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Solid Organ MalignancyBreast cancer
Dr Graham DarkSenior Lecturer in Medical [email protected]
Approach to all cases
What is the diagnosis
Why did it happen
What complications are present (disease / treatment)
Introduction
Breast cancer is the most frequent cancer in women after non-melanotic skin tumours (32% of female malignancies)
Causes approximately 13,000 deaths per year in the UK(2002)
The lifetime risk of breast cancer is 1 in 9 women
In England (2001) 80% of patients are alive and disease-freeat 5 years from diagnosis
With improved awareness on the part of both women andhealth-care providers, more breast cancers are beingdiagnosed while still in-situ
UK Cancer incidence and mortality
Breast cancer: Rising incidence Epidemiology of breast cancer
In the UK, the incidence of breast cancer is approximately42,000 cases per year
It is the commonest cause of death in women aged 35 – 54years in England
Follows an unpredictable course with metastases presentingup to 20 years after the initial diagnosis
In England and W ales the 5-year age-standardized survivalrate in 1990 was 62% compared to over 70% in France, Italyand Switzerland. This has improved recently with earlierdetection by screening and improved treatment
Female to male ratio is approximately 100:1
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Epidemiology of breast cancer
RaceWhite women have a higher overall rate of breast cancer than Afri can-
American women; however, this is not apparent until age 40 and ismarked only after menopause
Breast cancer risk is extremely low in Native American women
Geography5-fold variation in incidence among different countries, being lower inJapan, Thailand, Nigeria, and India than in Denmark, the Netherlands,New Zealand, Switzerland, UK & US
Socioeconomic statusincidence of breast cancer is greater in women of higher socioeconomicbackground
Disease siteleft breast is more common than the right
most common locations o f the disease are the upper outer quadrant andretroareolar region
Reasons for fewer breast cancer deaths
Earlier diagnosis
One stop clinics
Screening
Better treatment
More women are cured
More cure saves money on subsequent treatments
Those who aren’t cured are living for longer
More treatments available
Sequential benefits
Breast cancer: Risk factors
Age
Family history / personal history
Previous benign breast disease
Reproductive and menstrual history
Early menarche / Late menopause
Nulliparous / late first pregnancy (>35 years)
Oestrogen therapy
OCP
HRT (relative risk 1.66 in long term users)
RadiationObesity
Alcohol
Risk of developing breast cancer
By age 30...1 out of 2,525
By age 40...1 out of 217
By age 50...1 out of 50
By age 60...1 out of 24
By age 70...1 out of 14
By age 80...1 out of 8
Familial breast cancer
Hereditary predisposition is implicated in around 10% ofbreast cancer cases
Multiple affected relativesYoung age at diagnosis
Multiple primary cancers
Male breast cancers
Ovarian cancer
Autosomal dominant pattern of inheritance
Family history of breast cancer
The overall relative risk of breast cancer in a woman witha positive family history in a first-degree relative (mother,daughter, or sister) is 1.7
Premenopausal onset of the disease in a first-degreerelative is associated with a three-fold increase in risk
Postmenopausal diagnosis increases relative ri sk by only1.5
If first-degree relative has bilateral disease: 5-fold riskincrease
If first-degree relative has bilateral disease prior tomenopause: 9-fold risk increase
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Breast cancer genes
BRCA1
BRCA2
p53 (Li-Fraumeni syndrone)
Others
Cowden syndrome (breast & GI cancers, thyroid disease)
Ataxia telangiectasia
Peutz-Jeghers syndrome
Characteristics of BRCA associated cancer
Younger age of onset
Frequent bilateral occurrence
Worse histological features:
more aneuploidy
higher grade
higher proliferation indices
higher proportion hormone receptor negative
Presenting symptoms
Mammographic findings: discovered in asymptomatic patientsthrough the use of screen ing mammography
Breast lump: the most common presenting complaint. Theincidence can range from 65-76% of patients
Paget’s disease: associated with intraductal carcinomainvolving the terminal ducts of the breast and may have anassociated invasive component. Presents as an eczematoidchange in the nipple, a breast mass, or bloody nippledischarge
Other local symptoms
Breast pain 5%
Breast enlargement 1%Skin or nipple retraction 5%
