Breast Flashcards
1) Early breast cancer is defined as:
2) St Gallan’s definition of low risk:
1) Limited to breast and axilla
2) Age >35, AND Node -Ve AND T<=2cm AND no LVSI/peritumoral vascular invasion AND ER/PR expressed AND no HER2/neu amplification/overexpression
St Gallan’s intermediate risk group features:
1) Int Risk NODE -Ve &1 OR more of the following:
Age <35, T>2cm Gr II/III, Extensive LVI, ER and PR absent, HER2/neu amplification/overexpression
2) Int Risk NODE +Ve (1-3) & ER/PR expression AND no HER2/neu amplification/overexpression
St Gallan’s high risk group features:
1) Node + ve (1-3) AND lack of ER and PR, OR HER2/neu amplification/overexpression
OR
2) 4 or more nodes +Ve
“non-genetic” Risk Factors for breast cancer:
1) Estrogen Exposure: Female gender, older age, early menarche, nulliparity, older age at first birth
(>30 years), lack of breastfeeding, late menopause (>55 years), hormone replacement therapy.
2) Lifestyle/Exposure: High-fat diet, postmenopausal obesity, sedentary lifestyle.
3)Personal History of Breast Disease: Prior breast cancer, DCIS, LCIS, atypical ductal hyperplasia.
4) dense breast tissue.
5) history of RT during youth (age <30 years).
Describe how risk of BrCa changes with increasing family Hx.
Key High risk genes:
1) Family History: Risk increases with more first-degree relatives.
2 ) Genetics (5%–10% hereditary):
BRCA1 (17q21)
BRCA2—(13q12)
Li–Fraumeni—AD (17p), p53,
Cowden syndrome—AD (10q23), PTEN,
ATM;
Peutz–Jeghers.
Site of chromosomal abnormality of BRCA 1 &2
Normal role of these genes
BRAC1 = 17q21
BRAC2 = 13q12
Normal function in DNA repair: Homologous recombination, crosslink repair, and protection of stalled repair sites.
Leading to cell survival and genomic integrity.
Contribution of genetics to BrCa risk:
Describe the BRCA 1 cancer risks:
Describe the BRCA 2 cancer risks:
Genetics (5%–10% hereditary):
BRCA1—AD (17q21), 60% to 80% lifetime risk of breast cancer, 30% to 50% lifetime risk of ovarian cancer, higher risk of triple negative (ER−/PR−/HER2−);
BRCA2—AD (13q12), 50% to 60% lifetime risk of breast cancer
10% to 20% lifetime risk of ovarian cancer, male breast cancer, prostate, bladder, endometrial, and pancreatic ca.
Describe the BRCA 2 cancer risks:
BRCA2—AD (13q12), 50% to 60% lifetime risk of breast cancer
10% to 20% lifetime risk of ovarian cancer, male breast cancer, prostate, bladder, endometrial, and pancreatic ca.
Describe the glandular tissue of the breast.
With reference to this, outline the both the most, and the least common sites of cancer:
Glandular tissue is arranged in 15 to 20 lobes with a system of lactiferous ducts that open at the nipple.
UOQ contains the greatest volume of glandular tissue (most common location of breast cancers).
The least common location is the lower inner quadrant.
Very simple description of the location of axillary node levels I, II and III
Relative to pec minor which inserts into the corocoid process of the scapula:
Levels I = inferolateral,
II = Deep
III = superomedial to pectoralis minor
Where is Rotter’s?
Between pec maj and min (anterior to level II).
Anatomical location of IMN:
Frequency of node +ve tumours draining to this site
IMNs are situated along IM vessels adjacent to sternum in the 1st 3 intercostal spaces, ~2 to 3 cm lateral to midline, and 2 - 3 cm deep.
Approx 30% of medial tumors and 15% of lateral tumors drain to the IMN.
Fill in the gaps:
ER and/or PR are expressed in X% of tumors (more common in ?).
