Complete Breast Cancer

152 terms by ryangcarlson

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What are the criteria for a population screening exam

a. WHO guidelines (1960s era)
1. The condition should be an important health problem.
2. There should be a treatment for the condition.
3. Facilities for diagnosis and treatment should be available.
4. There should be a latent stage of the disease.
5. There should be a test or examination for the condition.
6. The test should be acceptable to the population.
7. The natural history of the disease should be adequately understood.
8. There should be an agreed policy on whom to treat.
9. The total cost of finding a case should be economically balanced in relation to medical expenditure as a whole.
10. Case-finding should be a continuous process, not just a "once and for all" project

What are the recommendations for staging mammograms

a. BC guidelines - woman aged 40- 79
1. 40- 50 get one yrly to every 18/12
2. >50 - q2 yr

What is the benefit of screening mammograms

a. Film mammography - 1.6% of mammograms will lead to a biopsy and 0.53% will lead to a breast cancer diagnosis in 1 year

- 34% reduction in breast cancer mortality by 7 years (20-35% reduction for 50-69 yo across studies)

- Elwood metaanalysis '93 - see uptodate "screening for breast cancer"

- for women 40-49: Swedish study showed a 25% lower breast cancer mortality if invited for screening vs not invited

What is the sensitivity, etc. of mammograms

1. 39%
b. Specificity of mammograms

1. 95%
c. Predictive value - 8.5%

What is the sensitivity and specificity of MRI

a. Sensitivity - 88.1%
b. Specificity - 67.7%

What features are suspicious for malignancy on mammogram

a. Pleomorphic, irregular calcifications
b. Clustered in a linear array (along a duct)
c. Most are fine
d. Can be spiculate

What is the benefit of self exams

a. Randomized Chinese study of 266,064 f - no difference between groups for br ca but more benign in self exam group

What is BIRADS

And what does it mean?
a. BIRADS is a standardized reporting criteria for mammography and US that determines the recommendation and probability of malignancy

sensitivity and specificity screening MRIs

a. Sensitivity - 0.77
specificity - 0.86;
positive predictive value - 6.2%

How do you follow a woman that is known BRCA positive

a. WOMEN:
1. annual screening mammogram beginning at age 30
2. annual screening breast MRI from late 20s to age 65 - scheduled to alternate every 6 months with mammogram
3. careful clinical examination of breasts and regional lymph nodes every 6 months, in conjunction with appropriate imaging
4. monthly breast self-exam is an option chosen by some women
b. MEN:
1. regular physical examination by a doctor
2. careful attention to any changes in the chest/breasts
3. population screening guidelines for prostate cancer, unless family history suggests otherwise
c. Surgical options:
1. Bilateral prophylactic mastectomy with breast reconstruction:
1. associated with at least a 90% reduction in breast cancer risk
2. may be a complex personal decision due to potential long-term impact on body image, sexuality and other aspects of quality of life
3. currently covered by MSP
4. must include expert pathology review of excised breast tissue for the presence of cancer
2. Bilateral prophylactic salphingo-oophorectomy:
1. should be strongly considered due to the lack of effective ovarian cancer screening
2. must include expert pathology review of excised ovaries and fallopian tubes for the presence of cancer
3. in addition to reducing risk of ovarian and fallopian tube cancers, BSO is associated with 50% reduction in breast cancer risk if completed prior to menopause
4. most effective if done at age 35-40, and/or when childbearing is complete
5. impact of surgical menopause is important to address in decision-making and in post-op followup. Unless otherwise contraindicated, HRT is usually an important component of symptom management.
d. Options for chemoprevention may also be discussed. Oral contraceptives have been shown in some studies to reduce ovarian cancer risk; this may be an important consideration for BRCA1/2+ women of child-bearing age. Tamoxifen is not currently prescribed on a regular basis for reduction of breast cancer risk in BRCA1/2+ women.

Why are women with BRCA more likely to have cancer

a. BRCA 1 and 2 play an integral role for double-strand DNA repair through homologous repair
b. PARP - cellular enzyme that functions in single strand DNA repair
1. Therefore PARP inhibitors knock out the only way cells have for DNA repair and therefore they undergo cell cycle arrest, chromosome instability and cell death

What is the risk of developing breast cancer if a woman has BRCA1

Or BRCA2? (taken from Hristov)
a. 1: 60-85% (lifetime) for breast; 40-60% risk of ovarian
b. 2: Br: 60-85% (lifetime); Ovarian: 10%

What other cancers are ass't with BRCA1/2

a. 1: bilateral/multifocal breast tumour, prostate, colon, liver, bone cancers
b. 2: male breast cancer, pancreas, gallbladder, pharynx, stomach, melanoma, prostate cancer

When do you refer to hereditary cancer

Confirmed BRCA1 or BRCA2 gene mutation in a close family member • if possible, provide a copy of family member's test report with referral
Your patient's personal history

1) Refer to definitions of breast & ovarian cancer above. • breast cancer < age 35, or
• 2 primary breast cancers with at least 1 diagnosed < age 50, or
• ovarian cancer at any age
Your patient's family history (this may include your patient's cancer diagnosis)

1) Refer to definitions of breast & ovarian cancer above.
2) Close relatives include children, brothers, sisters, parents, aunts, uncles, grandchildren & grandparents on the same side of the family.
3) History of cancer in cousins and more distant relatives from the same side of the family may also be relevant.
• 1 breast cancer and 1 ovarian cancer in close relatives, or
• 1 male breast cancer and 1 breast or ovarian cancer in close relatives, or
• 2 close relatives with breast cancer, both diagnosed < age 50, or
• 2 close relatives with ovarian cancer, or
• 3 breast cancers in close relatives, with 1 diagnosed < age 50
Ashkenazi Jewish heritage

