Approach to all cases

Solid Organ Malignancy

Breast cancer

What is the diagnosis

Why did it happen
What complications are present (disease / treatment)

Dr Graham Dark
Senior Lecturer in Medical Oncology
graham.dark@ncl.ac.uk

Introduction

UK Cancer incidence and mortality

Breast cancer is the most frequent cancer in women after nonmelanotic 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-free
at 5 years from diagnosis
With improved awareness on the part of both women and
health-care providers, more breast cancers are being
diagnosed while still in-situ

Breast cancer: Rising incidence

Epidemiology of breast cancer

In the UK, the incidence of breast cancer is approximately
42,000 cases per year
It is the commonest cause of death in women aged 3554
years in England
Follows an unpredictable course with metastases presenting
up to 20 years after the initial diagnosis
In England and Wales the 5-year age-standardized survival
rate in 1990 was 62% compared to over 70% in France, Italy
and Switzerland. This has improved recently with earlier
detection by screening and improved treatment
Female to male ratio is approximately 100:1

2014 Centre for Cancer Education

Epidemiology of breast cancer

Reasons for fewer breast cancer deaths

Race

Earlier diagnosis

White women have a higher overall rate of breast cancer than AfricanAmerican women; however, this is not apparent until age 40 and is
marked only after menopause
Breast cancer risk is extremely low in Native American women

Geography
5-fold variation in incidence among different countries, being lower in
Japan, Thailand, Nigeria, and India than in Denmark, the Netherlands,
New Zealand, Switzerland, UK & US

Socioeconomic status
incidence of breast cancer is greater in women of higher socioeconomic
background

Disease site
left breast is more common than the right

One stop clinics

Screening

Better treatment
More women are cured
More cure saves money on subsequent treatments

Those who arent cured are living for longer

More treatments available
Sequential benefits

most common locations of the disease are the upper outer quadrant and
retroareolar region

Breast cancer: Risk factors

Risk of developing breast cancer

Age

By age 30...1 out of 2,525

Family history / personal history

By age 40...1 out of 217

Previous benign breast disease

Reproductive and menstrual history
Early menarche / Late menopause
Nulliparous / late first pregnancy (>35 years)
Oestrogen therapy

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

OCP
HRT (relative risk 1.66 in long term users)
Radiation
Obesity
Alcohol

Familial breast cancer

Family history of breast cancer

Hereditary predisposition is implicated in around 10% of

breast cancer cases

The overall relative risk of breast cancer in a woman with

a positive family history in a first-degree relative (mother,
daughter, or sister) is 1.7

Multiple affected relatives

Young age at diagnosis
Multiple primary cancers
Male breast cancers

Ovarian cancer
Autosomal dominant pattern of inheritance

Premenopausal onset of the disease in a first-degree

relative is associated with a three-fold increase in risk
Postmenopausal diagnosis increases relative risk by only
1.5

If first-degree relative has bilateral disease: 5-fold risk

increase
If first-degree relative has bilateral disease prior to
menopause: 9-fold risk increase

2014 Centre for Cancer Education

Breast cancer genes

Characteristics of BRCA associated cancer

BRCA1

Younger age of onset

BRCA2

Frequent bilateral occurrence

p53 (Li-Fraumeni syndrone)

Worse histological features:

more aneuploidy

Others
Cowden syndrome (breast & GI cancers, thyroid disease)

higher grade

Ataxia telangiectasia

higher proliferation indices

Peutz-Jeghers syndrome

higher proportion hormone receptor negative

Presenting symptoms

Clinical signs

Mammographic findings: discovered in asymptomatic patients

through the use of screening mammography

Neck and axilla: lymphadenopathy

Breast lump: the most common presenting complaint. The

incidence can range from 65-76% of patients
Pagets disease: associated with intraductal carcinoma
involving the terminal ducts of the breast and may have an
associated invasive component. Presents as an eczematoid
change in the nipple, a breast mass, or bloody nipple
discharge
Other local symptoms

Nipple: discharge or retraction

Breast: discolouration, oedema, peau dorange,
erythema, nodules, ulceration, lack of symmetry, skin
thickening
Chest: signs of consolidation, nodules in skin
Abdomen: hepatomegaly

Breast pain 5%

MS: focal tenderness in axial and peripheral skeleton

Breast enlargement 1%

Distant metastases:

Skin or nipple retraction 5%

Nipple discharge 2%, nipple crusting or erosion 1%

bone 70%, lung 60%, liver 55%, pleura 40%, adrenals 35%, skin
30%, brain 1020%

Pagets disease of the breast

Erythematous keratotic patches

over the areola area

Extramammary Pagets is
associated with internal
malignancy in 50% cases

2014 Centre for Cancer Education

Breast self-examination

Evaluation of a cystic mass

Recommendation to begin monthly breast self-examination at

the age of 20

Fine-needle aspiration (FNA)