HER2/neu (c-ERbB-2 or human epidermal growth factor receptor 2) is a ______ ________ _______, with HER2 amplification seen in Z% to Y% of invasive cancers.
Trip -ve occurs in ~W% of cases and more commonly
found in _____ mutation carriers.
ER and/or PR are expressed in 70% of tumors (more common in postmenopausal
patients).
HER2/neu (c-ERbB-2 or human epidermal growth factor receptor 2) is a receptor tyrosine kinase, with HER2 amplification seen in 25% to 30% of invasive cancers.
TNBC occurs in ~15% of cases and more commonly
found in BRCA mutation carriers.
Differentiate between N1, N2, and N3 breast cancer
cN1 = moveable level I or II ipsilateral nodes
cN2 = Fixed
cN3 = Level III nodes or SCF or IM + level I &/or II
Key pathological features of Invasive ductal carcinoma:
80% cases. Often well seen on mammogram. Firm mass with desmoplastic reaction, invades through basement membrane, solid
cords of cells.
Invasive carcinoma with evidence of mammary epithelial origin either by morphology or immunohistochemistry
Diagnosis of exclusion, lacks the histologic features to classify morphologically as a special subtype of breast cancer.
Desmoplastic reaction to tumor = the growth of fibrous connective tissue around tumor cells
Key pathological features of Invasive lobular carcinoma:
10 to 15% of cases overall, more common in women 45-55, estrogen exposure appears a greater risk factor (e.g. HRT),
CDH1 mutation increase risk of lobular but not ductal cas,
BRAC2 increases risk of both : rubbery texture, poorly visible on mammogram (better w/ MRI).
“Indian filing” histology,
Often bilateral/multicentric,
>80% ER+,
spreads to unusual locations such as meninges, serosal surfaces, BM, ovary, and RP - ?WHY????
Example of in-situ hybridisation test for breast cancer
HER2 status into absent, equivocal or present (0-1, 2+, 3+) based on IHC and FISH single probe (for gene copies, >= 6 suggests +ve) and double probe for ratio Her2:CEP17 where >=2 suggests Her2 +ve
What does CEP17 mean?
CEP17 stands for chromosome enumeration probe 17, which means that the cancer cells have more than one chromosome 17
Examples of some DNA microarray tests in breast cancer
Of prognostic value, only Oncotype Dx has validation for prediction and can be potentially beneficial in identifying low-risk patients not requiring CTX.
Oncotype Dx - 21 gene array (16 cancer genes and 5 controls). The current on
Mamma Print (Amsterdam-70) - RCT prognostic validation - despite clinical high risk, low genomic risk pts have 95% distant met free survival without chemo
Some gene profiling models for breast cancer:
Amsterdam 70-gene good-versus-poor outcome model (low signature vs. high signature),
The 21-gene recurrence score model (Oncotype Dx)
Intrinsic subtype model
Why was oncotype DX developed:
Key finding for 1 group in this study
The 21-gene recurrence score (Oncotype DX) was developed for pts w/ LN-negative, ER+ BrCas, receiving tamox ± CHT on NSABP B-14, and is stratified into low risk (<18 score), intermediate risk (18–30), and high risk (>30) of recurrence in order to estimate the relative benefit of CHT in addition to hormonal therapy.
Rates of distant recurrence in the low-risk, intermediate-risk, and high-risk groups were 6.8%, 14.3%, and 30.5% at 10 yrs. TAILORx found noninferiority of endocrine therapy alone over endocrine + CHT in women w/ int risk (score of 11–25)
NZ screening guidelines for general population.
Compare (if you can be bothered) to the
Mammo every 24 months if:
1) Aged 45 – 69 years (in Aust women 40-50 can ask and get)
2) no sx of breast cancer
3) not had a mammogram in the last 12 months
4) not pregnant or breastfeeding
USPSTF: Biennial screening for age 50 - 74,
- no routine screening for 40 to 49 (self-ex controversial).
- High-risk women should begin screening 10 years before age of youngest first-degree relative diagnosed.