1) Refer to definitions of breast & ovarian cancer above. • personal or family history of breast or ovarian cancer

Are there any other syndromes associated with breast cancer

a. Li-Fraumemi Syndrome - p53 mutation
1. autosomal dominant condition
2. inc risk of soft tissue sarcoma, osteosarcoma, leukemias, gliomas, adrenocortical malignancies, breast cancer
3. BrCa - usually dx before 45
1. screening - 6 month exam; annual mammo and or breast MRI starting at age 20-25 yrs
i. or 5-10 yrs before the earliest know br cancer in family
b. CHEK2 Mutations
1. 2-3 fold increased risk of breast cancer
c. Ataxia-Telangiectasia
1. auto dominant characterized by progressive cerebellar degeneration, dilated blood vessels in eyes and skin, immunodeficiency, chromosomal instability, inc sensitivity to RT and predisposition to cancer
2. mutation in ATM gene (chromo 11q22.3) which fxns in detection of DNA damage
3. tumours - breast, stomach, ovary, melanoma
d. Cowden Syndrome (aka multiple hamartoma syndrome)
1. auto dom condition characterized by multiple hamartomatous lesions because of mutation in PTEN
2. early onset breast, uterine, and non-medullary thyroid cancer
3. ~75% will have a benign breast condition
4. 25-50% risk of breast cancer
e. Peutx-Jeghers syndrome
1. auto dom characterized by hamartomatous polyps in the GI tract and mucocutaneous melanin deposits
2. mutation in serine threonine kinase chromo 19p13.3
3. Inc risk of GI cancer (small bowel, stomach, CRC, pancreas) and lung, breast, uterus, ovary
1. overall cancer risk - 93% by age 65
2. br ca risk - 55% (b/w age 15-65) therefore similar to BRCA
f. Hereditary diffuse gastric cancer (CDH1 mutation)
1. inherited form of diffuse gastric cancer with a lifetime risk of >80%
2. inc risk of lobular br cancer in woman - with risk ~60% over lifetime
g. Lynch syndrome (Hereditary nonpolyposis CRC)
1. mutation in mismatch repair genes (MSH2, MLH1, MSH6, PMS1 and PMS2)
2. main risk of colon and uterine ca but also ovaries, stomach, small bowel, hepatobilary tract, ureter, renal pelvis and brai
3. limited data correlated with breast cancer
h. PALB2 gene
1. partner and localizer of BRCA2
2. ~2-4 fold increased risk of breast cancer (18-35% lifetime risk)


Major breast cancer susceptibility genes
Gene Associated syndrome Chromosome site Gene frequency Other cancers
BRCA1 HBOC 17q21 Rare Ovary, fallopian tube, male breast, pancreas, prostate*, possibly cervix and uterus
BRCA2 HBOC 13q12-13 Rare Ovary, fallopian tube, male breast, pancreas, prostate*, possibly biliary tract, stomach and melanoma
p53 Li-Fraumeni 17p13.1 Very rare Soft tissue and bone sarcomas, leukemia, brain, adrenocortical malignancies
PTEN Cowden 10q22-23 Very rare Hamartomas (papillomas of the lips and mucous membranes, acral skin keratoses, trichillemomas of skin), uterus, non-medullary thyroid
CDH1 Hereditary Diffuse Gastric Cancer Syndrome 16q22.1 Rare Lobular breast cancer, diffuse gastric cancer
STK11 Peutz-Jeghers 19p13.3 Very rare Hamartomatous gastrointestinal tract polyps, small bowel, stomach, colorectal, pancreas, lung, uterus, ovary

What are the risk factors for Br Cancer

: (from DeVita)
a. Major (RR>4):
1. LCIS
2. BRCA1/2
3. Atypical hyperplase
4. Radiation exposure <30 yo
b. Intermediate (RR2-4)
1. First degree relative with breast cancer
2. CHEK2 mutation
3. Age >35 y for first birth
4. Proliferative breast disease
5. Mammographic breast density
c. Low (RR<2)
1. Early menarche
2. Late menopause
3. Nulliparity
4. Estrogen plus progesterone
5. HRT
6. Alcohol use
7. Postmenopausal obesity

What is a 'normal' woman's risk of breast cancer

a. 1:9 women will develop breast cancer
b. 1:6 women will develop either in-situ or invasive br cancer

With a positive family history

a. 1.5 to 3 fold increased risk vs a 'normal' woman

What is risk in BRCA + patients

Type of cancer
- General Population Risk /BRCA1 carrier risk /BRCA2 carrier risk

breast - women
11% /47-66%/ 40-57%
breast - men
0.1%/ up to 6%/ 6%
Ovarian
1-2% /35-46% /13-23%
Prostate
12% /2-3 times higher /2-3 times higher

How do you stage a breast cancer

a. Early - hx (to r/o mets), PE, routine bloodwork, bilateral mammograms
1. Rate of positive bone scan with stage I - 0.5% and CXR - 0.1%
2. StageII - bone scan 2.4%; CXR - 0.2%
b. When do you need to do complete staging
1. Node positive disease (stage IIa - therefore also <2cm lesions)
2. By stage III - ~20% will have occult metastatic disease
c. What is included in complete staging
1. Same as early but then add bone scan
d. When do breast MRI
1.
e. When need PET scan
1. Specificity - 80%; sensitivity - 88%
2. Useful in restaging breast cancer, evaluation to response and additional imaging if conventional imaging is equivalcal

What about on U/S

a. Malignant - ill defined margins, heterogeneous internal echoes, and irregular internal shadowing
b. Benign - sharply defined borders, central enhancement, no internal echoes