If the mass is a cyst it can simply be aspirated with a fine
needle, which should yield non-bloody fluid and result in
complete resolution of the lesion
Ultrasonography
Used to determine whether a lesion is solid or cystic, and
whether a cyst is simple or complex
Biopsy
A biopsy is indicated if the cyst fluid is bloody, the lesion does
not resolve completely after aspiration, or the cyst recurs after
repeated aspirations

Meta-analysis of 12 studies involving a total of 8,118 patients

with breast cancer correlated the performance of breast selfexamination with tumour size and regional lymph node status
Women who performed breast self-examination were more
likely to have smaller tumours and less likely to have axillary
node metastases than those who did not

A major problem with breast self-examination as a screening

technique is that it is rarely performed well. Only 2-3% of
women do an ideal examination a year after instruction has
been provided

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

Evaluation of a non-palpable mass

The decision to observe a patient with a breast mass that

appears to be benign should be made only after careful
clinical, radiological, and cytological examinations
Mammography
To assess radiological characteristics of the mass and
evaluation of the remainder of the ipsilateral breast as well as
the contralateral breast
FNA
Simple method for obtaining material for cytological
examination. False-positive results from 0%-2.5% and falsenegatives varies from 3-27%
Biopsy
A core biopsy (18 gauge or larger needle biopsy) can be
advantageous since architectural as well as cellular
characteristics can be evaluated. An excisional biopsy, in
which the entire breast mass is removed, definitively
establishes the diagnosis

Wire excision biopsy

Tumour marker: CA 15.3

Pathology

Elevated serum levels found in 12.5% of women with benign breast

disease, preoperatively in 11% of women with operable breast
cancer, and in 64% of women with metastatic breast cancer

Invasive ductal carcinoma

Has no value in screening because of low sensitivity for the early

stages of disease

Invasive lobular carcinoma

False positive: Elevated in gynaecological cancers

CA 15.3 elevation increases with increasing stage of disease and
highest 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-up
can detect relapse 2-9 months before clinical signs or symptoms
develop
Rising levels indicated recurrence in 73% of those with a recurrence
and in 6% of those without a recurrence

2014 Centre for Cancer Education

Stereotactic-guided core biopsies

Ultrasound-guided core biopsies
Breast MRI

With or without ductal carcinoma in situ is the commonest

histology accounting for 70%
Accounts for most of the remaining cases
Ductal carcinoma in situ (DCIS)
20% of screen-detected breast cancers. It is multifocal in onethird of women and has a high risk of becoming invasive (10%
at 5 years following excision only). Pure DCIS does not cause
lymph node metastases, although these are found in 2% of
cases where nodes are examined, owing to undetected
invasive cancer
Lobular carcinoma in situ (LCIS)
A predisposing risk factor for developing cancer in either breast
(7% at 10 years)

Breast cancer: Triple assessment

Clinical examination
Breast imaging
Mammography
Ultrasound
MRI

Fine needle aspiration

Needle core biopsy
Mammotome (vacuum assisted biopsy)

Cytological assessment
Reported as
C1-5

1: no cells
2: insufficient
3: normal
4: suspicious
5: malignant

Predictive value of investigations

Modality Imaging
Cytology Risk of
Cancer %

Disposable cutting needle

5

7.3

22.5

69.3

95.1

13.6

2.3

8.0

40.3

85.2

5.3

0.8

3.0

19.4

67.3

11.6

1.9

6.8

36.0

82.8

83.5

43.2

73.6

95.6

99.5

99.2

94.8

98.5

99.8

100

0 or 1

2014 Centre for Cancer Education

HercepTest staining guide

O
Negative

No staining is observed or
membrane staining is observed in
less than 10% of the tumour cells

1+
Negative

Faint membrane staining is detected

in more than 10% of tumour cells.
The cells are only stained in part of
their membrane

2+
Weak
Positive

Weak to moderate complete

membrane staining is observed in
more than 10% of the tumour cells

3+
Strong
Positive

Moderate to strong complete

membrane staining is observed in
more than 10% of the tumour cells

Radioisotope bone scan

FISH for HER-2

Normal gene copy

number

Amplified gene copy

number

Bone metastasis
Most of the people who die of cancer each year have
tumour metastasis
Bone is the third most common organ involved by
metastasis, behind lung and liver
In breast cancer, bone is the second most common site of
metastatic spread, and 90% of patients dying of breast
cancer have bone metastasis
Breast and prostate cancers metastasise to bone most
frequently, which reflects the high incidence of both of
these tumours, as well as their prolonged clinical courses
Other tumours that commonly cause symptomatic bone
metastases include kidney and thyroid cancer, and
multiple myeloma