- Insufficient evidence for benefit/harm of clinical exam; however, recommended against teaching breast self-examination.
Evidence for breast screening in elderly women
There is no evidence that regular breast screening reduces the rate of deaths from breast cancer in women over 75 years.
This does not apply to:
- Pt w/a mother or sister who had brCa before menopause or developed bilat cancer
- Prev breast cancer
- Prev Bx of breast tissue showing an ‘at-risk lesion’.
Benefit of breast screening program
Evidence suggests that for women >=50, risk of death from brCa is reduced by ~1/3 with 2 yearly mammograms. In women 45 - 50 yrs, the risk of death from brCa is reduced by a 1/5 with reg mammography.
Evidence for general BrCa screening before age 45
The false positive rate (due to lower incidence and more importantly dense breast tissue causing poorer scan and higher frequency benign lesions) is high and leads to unnecessary invasive investigations,
Which younger women (define younger) may benefit from screening? - what is the general advice?
For women ages less than 45, (ACS) indications are:
Screen at 25 to 30 y/o for BRCA mutation carriers and untested first-degree relatives of carriers;
Screen 8 years after or at 25 y/o (whichever is later) for women who received mantle RT/thoracic
RT between 10 and 30 y/o.
Screen annually for women with biopsy-proven lobular neoplasia, atypical ductal hyperplasia, or personal history of breast cancer beginning at diagnosis, but not
when <30 y/o.
Evidence for self Exam:
Meta and RCT show no diff in size or stage of BrCa at Dx or in the number of deaths from BrCar for women taught to use a systematic approach for breast self-examination vs those who did not receive instruction. Trials were in Russia and China and involved large numbers. While applicability for Australia/NZ has been questioned.
A UK study of over 63,000 women 45–64 has shown no difference in the number of deaths from breast cancer after 16 years of follow-up.
For women at high risk of breast cancer and age <50 what should be considered
Bilateral breast MRI screening (funded by medicare).
ACS guidelines: screening MRI for women with 20- 25% or greater lifetime risk of BrCa, including women with hereditary mutations (BRCA, Li–Fraumeni, Cowden), strong FamHx of br/ovarian ca, and women who received prior thoracic RT for Hodgkin’s disease before age 30
On Hx a breast mass is less concerning for malignancy if?
Is less concerning if associated with changes in menstrual cycle.
The “benefit” of whole breast irradiation following BCS for early breast cancer:
Large population Prevalence statistics and meta analysis of numerous RCT trials suggests: WBI after BCS improves LR rates (from 26% to 7% at 5 years about a 2/3 reduction) and OS by 5% at 15 years.
“Cancer treatment and survivorship statistics, 2019”
Older meta-analysis (2014) suggests that for post menopausal women on systemic therapy (mostly Tamox), with ER+ve, node -ve, <=T2, an NNT of 24 to prevent 1 recurrence.
The most common histologic scoring system for determining breast cancer grade:
Nottingham Histologic Score system (also termed “the Elston-Ellis modification of Scarff-Bloom-Richardson grading system” modified SBR)
Broad outline of Nottingham Histologic Score system
Each of the 3 features graded 1-3:
1) Amount of gland formation (how well cells differentiate into normal glands, e.g >75% gland = grade I)
2) Nuclear features (degree of pleomorphism, e.g vesicular nuclei + prominent nucleoli + marked nuclear variation in size and shape = grd 3)
3) Mitotic activity/ 10HPF (grd 1 =<7 & grd 3>16)
The final total score (range 3-9):
Grade I tumors have a total score of 3-5
Grade II tumors have a total score of 6-7
Grade III tumors have a total score of 8-9
Cystosarcoma Phyllodes - risk factor, cell origin, histo, and grading.
Linked w/ Li-Fraumeni (p53 tumour suppressor gene) syndrome (SBLA)
Origin is stromal cells
Fibroepithelial, “leaf-like” (Phyllode is Greek for leaf) large, encapsulated tumors, usually benign
w/o invasion.