What is the TNM staging system

a. Tstage (note disease measuring at the high end of range will be staged at lower stage)
1. Tis - in-situ disease
2. T1mi - dz <0.1mm
3. T1a - >0.1mm to 0.5 mm
4. T1b- 0.5-10mm
5. T1c - 1cm to 2 cm
6. T2 - 2-5 cm
7. T3 - >5cm
8. T4a - involvement of chest wall (but not pectoralis)
9. T4b - skin involvement with ulceration, ipsilateral satellite nodules and/or peau d'orange (skin edema)
1. Note - involvement of dermis is not T4b
10. T4c - both chest wall and skin involvement
11. T4d - inflammatory breast cancer
b. Clinical N stage (all ipsilateral)
1. N1 - mobile ipsilateral axillary LN
2. N2a - axillary LN that are fixed or matted
3. N2b - IMC LN with no axillary LN
4. N3a - LN in infraclav (level III)
5. N3b - LN in both IMC and axilla
6. N3c - supraclav LN
c. Pathological N stage
1. N0i+ - malignant cells in regional LN <0.2mm
2. N0mol+ - positive molecular findings (RT-PCR) but not detected by H+E or IHC
3. N1mic - micrometastasis 0.2-2mm
4. N1a - 1-3 axillary LN
5. N1b - IMC LN detected by SLNBx but not clinically detected
6. N1c - 1-3 axillary LN with IMC detected by SLNBx but not clinically
7. N2a - 4-9 axallary LN
8. N2b - clinically detected IMC but no axillary LN
9. N3a - >9 axillary LN
10. N3b - clinically detected IMC and positive axillary LN
11. N3c - ipsilateral supraclavicular LN
d. Mets
1. M0i+ - no clinical or radiographical evidence of distant mets but deposits <0.2 mm in blood, bone marrow or nonregional nodal tissue
2. M1 - metastatic disease

What are each of the stage groupings

IA: T1
IB: T1 N1mic

IIA: T1N1; T2N0
IIB: T2N1; T3N0

IIIA: T1-2N2; T3N1-2
IIIB: T4N0-2
IIIC: Any T N3

IV: M1

What are the histological subtypes

a. Ductal
1. Intraductal (in situ)
2. Invasive with predominant intraductal component
3. Invasive, NOS
4. Comedo
5. Inflammatory
6. Medullary with lymphocytic infiltrate
7. Mucinous (colloid)
8. Papillary
9. Scirrhous
10. Tubular
11. Other
1. Micropapillary - less favorable overall prognosis because has a high incidence of LVI and LN mets
b. Lobular
1. In situ
2. Invasive with predominant in situ component
3. Invasive
c. Nipple
1. Paget's disease, NOS
2. Paget's disease with intraductal carcinoma
3. Paget's disease with invasive ductal carcinoma
d. Other
1. Undifferentiated carcinoma

How can you determine invasive disease over DCIS

Identification of myoepithelial layer around DCIS

How do you grade a breast cancer

a. Nottingham Score
1. Score of the grade of tumour by looking at three areas:
1. Tubule formation
i. >75%
ii. 10-75%
iii. <10%
2. mitotic rate (could be most impt prognostic),
i. <4 mitosis per square mm
ii. 4-7
iii. >7
3. nuclear pleomorphism
i. small and uniform
ii. moderate variation in size and shape
iii. marked nuclear pleomorphism
2. 3-5 is low (I) grade, 6-7 is intermediate (II), 8-9 is high (III)grade

What cell lines do ductal and lobular cancers come from

a. All arise within the lobules of the mammary tissue

What is the Allred score

a. A way to grade the ER status by looking at the intensity and percent of cells staining
b. Scale 0-3
1. 0 - Allred 0-2
2. 1 - 3-4
3. 2 - 5-6
4. 3- 7-8

How does IHC work

a. Antibodies to specific antigens (proteins) in cells are incubated on the pathological slides. A stain that will bind to the antibodies is then applied such that the antibodies will have a different colour (usually perioxidase and the positive cells will be brown)

How is Her2 tested

a. Originally by IHC but if 2+ staining then will proceed with FISH

How does FiSH work

a. Flourence in-situ hybridization is incubating a fluorencent labeled DNA or RNA probe for the desired gene with a cell such that the probe

What is the significance of PR

a. Not really known but part of Oncotype Dx as well
b. PR - tumours have a less response rate with hormonal agents
1. BCCA website:
1. ER/PR+: 78% RR
2. ER+/PR-: 34%
3. ER-/PR+: 45%
4. ER/PR-: 10%

What are the 6 tissue microarray subtypes of breast cancer (i.e. basal, luminal, etc)

ER positive:
a. Luminal A
b. Luminal B

ER negative:
c. HER2 enriched
d. Normal-like
e. Basal type (triple negative)

Other:
Claudin-low

(see end of cue cards for more info)

What is your risk of cancer with DCIS

Ipsi and contralateral
a. Ipsilateral - ~30% will progress to invasive disease at 10 yrs
b. Contralateral risk - 8/1000 (0.8% at 10 yrs) - RCTs of tam vs no in DCIS

What is your risk of cancer with LCIS

Ipsi and contralateral
a. Ipsilateral = contralateral risk
b. Total risk is 25-50% (Hristov)
1. Gunderson - NSABP trials - ~5% risk of invasive recurrence per breast - therefore 10% total risk

How is a partial mastectomy performed

a. Concerning lesion is localized (clinically or with a fine wire under ultrasound) and a wide rim of normal tissue is removed. Typically go down to chest wall to prevent a positive/close posterior margin