Bone metastasis

Bone metastasis

Patients with bone metastasis from breast cancer have

an average 2-year survival from the time of presentation
with their first bone lesion

There are four main goals in managing patients with

metastatic disease to the skeleton:

More patients are living with bone metastases, and thus

the challenge is to improve their quality of life
Early detection and aggressive management of
metastases is the goal

Maintain and maximize patients' quality of life and

functional level
Currently, care is optimised in only a fraction of patients
with bone metastases

2014 Centre for Cancer Education

pain relief
preservation and restoration of function
skeletal stabilization

local tumour control (e.g., relief of tumour impingement on

normal structures, prevention of release of chemical
mediators that have local and systemic effects)

Spinal cord compression

Spinal cord compression

Diagnosis is clinical

The finding of bilateral UMN signs should be considered

spinal cord compression until proved otherwise

confirmation can only be

made radiologically

SCC from metastatic cancer remains an important source

of morbidity despite the fact that with early diagnosis,
treatment is effective in 90% of patients

MRI is investigation of choice :

Thoracic 70%

Malignant spinal cord compression is defined as the

compressive indentation, displacement, or encasement of
the spinal cord's thecal sac by metastatic or locally
advanced cancer

Lumbar 15%
Cervical 10%
Sacral 5%

Any neoplasm capable of metastasis or local invasion can

produce malignant spinal cord compression

Spinal cord compression

Spinal cord compression

Response to nonsurgical therapy and the duration of

survival following treatment can vary considerably among
different histological tumour types

Tumour type

Frequency %

The degree of pretreatment neurological dysfunction is

the strongest predictor of treatment outcome

Breast cancer

29

Lung cancer

17

Ambulation can be preserved in greater than 80% of

patients who are ambulatory at presentation

Prostate

14

Myeloma

Key to successful management is a heightened

awareness of signs and symptoms, specifically newly
developed back pain or motor dysfunction, leading to
early diagnosis and treatment.

Renal

Lymphoma

Leptomeningeal metastasis

Sarcoma

Other

23

TNM Staging
T

CSF

Primary tumours
T0
T1

No palpable tumour
Tumour <=2cm

T2
T3

Tumour > 2cm but < 5cm

Tumour > 5cm in greatest dimension

T4

Tumour of any size fixed with direct extension to chest wall, skin, rib
intercostal muscles, serratus anterior muscle (not pectoral muscle)

N Regional lymph nodes

N0
No palpable homolateral lymph nodes
N1a Palpable nodes, not felt to contain tumour
N1b Palpable nodes thought to contain tumour
N2
Nodes > 2cm or fixed to one another or other structures
N3

Supraclavicular or infraclavicular nodes involved

M Distant metastases
M0
M1

2014 Centre for Cancer Education

No evidence of distant metastases

Distant metastases present including skin involvement beyond the breast area

Survival by number of involved axillary nodes

Number of
positive nodes

Percent Surviving
100

0
1
2-3
4-5

80

60

6-10
11-15
16-20

40

21 or more

20

0
1

2
3
Years after diagnosis

Lymph node surgery

Progression through lymph nodes

Sentinel

98.7% - orderly progression

Radioisotope/Blue dye directed sample

Sample
4-6 nodes from the lower axilla sampled

Level 1
Lateral to pectoralis minor

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

Level 2
Posterior to pectoralis minor

Level 3
Medial to pectoralis minor

Who to stage for early breast cancer

Staging results

1076 patients, Early Breast Cancer Trial

30 (2.8%) patients found to have distant metastases

All were asymptomatic

130 (12.0%) suspected but not confirmed on CT, MRI or

PET

All staged with CXR, US, bone scan

All suspicious findings explored further with CT, MRI or
PET

7 of these 130 confirmed to have metastases within 6

months
916 (85.2%) metastases excluded

2014 Centre for Cancer Education

Risk factors for distant metastasis

Recommendation for staging

> 3 involved lymph nodes (p=0.06)

Tumour > 5 cm

> 10 involved nodes (p=0.002)

> 3 Nodes (clinically palpable nodes)

T3/4 tumour (p=0.08)

Clinical suspicion

36/37 patients with metastatic disease had one of these

risks

All should have CXR, US, bone scan

36/269 (13.4%) with risk factors had metastasis

1/807 (0.12%) without risk factors had metastasis

1 in 7.5 will have metastases

1 in 800 will be missed

Recommendation for staging

Breast cancer treatment

CT or MRI are used if there is a clinical suspicion of

metastasis

Surgery

Tumour markers? (not as part of staging )

