21 Breast cancer Flashcards
Which one has a better prognosis:
ER positive or PR positive
1) Both are associated with a better prognosis;
2) Showed benefit from hormone-targeted therapies like tamoxifen.
ER
estrogen recepter
PR
progesterone receptor
What is the original hormone receptor test used to detect the level of ER or PR in breast cancer?
Ligand-binding assays:
1) use fresh tissue;
2) inability to separate our the contribution of
noninvasive tissue from invasive;
3) use radioactive probe
What is still the standard hormone receptor testing for breast cancer?
IHC for hormone recepters
How is FISH used in breast cancer diagnosis?
1) Detect the gene amplification of HER2 (human epidermal growth factor receptor 2)
2) New standard practice
HER2
1) human epidermal growth factor receptor 2;
2) A transmembrane receptor tyrosine kinase;
3) located on chr. 17
Germline mutations testing for breast cancer
BRCA1 and BRCA2
Breast cancer risk management testing
Genetic testing:
1) BRCA1 and BRCA2;
2) test for resistance to endocrine therapy
single-marker testing for breast cancer
1) hormone receptor ER or PR testing;
2) HER2 FISH
% of breast cancer associated with HER2 overexpression
1) 10-15%;
2) HER2 overexpression drives an aggressive clinical course
what causes the HER2 overexpression in patient?
1) HER2 gene amplification;
2) leads to 40- to 100-fold increase of HER2 protein
HER2 positive breast cancer prognosis
aggressive and poor survival rate
Trastuzumab (aka. Herceptin)
1) The humanized monoclonal antibody;
2) Bind to HER2 and block downstream signaling pathways
3) Herceptin is for HER2 positive patient
HER2 testing CAP and ASCO guidelines
1) First HER2 overexpression IHC
2) if the result is equivocal (uncertain), do FISH or other in situ hybridization for HER2 overexpression
what causes HER2 IHC false positive?
over-staining or over interpretation
Describe HER2 FISH
1) use fluorescent-labeled DNA to detect:
– HER2 alone (single-probe);
– HER2 and centromere of chromosome 17 (CEP17) (dual-probe);
2) Specimen: FFPE;
3) need to make sure only the invasive carcinoma is scored;
4) Count the clusters with more than 10% of HER2 amplification;
5) Count a minimum of 10 cells/area, and count two areas at high power (oil immersion)
What is reported out for single-probe HER2 FISH?
HER2 copy number
What is reported out for dual-probe HER2 FISH?
1) CEP17 is used as an internal control;
2) Signals ratio of HER2:CEP17 is reported;
3) Mean HER2 and CEP17 absolute per cell counts are also reported
For FISH HER2 or HER2/CEP17, what is the criteria for “Positive HER2 amplification” category?
Ratio ≥ 2 and/or Gene copies ≥ 6
For FISH HER2 or HER2/CEP17, what is the criteria for “Equivocal HER2 amplification” category?
Ratio <2 and Gene copies 4.0 - 5.9
For FISH HER2 or HER2/CEP17, what is the criteria for “Negative HER2 amplification” category?
Ratio <2 and Gene copies <4
What are the nonclassical results of FISH HER2 considered as HER2 positive and eligible for treatment with HER2-targeted agents?
1) polysomy or coamplified cases (≥6 HER2 copies/cell with concurrent increases in CEP17);
2) Monosomy: cases with amplified ratio but less than 4 HER2 copies/cell;
3) Low amplified: cases with Ratio ≥ 2 but Gene copies 4.0 - 5.9;
4) Heterogenous: cases with a clustered subpopulation of cells with HER2 amplification in at least 10% of the total population
Four main molecular/intrinsic subtypes of breast cancer
1) Luminal A: ER positive, PR +/-, HER2 -, low ki67;
2) Luminal B: ER positive, PR +/-, HER2 +/-, increased ki67
3) HER2-related: HER2 positive, ER +/-, PR +/-
4) Basal-like: triple negative (ER - , PR -, HER2 -)
Which molecular subtypes of breast cancer are ER+?