What are the contraindications to BCT - Absolute and relative

(from DeVita)
a. Absolute:
1. Pregnancy
2. Multicentric disease (i.e. 2 or more tumours in different quadrants)
3. Hx of thoracic irradiation
4. Persistant positive margins
b. Relative
1. Hx of collagen vascular disease
2. Large tumour in a small breast
3. Extremely large breasts - as reproducibility an issue and hotspots if unable to have >6 MV

How is a radical mastectomy performed

a. The entire breast is removed with the pectoralis major fascia

What are the different types of mastectomy

a. Simple - removes breast alone
b. Modified Radical Mastectomy - simple plus axillary node dissection
c. Radical mastectomy - removes entire breast, axillary LN, pec major and minor
d. Skin-sparing mastectomy - breast tissue removed through a conservative incision around the areolar complex
e. Nipple sparing mastectomy - mastectomy but the nipple-areolar complex is preserved
f. Extended radical mastectomy - radical mastectomy with intrapleural en bloc resection of internal mammary LN by sternal splitting

How is a sentinel lymph node biopsy performed

a. Note - in BC we map the drainage of the breast and not the tumour
b. Therefore radiology injects the radioactive tracer around the nipple and the surgeon injects the blue dye (isosulfan blue) in a similar area
c. An incision over the axilla is performed and a Geiger counter finds the hot node which is removed. Visual inspection of the axilla finds the blue node which is also removed (usually the same). Abnormal appearing LN can also be removed

What are the contraindications to a SLNBx

a. Advanced cancer consideration:
1. T3/T4 lesions
2. Locally advanced or inflammatory breast cancer
3. Multicentric breast cancer
4. Clinically positive axillary or supraclavicular LN
5. Metastatic breast cancer
b. Relative contraindications
1. Precious surgical resection for breast malignancy
2. Previous removal of any ispsilateral axillary LN
3. Previous breast irradiation
4. Pre-operative chemotherapy
5. Breast implants
6. Previous reducation mammoplasty
c. Other
1. Adverse rxn to Isosulfan blue or 99mTc sulphur colloid radionucleotide
2. Pregnant
3. Breast feeding

How is a SLN processed in pathology

a. Each sentinel LN is serially sectioned at 2-3 mm
b. 3 slides are stained with H&E and 1 witth cytokeratin (IHC) (and one with negative control for cytokeratin
c. Note - axillary LN are bisected and stained with H&E and possibly cytokeratin

How is an axillary LN dissection performed - What are the surgical landmarks

a. Removes level 1 (nodes in axillary fat pad) and 2 (below pec major and behind pec minor muscles

what are the risks of side effects with ALNDx

a. Intercostobrachial nerve syndrome - constant paresthesias and dull, aching or burning pain in upper arm, shoulder or axilla

What is risk of lymphedema with SLNBx vs ALNDx

a. SLNBx - 7% vs SLNBX+ALNDx - 14%

What do you need to know from the surgical report

- location of lesion
- way it was localized (ie wire, exam, etc)
- postop mammogram of specimen
- excision down to pec facsia
- clips placed
- axilla operation and any difficulties
- complications

What do you need to know on pathology

a. Size, histological type, margins, grade, LVI, skin and nipple involvement, receptor status, associated DCIS,
b. LN: number, number involved, size of LN mets, ENE

What are the indications for chemotherapy

a. Node positivity
b. If node negative then look at ADJUVANT online
c. If node negative - tumour size, grade and LCI most important factors
1. Also young age is an important factor
Extreme Risk
R ≥50 % High risk
R ≥30 % Intermediate Risk
R 20-30% Low Risk
R <20 %
Pathological or clinical T4, or
Pathological or Clinical any T, N2 or N3,M0
or
Pathological or Clinical T3,N1,M0
Positive axillary nodes
or
T1, Node-negative
and
significant LVI+
or
T2 Grade 2, 3 T2 grade 1 or
T 1c grade 2 or 3
and LVI and Node negative T1c low grade or
T1a/b,and LVI and Node negative

What key side effects to you expect with each regimen

a. How do you manage these

how do you evaulate and treat febrile neutropenia

1) Hx: thorough ROS
- common infected sites: CNS, pharynx, lower esophagus, lung, GI tract and perineum, skin, nails, vascular access devices

2) PE:
- meningismus, sinusitis, mucositis, dental disease, lungs, abdo, GU, derm, exam vascular access site

3) Investigations:
- CBCd
- Transaminases and bilirubin
- lytes, BUN and cr
- 2 blood cultures from 2 sites (one from vascular access)
- U/A and C/S
- CXR
- Other: LO, stool cultures, wound cultures

4) treatment:
Low risk - outpatient: oral cipro and amox/clav vs cipro and clinda (if allergy to beta-lactam)

High risk - admit
- IV imipenem/meropenem
- IV ceftazidime
- IV gentamicin AND Timentin/imipenem/ceftazidime
- ADD vancomycin if cather-related infection, positive blood culture, MRSA,

how do you treat a drug reaction

Always stop infusion

Moderate:
- benadryl 25-50mg IV and/or hydrocortisone IV
- restart infusion once rxn subsides

Severe:
- ABCs
- Epi 0.5mg IM stat and repeat q5min x2
- benadryl 50 mg IV push and/or hydrocortisone

Prophylaxis:
- dexa 20 mg given 12 h and 6h pre chemo
- benadryl 50 mg q30 min pre-chemo
- ranitidine 50 mg 30 min pre-chemo

What are options for first line chemo for metastatic disease

Aim to palliate symptoms, prolong survival and maintain quality of life

- Hormonal therapy: old studies showed that chemo gave a higher RR (rel risk 1.25) but no diff in OS
- chemotherapy is used firstline if end-organ dysfunction or rapidly progressive (can be single agent vs combos)
- if bone mets then treate with osteoclast inhibitor (bisphosphonate or RANK ligand inhibition): reduces morbidity including need for surgery/RT, SCC and hypercalcemia

Are there any subgroups of woman who do not need hormonal therapy (HT)

consider if:
age >=60
node negative
tumour <1cm
grade 1

(but also benefit in reducing contralateral breast primary)

What is the benefit of HT in DCIS

Any evidence in LCIS?