Radiotherapy
Hormone therapy
Chemotherapy
Biological therapy
Everything else

Breast cancer: Radiotherapy

NCN Guidelines for radiotherapy

Mandatory for the conserved breast

Breast conserving surgery

May be used as an alternative to surgery to the axilla

Radiotherapy to the chest wall and/or axilla reduces the
local recurrence rate in patients who have heavy lymph
node infiltration
Radiotherapy to lymph node areas improves cause
specific survival

2014 Centre for Cancer Education

All patients

Post mastectomy
All tumours > 5cm
Tumours deep in the breast where surgical clearance is
3mm or less
All patients with 4 or more lymph node metastases

Use of tamoxifen: Oxford overview 1995

Aromatase inhibitors
Some advantages compared to tamoxifen for diseasefree survival

% Reduction in mortality

% Reduction in recurrence

Only of value in POSTMENOPAUSAL women

No clear advantage in survival except in extended

adjuvant setting
Trial data for aromatase inhibitors ab initio or after 2/3 or
5 years of tamoxifen

Incidence of contralateral breast cancer

Adjuvant chemotherapy
Use of cytotoxic drugs to reduce the risk of recurrence
and death

Number 60
of
50
cases
40

HR

95% CI

p-value

HR+

0.47

(0.290.75)

0.001

ITT

0.58

(0.38-0.88)

0.01

53
5 DCIS

Newer drugs
CMF > Surgery alone
Anthracyclines > CMF

30

26

20

5 DCIS
21
Invasive*

10
0

Trials have shown incremental advantages with the

addition of:

48
Invasive*

Taxanes > Anthracyclines

Different combination strategies
Increase in dose density

Anastrozole
(n=2618)

Tamoxifen
(n=2598)

Block sequential regimens

*p=0.001 for invasive cancers

Effect of polychemotherapy vs. control

Anthracycline vs. CMF: Overall survival

100

80.2%

80
68.0%
76.7%

3.6% (SE 0.8)

60
63.4%
4.6% (SE 1.2)

40
Actuarial estimate and SE:
allocated A/E+
allocated CMF

0
Annual death rates
A/E+
CMF

5
Years 0-4

10
Years 5-9

4.40% (SE 0.12) 3.63% (SE 0.17)

5.07% (SE 0.15) 3.81% (SE 0.20)

years
Years 10+
2.87% (SE 0.36)
4.16% (SE 0.59)

Deaths/woman-years
A/E+
CMF

2014 Centre for Cancer Education

1246/28305
1219/24067

470/12940
372/9758

64/2233
49/1177

10

Addition of taxanes: Overall survival

Breast cancer prevention

Mastectomy

100

92%
90

Ovarian ablation

TAC

Drugs

% Alive

87%

Surveillance

FAC

80

70
# Events
TAC

60

57

FAC

76

Total

133

RR

p-value

0.76

0.11

50
0
Number at Risk
TAC 745
FAC 746

12

18
24
Months

30

36

42

48

741
738

732
728

718
713

393
375

171
171

24
33

1
1

700
678

Risk reducing mastectomy

Surgical oophorectomy in BRCA1 carriers

Reduces risk of breast cancer because it reduces volume

of breast tissue
In patients with BRCA mutations, risk is reduced to 1%

Tamoxifen: NSABP P1 Trial

Tamoxifen: NSABP P1 Trial

13388 women at increased risk of breast cancer

Tamoxifen 20 mg/day
x 5 years
(6681)

2014 Centre for Cancer Education

Placebo daily
x 5 years
(6707)

11

NSABP P1 Trial: endometrial cancer

NSABP P1 Trial: Results

Tamoxifen advantages
49% less invasive cancer (p<0.00001)
50% less DCIS (p<0.002)
Only prevented ER+ tumours

Tamoxifen disadvantages
2.53 x more endometrial cancer

Increased DVT and PE risk

No clear cut impact on SURVIVAL

Aromatase inhibitors in prevention

Breast surveillance in young women

Secondary prevention has been an endpoint in adjuvant

studies of aromatase inhibitors

Increasing evidence that the combination of

mammography and MRI is superior to either modality
alone

Aromatase inhibitors reduce contralateral cancer

incidence

Ultrasound has little or no value as a screening tool

Now being used in prevention trials in postmenopausal

women

Breast cancer: Summary

Timely and accurate diagnosis
Appropriate staging investigations
Meticulous surgery
Appropriate post surgical therapy
Radiotherapy
Hormones

Chemotherapy
Targeted therapies

Treatment should be tailored to the patient and to cancer

biology

2014 Centre for Cancer Education

12