Steps in the Progression
of Breast Cancer
Precancer
Cancer in situ
Invasion of normal breast
Spread to regional
lymph nodes
Hematogenous distribution
to distant organs
Death
Natural History of Breast Cancer
Characterized by
• Long Duration
• Marked Heterogeneity
Long Duration
with a prolonged preclinical period
Growth Rates & Clinical Events
Assume Doubling Time of 100 days
Number of Cells
Diameter cm
1
2
3
4
5
6
7
8
0.5
1
2
9
10
11
Years of Growth
12
16
13
Death
1012
1 kg
1010
108
106
104
8
Preclinical
1 cm
Premammographic
1 mm
1
10
20
30
Number of Cell Doublings
40
Gullino Cancer 1977
Growth Rates & Clinical Events
Number of Cells
Diameter cm
0.5
1
2
1 kg
1010
1
16
Death
1012
108
106
104
8
Preclinical
1 cm
Premammographic
1 mm
Presentation Point for
Untreated Patients
Untreated Breast Cancer
Survival from Onset of Symptoms
100
% Alive
86%
70
Middlesex Hospital
1805 – 1933
N = 250
83%
68%
56%
Aged matched
No Cancer
50
54%
41%
44%
30
28%
18%
9%
10
1 2 3 4
5
Median Survival
2.7 Years
Untreated
3.6% 2%
10
Years
0.8%
15
20
HJG Bloom et. al. BMJ 1962
Growth Rates & Clinical Events
Number of Cells
Assume Gompertzian Growth
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Years of Growth
1012
1010
108
106
104
Clinical
Preclinical
1 cm
Premammographic
1 mm
1
10
20
Number of Cell Doublings
30
15
Growth Rates & Clinical Events
Number of Cells
When do distant metastases occur?
Where do they occur?
How fast do they grow?
1012
1010
108
106
104
1
Preclinical
1 cm
Premammographic
1 mm
• The theory that lead to screening asymptomatic
women to detect smaller breast cancer lesions
is based on the assumption that many distant
metastases occur during the interval when the
cancer can be detected by mammography and
when it can be felt on physical examination.
– The (limited) success of screening mammography
has proven that this is true for at least some breast
cancers.
Growth Rates & Clinical Events
Number of Cells
Distant metastases occur even before the primary
can be detected in many instances and is likely one
reason for the limited success of mammography.
1012
1010
108
106
104
1
Preclinical
1 cm
Premammographic
1 mm
• The theory behind the use of adjuvant systemic
therapy is that metastases are established prior
to diagnosis, even when detected at a small size
(and therefore at an earlier time course). These
metastases will not be affected by local
treatments
– The success of adjuvant systemic therapy strategies
proves that this is true.
– The relatively small overall benefit from these treatments
is likely due to multiple factors including the limited
efficacy of the treatments and the fact that many patients
diagnosed with breast cancer do not have distant
metastases at diagnosis.
• The theory behind the use of adjuvant systemic
therapy is that metastases are established prior
to diagnosis, even when detected at a small size
(and therefore at an earlier time course). These
metastases will not be affected by local
treatments.
• A second theory to explain why adjuvant
chemotherapy will be more effective in the
preclinical period is based on the assumption
that these micrometastases are growing
logarithmically and are more sensitive to
chemotherapy.
Growth Rates & Clinical Events
Number of Cells
The clinical period may be better
characterized by Gompertzian growth
1012
1010
108
106
104
1
Clinical
Preclinical
1 cm
Premammographic
1 mm
Many long standing assumptions about the
preclinical growth patterns of breast cancer have
been challenged by new understanding of
angiogenesis and its importance in determining
growth patterns of both the primary and micrometastases.
Growth Rates & Clinical Events
Number of Cells
Even the preclinical period may be characterized
by periods growth alternating with plateaus
1012
1010
108
106
104
1
Preclinical
1 cm
Premammographic
1 mm
• Patients with breast cancer have a much more
prolonged clinical course than patients with
many other types of cancer.
• During this time they may receive and have at
least some benefit from many different types of
treatment.
• And there is good reason to believe the
preclinical period is also prolonged, albeit the
events in the preclinical period are clearly more
varied and complex than thought only a few
years ago.
Few cancers metastasize as widely as
breast cancer.
Pooled Results of 8 Autopsy Series, 1922 - 1960
Site of Metastases Pooled Frequency
Bone
58%
Liver
54%
Lung
66%
Range
44 – 71
35 – 63
54 – 77
Skin
22%
7 - 39
Brain
16%
9 – 29
Ovary
Adrenal
13%
34%
4 – 23
8 - 51
Haagensen 1971
Does a breast cancer patient ever
return to ‘normal’ life expectancy?
Addenbrooke Hospital
N = 704
1947 - 1950
% Survival
100
80
60
40
30.5
18.5
10
8
0
5
10
15
20
25
Years of Follow-up
Brinkley & Haybittle, 1977
Marked Heterogeneity
% Dying of Breast Cancer
Each Year
Mortality from Breast Cancer
Connecticut SEER Registry
1950 - 1973
10
5
5
10
15
20
Year After Diagnosis
Fox, JAMA, 1979
Changing Definitions of Breast Cancer
• Prior to mid-19th century:
Clinical Signs
This probably remained true into
the first 3rd of the 20th century.