What is the benefit of tamoxifen for 5 years

- reduced 15 yr probability of breast cancer recurrence by 13% (46 to 33% = 39% reduction in the annual recurrence rate)
- reduced 15 yr BrCa mortality by 9% (33 to 24% = 30% reduction in the annual mortality rate)

What are the indications to use an AI alone

BCCA website:

early relapsers:
- N2, T3N+ or T4 (stage III or higher)
- OR high grade
- OR low ER status

What is the benefit of an AI over tam

Improved DFS by <5% abs difference
Decreased locoregional recurrence
Decreased contralateral breast cancer (<1% abs difference)

What evidence to use the switch

ASCO guidelines recommend that all postmenopausal women require AI at some point. No difference in trials of Tam/AI vs AI alone.

# of trials - BIG 1-98, ABCSG-8, ITA, TEAM, IES, N-SAS BC-03, ARNO 95

Which patients are eligible for Tamoxifen alone

low grade, T1N0 tumours
- ? consider in advanced age as well

Is it better to start with AI or Tam

Start with Tam. If concerned then should proceed with AI alone.

BIG 1-98 had a AI to Tam arm with no difference

Tamoxifen: What are the side effects and how do you manage these

Hot flashes: effexor, gabapentin, megace, exercise, diet changes
Mood disturbances
Poor sleep
Weight gain
Decreased libido
Vaginal dryness
1-2% abs inc risk of VTE
<1% abs inc risk of uterine cancer

Protective for: CAD, osteoporosis

What are the different AIs and the adv/disadv of each

Exemestane
Letrozole
Anastrazole
** look into the adv/disadv of each**

What is the role of HT in metastatic disease

Can be first line treatment if early metastatic disease or after chemotherapy if have a good response

What are the indications for radiation to the breast

a. Post lumpectomy: decrease local failure from ~30% to <10%
b. Post mastectomy
1. Size >5cm
2. Node positive
3. positive margins
4. T4 disease

What is the evidence for the dose

a. Typical dose is 50 in 25
b. Hypofractionation - 4250 in 16
1. Whelan Ontario Trial - hypo not inferior to standard
1. 10 yr local recurrence - hypo-fx - 7.4% vs std - 7.5%
2. OS - 84% in both arms

When use extended fractionation

1. large separation (eg >24 cm)
2. significant postoperative changes (edema , skin thickening/ erythema, induration , large seroma, previous cellulitis)
3. reconstruction esp with implants (previous or anticipated)

What is the advantage of lumpectomy+RT vs lumpectomy alone

a. 2011 - Oxford overview:
1. 10 yr risk of recurrence (local or distant) 35 to 20%
1. local recurrence - 25% to 8% w XRT
2. 15 yr BrCa death - 25% to 21% (4% reduction)
3. Therefore need to treat 4 recurrences to prevent 1 breast cancer death

What is the risk of recurrence in modern trials with and without XRT

a. Z0011 trial - all - 3.4%; SLNBx - 1.8% and ALNDx - 3.6%
b. MA.20 - Local Control 96.8% (Nodal RT) vs 94.5% (Br RT)
1. therefore: RT - 3.2% (Nodal RT) vs 5.5% (Br RT)

Are there any subgroups that can have a lumpectomy alone

a. Older age with small (<2cm)ER+ tumours treated with tamoxifen alone
b. CALGB trial - 636 women w above +/- RT
1. risk of recurrence with tam alone 9% vs 2% w RT

What is your GTV, CTV and PTV when planning a BCT pt

a. No GTV b/c adjuvant treatment
b. CTV - high risk is seroma +0.5 cm margin; low risk is whole breast
c. PTV - add 0.5 cm

What constraints are used in planning and where do they come from

a. Lung <2cm
1. If WMT <3.5cm
b. Heart <1cm
c. ? MA 20 protocol

What borders are used (i.e. sup and inf)

a. Sup: 2nd rib
b. Inf: 2 cm below inframammary fold

where are the tattoos placed

a. x2: Z=0 (mid-breast) AP midline and affected lat @ mid axilla
b. Pt set up (RAPID trial)
1. 5 Board Angle
2. Arm: A5, 4, C
3. Wrist: D5
4. H/R: B2
5. Knee roll

What are the dose constraints for brachial plexus, lung, heart, esophagus

a. Brachial plexus - 60 Gy (Emami)
b. Lung - BCCA uses V20 <40-50% (b/c only 1 lung)
c. Heart - V25<10% for long term cardiac mortality<1%
d. Esophagus - Mean dose <34 Gy (Gr 3 esophagitis)
- V35<50%, V50<40%, V70<20% (Gr 2 esoph)
1. Emami: 1/3 60 Gy; 2/3 58Gy; 3/3 55Gy