Nipple discharge 2%, nipple crusting or erosion 1%
Clinical signs
Neck and axilla: lymphadenopathy
Nipple: discharge or retraction
Breast: discolouration, oedema, peau d’orange,erythema, nodules, ulceration, lack of symmetry, skinthickening
Chest: signs of consolidation, nodules in skin
Abdomen: hepatomegaly
MS: focal tenderness in axial and peripheral skeleton
Distant metastases:bone 70%, lung 60%, liver 55%, pleura 40%, adrenals 35%, skin30%, brain 10 –20%
Paget’s disease of the breast
• Erythematous keratotic patchesover the areola area
• Extramammary Paget’s isassociated with internalmalignancy in 50% cases
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Breast self-examination
Recommendation to begin monthly breast self-examination atthe age of 20
Meta-analysis of 12 studies involving a total of 8,118 patientswith breast cancer correlated the performance of breast self-
examination with tumour size and regional lymph node statusWomen who performed breast self-examination were morelikely to have smaller tumours and less likely to have axillarynode metastases than those who did not
A major problem with breast self-examination as a screeningtechnique is that it is rarely performed well. Only 2-3% ofwomen do an ideal examination a year after instruction hasbeen provided
Evaluation of a cystic mass
Fine-needle aspiration (FNA)If the mass is a cyst it can simply be aspirated with a fineneedle, which should yield non-bloody fluid and result incomplete resolution of the lesion
UltrasonographyUsed to determine whether a lesion is solid or cystic, andwhether a cyst is simple or complex
Biopsy A biopsy is indicated if the cyst fluid is bloody, the lesion doesnot resolve completely after aspiration, or the cyst recurs afterrepeated aspirations
Cystic carcinoma accounts for < 1% of all breast cancers An intraluminal solid mass is a concerning sign suggesting(intra) cystic carcinoma, and should be biopsied
Evaluation of a solid mass
The decision to observe a patient with a breast mass thatappears to be benign should be made only after carefulclinical, radiological, and cy tological examinations
MammographyTo assess radiological characteristics of the mass andevaluation of the remainder of the ips ilateral breast as well asthe contralateral breast
FNASimple method for obtaining material for cytologicalexamination. False-positive results from 0%-2.5% and false-negatives varies from 3-27%
Biopsy A core biopsy (18 gauge or larger needle biopsy) can be
advantageous since architectural as well as cellularcharacterist ics can be evaluated. An excisional biopsy , inwhich the entire breast mass is removed, definitivelyestablishes the diagnosis
Evaluation of a non-palpable mass
Wire excision biopsy
Stereotactic-guided core biopsies
Ultrasound-guided core biopsies
Breast MRI
Tumour marker: CA 15.3
Elevated serum levels found in 12.5% of women with benign breastdisease, preoperatively in 11% of women with operable breastcancer, and in 64% of women with metastatic breast cancer
Has no value in screening because of low sensitivity for the earlystages of disease
False positive: Elevated in gynaecological cancers
CA 15.3 elevation increases with increasing stage of disease andhighest levels are seen in patients with liver or bone metastases
It is not accurate enough to be used alone to define response
Several trials have shown that a rising CA 15.3 level during follow-upcan detect relapse 2-9 months before clinical signs or symptomsdevelop
Rising levels indicated recurrence in 73% of those with a recurrenceand in 6% of those without a recurrence
Pathology
Invasive ductal carcinoma
With or without ductal carcinoma in situ is the commonesthistology accounting for 70%
Invasive lobular carcinoma
Accounts for most of the remaining cases
Ductal carcinoma in situ (DCIS)
20% of screen-detected breast cancers. It is multifocal in one -third of women and has a high risk of becoming invasive (10%at 5 years following excision only). Pure DCIS does not causelymph node metastases, although these are found in 2% ofcases where nodes are examined, owing to undetectedinvasive cancer
Lobular carcinoma in situ (LCIS)
A predisposing risk factor for developing cancer in either breast(7% at 10 years)
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Breast cancer: Triple assessment
Clinical examination
Breast imaging
Mammography
Ultrasound
MRI
Fine needle aspiration
Needle core biopsy
Mammotome (vacuum assisted biopsy)
Cytological assessment
Reported asC1-5
1: no cells
2: insufficient
3: normal
4: suspicious