Luminal A and B
Which molecular subtype of breast cancer is triple negative?
Basal-like
How can you differentiate luminal A and luminal B breast cancers?
luminal B has:
higher proliferation rate; increased ki67;
lower levels of hormone receptors
Why is it important to identify ER+ breast cancers?
Patients can benefit form chemotherapy as an adjunct to hormone targeted therapies.
What is the demographic of basal-like breast cancer?
Younger patients;
African-American women
Are BRCA1-associated breast cancer associated more to luminal subtypes or basal-like?
Basal-like gene profile;
suggest a common pathways of carcinogenesis
Can basal-like or triple negative breast cancers predict BRCA1 mutations in the patients?
No
Can a patient HER2+ show luminal B molecular profile?
Yes;
Patient may not respond to HER2 targeted treatment but we should not withhold the treatment from these patient
Which molecular breast cancer subtypes has Good prognosis?
Luminal A
Which molecular breast cancer subtypes has Intermediate prognosis?
Luminal B
Which molecular breast cancer subtypes has Worse prognosis?
HER2 and Basal-like
What targeted therapy is used for luminal A and B breast cancers?
Tamoxifen;
Hormone therapies
What targeted therapy is used for HER2 breast cancers?
Herceptin;
HER2-targeted therapies
Which molecular breast cancer subtypes respond Better/Higher to chemotherapy?
HER2 and Basal-like
Which molecular breast cancer subtypes respond Lower to chemotherapy?
Luminal A
Which molecular breast cancer subtypes respond Intermediate to chemotherapy?
Luminal B
Commercial molecular tests used to classify breast cancer
Prosigna PAM-50 uses NanoString’s nCounter technology;
Agendia BluePrint - microarray, 80 genes used;
Agendia MammaPrint - microarray, 70 gene classifier used
What is NanoString’s Prosigna breast cancer assay?
1) based on the 50 gene expression signature;
2) The test outputs a risk of recurrence (ROR) score, risk category, and intrinsic subtype (Luminal A/B, HER2-enriched, Basal-like).
3) In USA, FDA only approved reporting of ROR
What is the technology used for NanoString’s Prosigna breast cancer assay?
1) NanoString’s nCounter technology:
uses a digital barcode that allows for direct multiplexed measurement of gene expression using color-coded probe pairs;
2) no amplification step
How is a MammaPrint done?
1) MammaPrint tests for a group of 70 genes.
The results of the MammaPrint test help predict the chance of metastasis for some ER-positive, HER2-negative breast cancers;
2) categories of high or low risk of metastasis;
3) Used with BluePrint to further classify luminal breast cancers into A and B
How well does PAM50 correlate with BluePrint?
1) correlation as low as 59%;
2) Both tests correlate well for Basal-like classification;
3) Variable in classify luminal A and B
Commercial molecular tests used to predict outcomes in breast cancer
1) OncptypeDX:
- to determine which ER+ but lymph node-negative patients may not benefit from chemotherapy;
- RT-PCR of 16 cancer-related genes and 5 control genes;
2) MammaPrint/BluePrint: most useful in ER+ patients;
3) PAM50
What kind of genes are used to predict recurrence risk of breast cancer by common commercial panels such as OncotypeDX, MammaPrint?
proliferative genes:
this makes sense since chemotherapy targeting rapidly dividing cells
Example of genes detected by OncptypeDX
ER, PR, HER2, ki67, other proliferative genes
What are the risk categories of OntotypeDX?
1) Low (RS<18)
2) Intermediate (RS=18-30)
3) High (RS>30)
The limitation of molecular tests in comparison to IHC and ISH testing in breast cancer
1) the possibility of the contribution of noncancer tissue to confound results: intermixed inflammation, in situ carcinoma or desmoplastic stroma may influence the result
Are there any genes can be used as molecular markers for tumor size or nodal status in breast cancer?
1) No.
2) prognostic information captured by histopathological method is not captured by current prognostic gene signatures