Classified into: benign, borderline and malignant grade. Based on stromal cellularity, atypia, mitotic count, stromal overgrowth, and the nature of tumour borders.
For SBLA syndrome, what does SBLA stand for
- Sarcomas
- Breast cancers (breast Ca before age 40 most common clinical presentation in females).
- Leukaemia
- Adenocortical carcinoma (almost pathognomonic)
Also primary brain, especially GBM (13%)
Relative incidence, clinical and pathological features of Lobular carcinoma:
5 to 10% of cases
Rubbery texture, less visible on mammogram
(better imaged with MRI),
“Indian filing” histology, often bilateral/multicentric, >80% ER+, spreads to unusual locations such as meninges, serosal surfaces, BM, ovary, and RP.
Name some rarer subtypes of breast cancer:
In general what histological criteria needs to met to allow such a Dx?
Need >90% Predominant Pattern:
1) Tubular—small, well-differentiated variant of IDC, >75% tubules (think SBR score), usually ER+/PR+.
2) Medullary—aggressive subtype of IDC a/w BRCA1, presents at younger age (<50), LNs are large/hyperplastic, most are triple negative. Appear lobular or nodular with foci of hemorrhage, often necrosis, and cystic degeneration
3) Mucinous/colloid—older patients, favorable.
4) Papillary—older patients, often multifocal/diffuse, often LN+ even when small size.
5) Cribriform—ER+/PR+.
Other uncommon variants include metaplastic (poor prognosis), squamous cell, invasive micropapillary, adenoid cystic, mucoepidermoid, secretory, apocrine, spindle cell, lymphoma, neuroendocrine small cell, and clear cell.
Mammary carcinoma is a mixture of invasive ductal and lobular carcinoma.
Features of mucinous and papillary breast carcinoma
1) Mucinous/colloid—older patients, mucinous component that comprises > 90% of tumor, ER and PR hormone receptor positive and HER2 negative (luminal A subtype), favorable prognosis.
2) Papillary—Rare subtype of IDC, older patients, often multifocal/diffuse, invasive papillary growth.
What is EIC? Definition?
What is its significance?
Extensive Intraductal Component: Defined as ≥25% DCIS within the invasive carcinoma specimen and extending beyond edges
of tumor.
Was identified as a risk factor for LR after BCT, but no longer considered the case provided margins are negative. (But think TROG 2022 DCIS boost study..)
Describe Paget’s disease of breast:
Chronic eczematous changes of the nipple–areolar complex, with underlying intraepidermal adenocarcinoma of the nipple (in 95%). About 50% have a palpable mass (>90% are invasive cancer) and 50% have no mass (typically DCIS).
Low risk of axillary nodal mets.
System for describing breast lesions on imaging:
BI-RADS
0 = incomplete imaging
1= Negative (<%1 risk malig)
6= Bx proven malignancy
Initial work-up (Hx and Ex) of a breast lump:
Full Hx&Ex:
Hx:
- Duration/1st noticed, growth, tenderness, size/Symptom relation to menstrual cycle.
Risk Factors: age, Fam Hx (1st degree relatives) previous Hx of cancer or thoracic radiation age <30.
Estrogen exposure (e.g. nullparity, age>30 1st child, HRT ect). EtOH, obesity/sedentary lifestyle.
Ex: full bilateral breast and nodal (Ax+SCF) - see other slide
Non-malignant DDx for a breast lump:
1) Fibroadenoma (solitary mass, well defined, mobile)
Cysts (more diffuse and less firm, suspicious if blood in aspirate or contents reaccumulate quickly);
2) Infection (mastitis or abscess);
Mondor’s cord (thrombophlebitis of superficial breast veins);
3) Fat necrosis;
4) Intraductal papilloma (common cause of bloody discharge);
5) Sclerosing adenosis (nodular benign condition consisting of hyperplastic lobules of acinar tissue);
6) lactocele.