5: malignant
Predictive value of investigations
Modality Imaging 2 3 4 5
Cytology Risk ofCancer %
7.3 22.5 69.3 95.1
0 or 1 13.6 2.3 8.0 40.3 85.2
2 5.3 0.8 3.0 19.4 67.3
3 11.6 1.9 6.8 36.0 82.8
4 83.5 43.2 73.6 95.6 99.5
5 99.2 94.8 98.5 99.8 100
Disposable cutting needle
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No staining is observed ormembrane staining is observed inless than 10% of the tumour cells
Faint membrane staining is detectedin more than 10% of tumour cells.The cells are only stained in part oftheir membrane
Weak to moderate completemembrane staining is observed inmore than 10% of the tumour cells
Moderate to strong completemembrane staining is observed inmore than 10% of the tumour cells
O Negative
1+ Negative
2+ Weak
Positive
3+
StrongPositive
HercepTest staining guide FISH for HER-2
Normal gene copynumber
Amplified gene copynumber
Radioisotope bone scan Bone metastasis
Most of the people who die of cancer each year havetumour metastasis
Bone is the third most common organ involved bymetastasis, behind lung and liver
In breast cancer, bone is the second most common site ofmetastatic spread, and 90% of patients dying of breastcancer have bone metastasis
Breast and prostate cancers metastasise to bone mostfrequently, which reflects the high incidence of both ofthese tumours, as well as their prolonged clinical courses
Other tumours that commonly cause symptomatic bonemetastases include kidney and thyroid cancer, andmultiple myeloma
Bone metastasis
Patients with bone metastasis from breast cancer havean average 2-year survival from the time of presentationwith their first bone lesion
More patients are living with bone metastases, and thusthe challenge is to improve their quality of life
Early detection and aggressive management ofmetastases is the goal
Maintain and maximize patients' quality of life andfunctional level
Currently, care is optimised in only a fraction of patientswith bone metastases
Bone metastasis
There are four main goals in managing patients wi thmetastatic disease to the skeleton:
pain relief
preservation and restoration of function
skeletal stabilization
local tumour control (e.g., relief of tumour impingement onnormal structures, prevention of release of chemicalmediators that have local and systemic effects)
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Spinal cord compression
Diagnosis is clinical
confirmation can only bemade radiologically
MRI is investigation of choice :
Thoracic 70%
Lumbar 15%
Cervical 10%
Sacral 5%
Spinal cord compression
The finding of bilateral UMN signs should be consideredspinal cord compression until proved otherwise
SCC from metastatic cancer remains an important sourceof morbidity despite the fact that with early diagnosis,treatment is effective in 90% of patients
Malignant spinal cord compression is defined as thecompressive indentation, displacement, or encasement ofthe spinal cord's thecal sac by metastatic or locallyadvanced cancer
Any neoplasm capable of metastasis or local invasion canproduce malignant spinal cord compression
Spinal cord compression
Response to nonsurgical therapy and the duration ofsurvival following treatment can vary considerably amongdifferent histological tumour types
The degree of pretreatment neurological dysfunction isthe strongest predictor of treatment outcome
Ambulation can be preserved in greater than 80% ofpatients who are ambulatory at presentation
Key to successful management is a heightenedawareness of signs and symptoms, specifically newlydeveloped back pain or motor dysfunction, leading toearly diagnosis and treatment.
Spinal cord compression
Tumour type Frequency %
Breast cancer 29
Lung cancer 17
Prostate 14
Myeloma 4
Renal 4
Lymphoma 5
Sarcoma 2 Other 23
Leptomeningeal metastasis
CSF
TNM StagingT Primary tumours
T0 No palpable tumourT1 Tumour 2cm but < 5cmT3 Tumour > 5cm in great est dimension
T4 Tumour of any size fixed with direct extension to chest wall, skin, ribintercostal muscles, serratus anterior muscle (not pect oral muscle)
N Regional lymph nodes
N0 No palpab le homolater al lymph nodesN1a Palpable nodes, not felt to contain tumour
N1b Palpable nodes thought to contain tumourN2 Nodes > 2cm or fixed to one another or other structures
N3 Supracla vicular or infracla vicular nodes involved
M Distant metastases
M0 No evidence of distant metastasesM1 Distant metastases present including skin involvement beyond the breast area
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Survival by number of involved axillary nodes
Number ofpositive nodes