Untreated vs. Halsted Patients
100
Halsted radical mastectomy
1889 - 1931
Middlesex Untreated
1805 - 1933
% Alive
80
60
40
20
2
4
6
8
10
12
14
16
18
20
22
Years since 1st Symptoms
Henderson & Canellos, NEJM 1908
Changing Definitions of Breast Cancer
• Prior to mid-19th century:
Clinical Signs
• Mid-19th to mid-20th century
Histological Evidence of Invasion
In situ breast cancer 1st described
in the 1930’s
Changing Definitions of Breast Cancer
• Prior to mid-19th century:
Clinical Signs
• Mid-19th to mid-20th century
Histological Evidence of Invasion
• Mid-20th to early 21st century
Microinvasion
• 21st century?
Molecular markers
Changing Definitions of Breast Cancer
The only definition of breast cancer that has
been correlated with death in untreated
patients is ‘clinical signs and symptoms.’
By most people’s definition, “cancer” is a
tumorous growth that will kill if left untreated.
In practice, “cancer” is an histological entity.
Ethical constraints make it very difficult
to circumvent this problem.
Is the breast cancer treated in
breast cancer between 1950 and
1973 the same breast cancer that
was treated in the Middlesex
hospital between 1805 and 1933?
Breast Cancer Incidence & Mortality
Connecticut 1935 - 1975
% Dying of Breast Cancer
Each Year
Mortality from Breast Cancer
Connecticut SEER Registry
1950 - 1973
10
5
5
10
15
20
Year After Diagnosis
Fox, JAMA, 1979
Connecticut SEER Registry
1950 - 1973
40% die at rate of 25% per year
80
70
Relative Survival %
Subpopulations
of Breast Cancer
Patients
100
90
60
50
40
30
20
60% die at rate of 2.5% per year
10
Fox, JAMA, 1979
5
10
15
20
25
Year after Diagnosis
100
90
Connecticut
1950 - 1973
70
70
60
60
50
50
40
40
30
20
10
Middlesex
1805 - 1933
80
Survival %
Relative Survival %
80
100
90
30
20
5
10
15
20
25
Year after Diagnosis
10
5
10
Year after 1st Symptom
Natural History of Breast Cancer
Implications
• Because the definitions of breast
cancer are changing, comparisons
of results obtained today with those
in an historical series are often
(usually) misleading.
Time
Tumor Size
Natural History of Breast Cancer
Implications
• Comparisons between subgroups
defined in two different time periods
are even more misleading.
This is the reason that 5 – 7 million
women were treated with the Halsted
radical mastectomy before we
demonstrated in randomized trials that it
was not superior to less mutilating
surgery.
Natural History of Breast Cancer
Implications
• Because the definitions of breast
cancer are changing, comparisons
of results obtained today with those
in an historical series are often
(usually) misleading.
• Randomized trials are usually
required to evaluate interventions.
Rate per 100,000
140
Incidence
120
Breast Cancer
Incidence and
Death Rate (US)
1973 - 1998
Black
100
80
60
40
20
Howe et. al. 2001
White
0
Deaths
Black
White
1973 19761979198219851988 199119941997
Rate per 100,000
180
AGE
150
Breast Cancer 120
Death Rates
90
By Age (US)
60
1973 - 1998
75+
65-74
50-64
30
Howe et. al. 2001
0
1973 1976 1979 1982 1985 1988 1991 1994 1997
<50
Clinical Course of Disease
• Presentation
–
–
–
–
A lump
Abnormality on screening
Symptoms of distant metastases
High risk characteristics
Clinical Course of Disease
• Presentation
• What do you do first?
–
–
–
–
Physical examination
Mammogram (+ ultrasound + MRI)
Aspiration
Biopsy
• Fine needle
• Incision/excisional
• Guided biopsy
Clinical Course of Disease
• Presentation
• What do you do first?
• Determining extent of disease
– Staging – TNM
– Evaluation for distant metastases
• Blood tests, chest X-ray, CT scans, bone scan
– Surgical staging (usually part of initial therapy)
• Lymph nodes
• Pathology: tumor grade, receptor status
• Bone marrow biopsy
Clinical Course of Disease
• Determining extent of disease
• Local treatments
– Lumpectomy
• Mastectomy: simple, radical, modified radical
– (Lymph node removal)
• Sampling, dissection
• Sentinel lymph node
– Adjuvant radiation therapy
• Chest wall
• Lymph nodes
Clinical Course of Disease
• Local treatments
• Adjuvant systemic treatments
– Endocrine therapy – ER+ patients
• Tamoxifen, ovarian ablation (oophorectomy),
aromatase inhibitors
– Chemotherapy
• Cyclophosphamide, methotrexate, 5-fluorouracil,
doxorubicin (A), taxane (paclitaxel, docetaxel)
• CMF, CA or CAF, CA->T
– Combination of endocrine and chemotherapy
Clinical Course of Disease
• Duration of primary treatment
– Diagnosis and workup: 3 – 6 weeks
– Surgery: 1 – 3 weeks
– Adjuvant radiation therapy: 4 – 6 weeks
– Adjuvant chemotherapy:4 – 6 months
– Adjuvant endocrine therapy: 5 – 10 years
Clinical Course of Disease
• Distant metastases
– Anytime – up to 40 years after diagnosis
– Presentation:
• Routine test
• Physical examination
• Symptoms: bone pain, loss of appetite, weight loss,
cough, shortness of breath, visual changes……..