How are these planned

a. Placed fields by oncologist
b. MLC compensation using step and shoot IMRT

Where is the prescription point

a. X (right/left): midseparation between the beams
b. Y (ant/post): 1/3 from chest wall and 2/3 from the skin
1. note - remember by thinking of the thickest part of the breast
c. Z (sup/inf): Mid breast (i.e. ½ way b/w the 2nd rib and 2 cm below the inframammary fold)
d. Therefore: "prescription point is located midseparation between the tangent fields and located 1/3 of the way from the chest wall to the skin at mid breast"

why ½ beam blocked

a. to prevent divergence into lung

Where are the wedges if used

a. Thick end at the superficial edge of beam

where are the hotspots? Why?

a. Wedging - three hotspots at nipple and lateral close to the chest wall
b. MLC comp - no hotspot at nipple (because compensate for that) but still have lateral hotspots
c. Max - 110% point dose; 107% 2cm2 area
d. Note - no minimum dose specified

When do you increase the energy

a. If the hotspots at the lateral edge are too hot

What are the toxicities of tangents

a. Acute:
1. Fatigue - usually mild an will resolve in 2 months
1. Munich prospective study - no correlating factors
2. Dermatitis - most will have mild skin irritation or itching
1. 10-15% will develop moist desquamation
3. Breast swelling and tenderness
4. Acute pericarditis - v rare with tangents
b. Subacute:
1. Radiation pneumonitis:
1. characterized by nonproductive cough, fever, non-specific infiltrated on chest xray
2. generally 4-9 months post RT
3. Risk with tangents - 0.2% in MA.20
c. Chronic:
1. Cosmetic changes:
1. decline over first 3 yrs and then stabilize
2. palor, telangectasia, fibrosis, asymmetry b/w breasts
2. Breast tenderness/pain
3. Lymphedema
1. If tangents and SLNBx - 7% (or even lower for clinically significant risk)
i. - <1%
2. Brachial plexopathy - 0-5% risk
3. Cardiovascular complications
2. latency of ~10 yrs or more
3. risk minimal if treated after 1980
4. UPenn Study - risk inc with time and may be as high as 3% at 20 yrs (6.4 (lt sided) vs 3.6%(rt sided))
5. but likely even better with CT planning
6. QUANTEC - V25<10% <1% risk of long-term cardiac mortality
4. Second malignancy
1. increased risk of contraleral breast, sarcomas, lung caner, esophageal and possibly leukemia
2. UpToDate - excess risk is only ~1% (higher than what we quote ... ie. Dr. Lim 1/1000)
i. 1/1000 - sarcoma risk
ii. But does not include lung, esophagus

How do you manage skin erythema, dry desquamation, wet desquamation

a. Betamethasone dose - 0.5% to 1% cream applied TID
b. Flamazine - 1% cream applied prn
c. Saline soaks

What are the recommendations for skin management during XRT

a. No increased dose to skin if apply lotion - therefore alcohol and scent free lotion prn
b. Wash with mild soap and water
c. Deodorant ok

What are the indications for post mastectomy chest wall irradiation

a. Truong paper:
1. LRR of ~20% if grade 3 with LVI OR grade 3 and T2 and no systemic therapy
b. Positive margins

Why is Partial breast irradiation an option

Rarely do we include a whole organ in our radiation field. Unknown if adding adequate margins will give same result of treating the whole breast

Also advantage to hypofractionate which leads to less strain on system and easier for pts

What dose for PBI

RAPID trial - 38.5 Gy in 10 bid fractions

How planned PBI

Use non-conformal technique
usually 4 field

Any trials reported

No RCT reported as of yet ... awaiting RAPID

When do we treat the axillary LN

Node positive

High risk node negative:
T3N0 - Goulart's retrospective review
*** see Troung's paper:
T2N0, grade 3, LVI+,

What evidence for treating axilla

Danish Trials (postmastectomy)
BC Postmastectomy trial
- showed a reduction of locoregional recurrence from 30% to 10% with RT
- similar magnitude of benefit in all subgroups

MA.20:
- postBCS RT in N1 pts
- improved LRC by 2.5%
- improved distant met recurrence by 5%
- trend to OS adv of 2-3%

Are there any node positive patients that do not need axillary RT

really no ... according to above everyone should get axillary RT
- official guidelines say N2 or higher disease
- N0i+ pts are treated as node negative

When treat if node negative and why

High risk of recurrence:
- T3N0
- T2N0, gr 3, LVI+

What is your GTV, CTV, PTV for 4 field

GTV: none because adjuvant setting
CTV: whole breast, Axillary LN 1-3, supraclavicular +/- IMCs
- high risk CTV = 0.5 cm around breast seroma
PTV: above with 0.5-1 cm margin

why we use an isocentric plan for a 4 field plan

To prevent overlap at junction and for ease of delivery (i.e. no need to move pt)

Where is the isocentre for a four field

Z: At the junction of the tangent and axillary fields
X and Y: equivalent to midplane at mid breast (i.e. at tatoos)

What are the prescription points and how is that planned

tangents:
- mid breast at z=0 and 2/3 between the skin and chestwall

Axilla:
- 3cm deep for the Ant field
- at the deepest node for the Post boost field

Dose contraints for lung and heart

Lung: V20 <40%
heart: no key value but want to ensure < 1 cm of heart in field AND avoid LAD arteries if possible

How do you treat radiation pneumonitis

Corticosteroids
- can also try azathioprine and cyclosporin A if don't respond to steroids

Prednisone 1mg/kg/day and then slow taper
*** confirm this on uptodate

What is the risk of lymphedema - W SLNbx, w ALNDx

SLNBx + RT = ~5%
RT + ALNDx = ~15% (according to Hristov)
BUT
MA.20 - RP rate was <5%

When do you do a short axilla

1-3 LN
>10 LN taken
No ECE
<2 cm

What advantage to a short axilla

Much smaller risk of lymphedema b/c there is no radiation to the surgically treated LN