7) Phylodes tumour
The Intrinsic Subtype Model of genetic risk suggests that their are X intrinsic sub stypes. What are they?
There are four main intrinsic subtypes (in order of risk):
Luminal A (best prognosis),
Luminal B,
HER2 enriched (HER2+), and
Basal-like (worst prognosis)
A 55yro woman presents with a 1 month Hx of a ~2cm firm/rubbery breast lump. Nil other concerning features on Hx and Ex. What further workup?
Bloods: LFT/alk phos (indicated distant disease) + RFTs (for suitability for systemic options).
Mammogram and uss (+/-Bx) are typical 1st steps.
Systemic staging workup is not routinely indicated per NCCN for anatomic stages I to II in the absence of suspicious symptoms, physical exam findings, or lab abnormalities (e.g., elevated alk phos or LFTs).
If suspicious, studies may include PET/CT or CT CAP and bone scan, ± MRI brain.
How are mammogram orientated?
Key indicator of study quality?
Key concerning findings?
On CC view, the lateral edge of the film is typically marked by “CC” marker. On MLO view, assess for image quality by ensuring pectoralis muscle is included. Concerning mammographic findings:
calcifications 100 to 300 microns,
>10 clustered linear calcifications,
spiculated lesions.
Role of USS in Ix of a breast lump:
Determine solid vs. cystic masses (not useful for calcifications) and evaluate nonpalpable masses identified on mammogram.
Compare mammogram to MRI for screening:
Possible indications for MRI:
Higher sensitivity (>90%) than mammography, but lower specificity (39%–95%) due to false
positives. Suspicious features for malignancy: strong, rapid contrast enhancement, spiculated margins, rim enhancement, heterogeneous appearance.
Possible MRI Indications:
Obscured breast (silicone implants), suspicious masses w/ -ve mammogram and uss,
evaluation of poorly imaged tumors such as ILC or DCIS without microcalcifications, or pts presenting with positive axillary nodes of unknown primary (MRI detects primary tumor 80%–90% of the time).
The utility of MRI prior to breast conservation surg:
MRI can change surgical management in 25% of cases but does not reduce +ve margins, re-excision rates, or LR rates.
Prognostic factors in early breast Ca
LN+ (strongest factor), young age, ER/PR
negativity, HER2/neu amplification (in the absence of HER2-directed therapy), high grade, LVSI+,
basal-like subtype
Predictive factors in early breast cancer:
Identification of clinically useful predictive markers has not been as successful as the identification of prognostic ones. Factors that predict response to directed therapies:
ER is probably the most powerful predictive marker (both in determining prognosis and in predicting response to HTs). The value of PR is less well established.
HER2 status - for HER2 directed therapies.
Oncotype 21 - int and high risk benefit from CHT in addition to hormone therapies.
Tumor infiltrating lymphocytes — there is a correlation between the extent of lymphocytic infiltration in the tumor or surrounding stroma, and chance of achieving complete path response with neoadj CT, particularly in HER2-ve and trip-ve
Types and role of different Bx techniques used to Ix a breast lump
1) Core Bx (see below)
2) Needle aspirate (if cystic on ultrasound).
3) FNA may detect abnormal cells, but cannot distinguish DCIS from IDC and cannot identify ER/PR/HER2 status.
As such core bx preferred:
USS core bx for palpable masses.
Stereotactic core bx or needle localization if nonpalpable lesion with suspicious calcifications.
MRI-guided biopsy if only visible on MRI.
Punch biopsy for Paget’s or if suspicious of dermal involvement (e.g., suspected inflammatory breast
cancer).
Criteria for T1 - T4 brCa tumour grade:
T1 (≤2cm): a=0.1-0.5, b>0.5 and ≤1cm, c = >1 cm and ≤2cm.
T2: >2 cm and ≤5cm
T3: >5 cm
T4a: Extension to chest wall (EXCEPt pec MAJ)
T4b: Peu d’orange
T4c = a+b
T4d = Inflammatory brCa
