A breast tumors?
ER+, PR+, HER2-, CK8+, CK18+
What is the usual receptor status for Luminal B breast turmors?
ER+, PR+/-, HER2 +/-
What is the usual receptor status for HER2 breast tumors?
ER-, PR-, HER2+
What is the Amsterdam signature?
A 70-gene expression profile described by Van de Vijver that were classified patients into a good or poor prognosis group. Currently being validated.
What is the Amsterdam signature 10-year disease-free survival in women with a good or poor prognosis.
Good 94.5%. Poor 50.6%.
What is Oncotype Dx?
A 21-gene assay using RT-PCR to estimate a recurrence score to predict risk of recurrence.
What is the Oncotype Dx 10 year disease-free survival in women with a high or low risk designation?
High 69%. Low risk 98%.
What is the TAILORx trial?
Trial dedicated to testing what therapy is best (hormonal or chemo/hormonal therapy) in Oncotype Dx intermediate-risk women.
What ER subunit is used in assays for clinical practice?
ER alpha subunit. Not beta. Not much is known about the beta subunit.
Is PR expressed as a result of ER activation?
Yes.
What is a SERM?
Selective ER modulator.
What are two commonly used SERMs?
Tamoxifen and raloxifene.
How does tamoxifen and raloxifene work?
They interact directly with the ER, binding to inhibit estrogen-dependent transcription in the breast but maintaining agonist activity at other sites.
How does fulvestrant work?
It is an ER antagonist, binds to ER, induces degradation of ER protein. No agonist activity.
Adjuvant tamoxifen reduces the odds of breast cancer recurrrence and death by
40-50% reduction in recurrence. 30% odds reduction in death.
What kind of receptors are EGFRs or the erbB family?
Epidermal growth factor receptors are transmembrane type 1 tyrosine kinase receptors
What are the erbB subtypes?
erbB1, erbB2 (HER2/neu), erbB3 (HER3), and erbB4 (HER4)
What are the 3 basic features of the erbB receptors?
- N-terminus extracellular ligand-binding region
- Transmembrane domain
- Intracellular region containing the tyrosine kinase domain
Do all of the erbBs have an endogenous ligand?
No. HER2 does not. All the others (erbB1, erbB3, erbB4) do not.
Of the erbBs which one has the strongest kinase activity?
HER2
What are the best described HER-induced signaling pathways?
PI3k/AKT, Ras/MAPk and PLC/PKC
Where is the HER2 gene located?
Chromosome 17q
What kind of gene is HER2?
Proto-oncogene
What is lapatinib?
An oral reversible small-molecule dual inhibitor of both HER1 and HER2 kinases.
Is HER2 dependent on its HER family partners (the other erbBs) for tumorignesis?
Yes. Particularly HER3.
What is the primary oncogenic signaling pathway activated by the HER2-HER3 heterodimer?
PI3K/AKT pathway, mediated through the tyrosine phosphorylation of HER3.
What cell functions are regulated by the PI3K/AKT pathway?
Proliferation, growth, apoptosis, angiogenesis and invasion of cancers
Other than HER2/HER3 activation, the PI3K/AKT pathway can also be activated by loss of what tumor suppressor gene?
PTEN
EGFR is also known as which of the erbBs?
erbB1 or HER1
What heterodimer has been proposed as the master regulator of the signaling network that drives breast CA epithelial cell proliferation?
HER2/EGFR
Trastuzumab inhibits what signaling pathway?
PI3K/AKT, NOT Ras/MAPK (the latter also activated by EGFR/HER2 heterodimer)
The EGFR/HER2 heterodimer activates which signaling pathways?
PI3K/AKT and Ras/MAPK
How are tumoral microvessels are different from normal vessels?
Tumoral microvessels frequently lack complete endothelial linings, and basement membranes, are irregular, tortuous, more permeable
What is bevacizumab?
Recombinant humanized monoclonal antibody that recognizes all isoforms of VEGF-A
What kind of breast cancer demonstrates high-expression levels of VEGF-A and VEGFR-2 (receptor-2)?
Inflammatory breast cancer
Mutations in BRCA1 and BRCA2 cause what cell deficits?
Inability of cells to properly sense DNA damage, transmit the damage response signal or repair DNA by homologous recombination.
What kind of DNA repair must cells with BRCA mutations use?
Single-strand annealing and nonhomologous end-joining mechanisms, which are particularly error-prone and lead to genomic instability
What is PARP1?
Poly-ADP-ribose polymerase-1: An enzyme that functions as a DNA damage sensor for both single- and double-strand breaks.
What is PARP2?
Poly-ADP-ribose polymerase-2: Plays a role in base excision repair by homodimerization and heterodimerization with PARP1.
What roles do PARP1 and PARP2 play with DNA maintenance?
Maintenance of genomic stability by regulating DNA repair mechanisms
What role do PARP1 inhibitors play with BRCA1 and BRCA2 tumors?
PARP1 inhibitors reduce repair of both single- and double-strand breaks, resulting in increased DNA damaging agents like cisplatin.
What are topoisomerases?
Enzymes that catalyze the transiet breaking and rejoining of DNA strands thereby regulating transcription
Where is the TOP2A chromosome location?
Topoisomerase II is located at 17q12-21 near the HER2/neu gene
How is TOP2A a target for chemotherapeutic agents?
TOP2A is inhibited by trapping DNA strand break intermediates, leading to peristent DNA cleavage. Thus TOP2A cannot regulate transcription.
What are microRNAs?
Non-protein-coding RNAs, 18-25 nucleotides in length, that modulate gene expression by targeting mRNAs for translational suppression or mRNA cleavage.
T/F: MicroRNAs may play a role in breast tumorignesis?
True. They may act as oncogenes or tumor suppressors.