How do you manage axillary nodal disease with an occult primary

a. 3 options (Cancer 10 article - see notes):
1. Radical treatment with mastectomy or breast/nodal RT - no difference b/w two according to SEER data
1. 10 yr OS - 65%
2. ALNdx alone - inferior outcomes
1. 10 Yr OS - 60%
3. Observation - 10 yr OS - 50%
4. breast conference pt (Dec 16, 11) - 1843296

When do you need to include the IMCs

If LN + and if feasible without lung or heart tolerance being broken
- increased chance if inner quadrant primary

What are the risk factors for IMC involvement

LN +

Inner Quadrant tumour

- ** look into exact risk***

What risk if you don't treat IMCs

???? unknown

were included in all major N+ trials

what indications aside from node positive to give chest wall

- Positive margins
- T2 grade 3 (~20% LN risk)
- T1/2, grade 3 and LVSI (~20% LN risk)

What is the benefit of a boost in young women

EORTC - decreased local failure @ 10 yr from 10.2% to 6.23% (4%) w most benefit in pts <40;
survival in both arms 82%.
Fibrosis inc to 4.5% from 1.5%.

Lyon - 3 yr LF dec from 4.5% to 3.6%

What is the benefit for +margins - How does this compare to reexcision

Risk of LR if margin + = 15-20% (from reports in late 90s)

IF margin - then ~5-10% risk

Which trials support the use of a boost

EORTC and Lyon trials see slide 107

How do you plan a boost

Direct electron field (if <=12 MeV electrons possible)

Other options:
- mini tangents
- 3 field
- non-coplanar PBI like boost

How to distinguish if Lobular vs ductal origin

e-caderhin is negative in lobular but positive in ductal carcinoma

What surgery is needed - When is a mastectomy warranted (DCIS)

usually BCS

Mastectomy if:
- diffuse malignant microcalcifications
- multicentric disease
- persistently + margins
- patient desire

what is the adv of adj RT (DCIS)

Meta-analysis (Goodwin et al 2009):
- 50% improvement in ipsilateral breast events (HR 0.49)
- 35% improvement in ipsilateral DCIS recurrence (HR 0.64)
- all subgroups benefited from RT
- no long term toxicity

Examples:
- B17- Ipsilateral local failure decreased from 30 to 15% (1/2 invasive, 1/2 DCIS)
- EORTC 10853 - total LR-free rate 74% to 85% (equal rates of inv vs is recurrences)
- South Sweden - total local failure 22% down to 7% (13 to 4% with non-invasive and 9 to 3% with invasive)

What subgroup does not need RT (DCIS)

Older woman
small (<0.5cm) tumour
unicentric
low grade
wide margins

van Nuys score - 4, 5 or 6

what is the van nuys prognostic score

Score based on:
- Size (<=1.5, 1.6-4.0 and >=4.1)
- pathology (low/int grade with no necrosis; low/int grade with necrosis; high grade with necrosis)
- margins (>=1.0, 0.1-0.9, <0.1cm)
- age (>60, 40-60, <40 yrs)

Outcomes by score (10 yr LRR):
4,5,6: 1-5%
7,8,9: 15-25%
10,11,12: 14-50%

BUT 10 yr BCSS:
100% for 4-6 and 98% for 7 or above

What is the risk of invasive disease with LCIS

a. 5% risk at 12 years for both ispilateral and contralateral disease (therefore ~10% risk)

How does tamoxifen modify that risk

a. NSABP P-01 - for woman with LCIS tamoxifen decreased risk of invasive disease by 56%

What is the evidence for neoadjuvant chemo in locally advanced

- response rates of 50-90% (highest in AC-T)
- pCR if HER2+ and treated with trastuzumab = 25-65%
- no change in survival with preop treatment (meta-analysis)

What is the recommendation for management of the axilla if neoadj chemo is given

Ideally, SLNBx performed prior to chemotherapy

Some evidence that SLNBx will detect residual disease after chemo but the problem is that we treat N1 pts with 4 field b/c of a survival benefit ... potential for undertreatment if SLNBX not performed prior to chemo or overtreatment if high risk of LN disease but actually N0 to begin with b/c we would treat these pts

What chemo regimen is usually used for locally advanced

AC-T
CAF
CEF
CEF + GCSF

Can a woman still have BCT post chemo

Yes:
- want surgeon to mark tumour with clips so that area can be localized if CR

How are patients followed after treatment

- q 6 month clinical exam x 5 yr
- mammo 6 months after treatment finished and then yearly
- after 5 yr - yrly exam and mammo

What do you do after 5 years of HT

Yearly exam and mammo

- can consider 3 yrs of AI but not a std approach

What is the OS expectations for each stage of breast cancer

AJCC 7th ed

I: 88%

IIa: 82%
IIb: 74%

IIIa: 67%
IIIb: 41%
IIIc: 50%

IV: 15%

Where are the most common sites for metastatic disease

Can be anywhere!

most common;
- bone
- lung
- liver
- lymph nodes
- chest wall
- brain

Only ~10% of newly diagnosed women present with metastatic disease

How long is median survival from metastatic disease presentation

median survival is 22 months
(data from Swedish study looking at pts dx in 2000-2004)

2 yr OS - BC data from 1997-2001 = 45%

What are the minimum standards for breast MRI

- Bilateral breast examination
- Magnet strength >=1.5 Tesla
- Coil - dedicatied breast coil to achieve spatial resolution
- prone position
- patient comfort (ie ear plugs)
- contrast with gadolinium
- images acquired within 45 seconds of contrast and then every 1-2 minutes with completion within 4 minutes
- slice thickness <=3mm