012-34-5
6-1011-1516-20
21 or more
Percent Surviving
100
40
20
1 2 3 4 5 Years after diagnosis
60
80
0
Lymph node surgery
Sentinel
Radioisotope/Blue dye directed sample
“Sample”
4-6 nodes from the lower axilla sampled
Level 1
Lateral to pectoralis minor
Level 2
Posterior to pectoralis minor
Level 3
Medial to pectoralis minor
Progression through lymph nodes
98.7% - orderly progression
54% - level 1 only
23% - levels 1 & 2
21% - levels 1, 2 & 3
1.2% - level 2 skipping level 1
0.1% - level 3 skipping levels 1 & 2
Who to stage for early breast cancer
1076 patients, Early Breast Cancer Trial
All were asymptomatic
All staged with CXR, US, bone scan
All “suspicious” findings explored further with CT, MRI orPET
Staging results
30 (2.8%) patients found to have dis tant metastases
130 (12.0%) suspected but not confirmed on CT, MRI or
PET7 of these 130 confirmed to have metastases within 6months
916 (85.2%) metastases excluded
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Risk factors for distant metastasis
> 3 involved lymph nodes (p=0.06)
> 10 involved nodes (p=0.002)
T3/4 tumour (p=0.08)
36/37 patients with metastatic disease had one of theserisks
36/269 (13.4%) with risk factors had metastasis
1/807 (0.12%) without risk factors had metastasis
Recommendation for staging
Tumour > 5 cm
> 3 Nodes (clinically palpable nodes)
Clinical suspicion
All should have CXR, US, bone scan
1 in 7.5 will have metastases
1 in 800 will be missed
Recommendation for staging
CT or MRI are used if there is a clinical suspicion ofmetastasis
Tumour markers? (not as part of staging …)
Breast cancer treatment
Surgery
Radiotherapy
Hormone therapy
Chemotherapy
Biological therapy
Everything else
Breast cancer: Radiotherapy
Mandatory for the conserved breast
May be used as an alternative to surgery to the axilla
Radiotherapy to the chest wall and/or axilla reduces thelocal recurrence rate in patients who have heavy lymphnode infiltration
Radiotherapy to lymph node areas improves causespecific survival
NCN Guidelines for radiotherapy
Breast conserving surgery
All patients
Post mastectomy
All tumours > 5cm
Tumours deep in the breast where surgical clearance is3mm or less
All patients with 4 or more lymph node metastases
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Use of tamoxifen: Oxford overview 1995
% R e
d u c
t i o n
i n r e c u r r e n c e
% R e
d u c
t i o n
i n m o r t a
l i t y
Aromatase inhibitors
Only of value in POSTMENOPAUSAL women
Some advantages compared to tamoxifen for disease-free survival
No clear advantage in survival except in extendedadjuvant setting
Trial data for aromatase inhibitors ab initio or after 2/3 or5 years of tamoxifen
0 10
20
30
40
50
60
21Invasive*
53
Tamoxifen(n=2598)
Anastrozole(n=2618)
26
5 DCIS
48Invasive*
Numberofcases
5 DCIS
*p=0.0 01 for invasive cancers
HR
0.47
0.58
HR+
95% CI
(0.29 –0.75)
(0.38-0.88)
p-value
0.001
0.01ITT
Incidence of contralateral breast cancer Adjuvant chemotherapy
Use of cytotoxic drugs to reduce the risk of recurrenceand death
Trials have shown incremental advantages wi th theaddition of:
Newer drugs
CMF > Surgery alone
Anthracyclines > CMF
Taxanes > Anthracyclines
Different combination strategies
Increase in dose density
Block sequential regimens
Effect of polychemotherapy vs. control
Annual death rates Years 0-4 Years 5-9 Years 10+
A/E+ 4.40% (SE 0.12) 3.63% (SE 0.17) 2.87% (SE 0.36)CMF 5.07% (SE 0.15) 3.81% (SE 0.20) 4.16% (SE 0.59)
Deaths/woman-years
A/E+ 1246/28305 470/12940 64/2233CMF 1219/24067 372/9758 49/1177
100
80
60
40
00 5 10 years
%
80.2%
68.0%76.7%
3.6% ( SE 0.8)
4.6% ( SE 1.2)63.4%
Actuarial estimate and SE: – allocated A/E+
– allocated CMF
Anthracycline vs. CMF: Overall survival
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TAC
FAC
0 6 12 18 24 30 36 42 48 Months
Number at Risk TAC FAC
745 741 732 718 700 393 171 24 1 746 738 728 713 678 375 171 33 1
50
60
70
80
90
100
% A
l i v e
# Events RR p-value
TAC 570.76 0.11
FAC 76
Total 133
92%
87%
Addition of taxanes: Overall survival Breast cancer prevention
Mastectomy
Ovarian ablation
Drugs
Surveillance
Risk reducing mastectomy
Reduces risk of breast cancer because it reduces volumeof breast tissue
In patients with BRCA mutations, risk is reduced to 1%
Surgical oophorectomy in BRCA1 carriers
Tamoxifen: NSABP P1 Trial
13388 women at increased risk of breast cancer
Tamoxifen 20 mg/day Placebo dailyx 5 years x 5 years(6681) (6707)
Tamoxifen: NSABP P1 Trial
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Tamoxifen advantages
49% less invasive cancer (p