What are contraindications for breast MRI

- pregnancy
- implated devices and foreign bodies
- gadolinium allergy
- diminished renal function

Indications for breast MRI

- assessment of breast implants
- detection of occult primary breast cancer in women with axillary mets (primary found in 40-100%; ~75% seems to be average)
- preoperative evaluation of newly diagnosed breast cancer pts
- measurement of response to neoadjuvant chemotherapy (controversial and trial underway)
- differentiating postoperative changes from recurrence
- evaluating inconclusive clinical or imaging findings
- screening in high risk woman (BRCA mutation, high BRCAPRO score, Hx of Chest irradiation)

What is BRCAPRO score

- genetic counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2

Characteristics of Luminal A tumours

- ~40% of breast cancers
- high expression of ER-related genes
- low expression of HER2 cluster of genes
- low expression of proliferation-related genes

Best prognosis of all subtypes
- BCSS - 84%
- 10 yr LRFS - 92% (BCCA data)

Characteristics of Luminal B tumours

- ~20% of breast cancers
- ER+
- HER2+ (variable)
- higher expression of proliferation cluster

10 yr LRFS - 88%

Characteristics of Her2 enriched tumours

-~10-15%
- high expression of HER2
- high proliferation cluster
- low expression of luminal cluster
(note: ~1/2 of HER2 + tumours; other half have a luminal subtype)

10 yr LRFS - 88%

Characteristics of Basal-like tumours

(similar to triple negative but discordance of ~30%)
- 15-20% of tumours
- low expression of luminal
- low expression of HER2
- high expression of proliferation cluster
- typically high grade
- high expression of EGFR
- strong ass't with BRCA1 (~80% are basal-like tumours)

10 yr LRFS - 80%

Characteristics of Claudin-low tumours

- subtype of non-basal triple-negative breast cancer
- expression of epithelial - mesenchymal transition genes and characteristics of stem cells
- slower growing than basal-like

Characteristics of normal-like tumours

difficult to know the significance of this subtype as it codes very similar to normal breast tissue
- could be a technical error of the assay but repeatedly arises

What are the first generation chemo regimens

CMF - cyclophosphamide,methotrexate and Fluorouracil

What are the second generation chemo regimens

addition of anthracyclines:

- AC x4: Adriamycin, Cylophosphamide
- FEC x6: Fluorouracil, Epirubicin, Cyclophosphamide
- CEF x6: Cyclophosphamide, Epirubicin, Fluorouracil
(Note: doses of epirubicin and Cyclo are lower than FEC)
- CAF x 6: Cyclophosphamide, Adriamycin, Fluorouracil (Need G-CSF)
• 5-FU can be substituted with capecitabine

What is the advantage of 2nd generation chemo

EBCTCG overview
- advantage with chemo = 15% rel risk reduction for death
- no adv of one polychemo over another
- anthracycline based over CMF = 4% absolute survival advantage

What are the third generation chemo regimens

Addition of taxane:

 ddAC-T: adriamycin and cyclophosphamide followed by paclitazel
• AC x4 q2w
• T (175 mg/m2) x4 q2w
• NEED G-CSF support throughout
 AC-wklyT
• AC x4 q3w
• T (80 mg/m2 weekly) given weekly x 12 weeks
 FEC-D: Fluorouracil, epirubicin, cyclophosphamide followed by docetaxel
• FEC x3 q 3w
• D x3 q3w
 DAC: docetaxel, adriamycin, cyclophosphamide
• DAC (all together) x6 q 3w
• NEED G-CSF support
 DC: Docetaxel and Cyclophosphamide
• DC x4 q3w

- note: all tested in node positive pts and therefore only 3rd gen recommended for high risk node negative = DC

Advantage of third generation?

DFS ARR of 5-6%
OS ARR of 3-4 %

Docetaxel is superior to paclitacel but more toxic

Advantage of trastuzamab

 HR for DFS - 0.5 (1/2)
 HR for OS - 0.67 (2/3)

hormonal therapy options in metastatic breast cancer

- ovarian suppression / ablation (premeno)
- SERMs (tamoxifen)
- Aromatase inhibitors (anastrzole, letrozole, exemestane)
- antiestrogens (fulvestrant)
- progestins (megestrol and medroxyprogesterone)

AIs: side effects and treatment

Hot flashes: effexor, megace, gabapentin, exercise, avoid dietary triggers
Other menopasusal symptoms
loss of libido
vaginal dryness
Arthralgias/myalgias
Osteoporosis: 2-4% abs difference b/w tam and AIs: treated with bisphosphonates
Dyslipidemia
HTN

What makes a breast tumour inoperable

- arm edema
- satellite skin nodules
- inflammatory
- SCV disease

What are Haagensen's Grave Signs

- skin edema of <1/3rd of the skin of breast
- ulceration
- chest fixation
- fixed/matted nodes
- axillary nodes >2.5 cm

group of signs that when present in pts with breast carcinoma indicate inoperability
- TWO or more gives poor prognosis

Prognostic factors in advanced breast cancer

- Tumour biology and receptor status
- performance status
- cancer-related symptoms
- sites of recurrence
- number of sites of recurrence
- prior adjuvant therapy
- disease-free interval
- prior therapy for metastatic disease
- response/duration of treatment with prior therapy for metastatic disease

Indications for chemotherapy in metastatic breast cancer

- symptomatic tumour progression
- pending visceral crisis
- resistence to multiple endocrine maneuvers

If present with extensive visceral or bone mets can start with chemo and then follow with endocrine therapy
- no benefit to combining hormonal and chemo together

Effect of Tamoxifen in metastatic disease

- 50% response rate
- median duration of 12- 18 months

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