steps in the progression of breast cancer

Steps in the Progression of Breast Cancer

Precancer

Cancer in situ

Invasion of normal breast

Spread to regional lymph nodes Hematogenous distribution

to distant organsDeath

Natural History of Breast CancerCharacterized by

• Long Duration

• Marked Heterogeneity

Long Durationwith a prolonged preclinical period

1 2 3 4 5 6 7 8 9 10 11 12 13Years of Growth

Growth Rates & Clinical Events

Diameter cm 0.5 1 2 8 16

1104

106

108

1010

1012Death

1 mm

1 cm

1 kg

Premammographic

Preclinical

Assume Doubling Time of 100 days

10 20 30 40Number of Cell Doublings

Num

ber o

f Cel

ls

Gullino Cancer 1977


Diameter cm 0.5 1 2 8 16

1104

106

108

1010

1012

Premammographic

Preclinical

Death

1 mm

1 cm

1 kg

Num

ber o

f Cel

ls

Presentation Point forUntreated Patients

Untreated Breast CancerUntreated Breast CancerSurvival from Onset of SymptomsSurvival from Onset of Symptoms

0.8%2%3.6%9%

18%28%

44%

56%

86% 83%

68%

54%

41%

Years1 2 3 4 5 10 15 20

% A

live

10

30

50

70

100

Median Survival2.7 Years

Middlesex Hospital1805 – 1933

N = 250

Aged matchedNo Cancer

Untreated

HJG Bloom et. al. BMJ 1962

121 2 3 4 5 6 7 8 9 10 11 13 14 15


10 20 30

1104

106

108

1010

1012

Premammographic

Preclinical

1 mm

1 cm

Assume Gompertzian Growth

Years of Growth

Number of Cell Doublings

Num

ber o

f Cel

ls

Clinical

Growth Rates & Clinical EventsWhen do distant metastases occur? Where do they occur? How fast do they grow?

1104

106

108

1010

1012

Premammographic

Preclinical

1 mm

1 cm

Num

ber o

f Cel

ls

• 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.


1104

106

108

1010

1012

Premammographic

Preclinical

1 mm

1 cm

Num

ber o

f Cel

lsDistant metastases occur even before the primary can be detected in many instances and is likely one reason for the limited success of mammography.

• 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.


1104

106

108

1010

1012

Premammographic

Preclinical

1 mm

1 cm

The clinical period may be better characterized by Gompertzian growth

Num

ber o

f Cel

ls

Clinical

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 micro-metastases.


1104

106

108

1010

1012

Premammographic

Preclinical

1 mm

1 cm

Even the preclinical period may be characterized by periods growth alternating with plateaus

Num

ber o

f Cel

ls

• 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.

Site of Metastases Pooled Frequency RangeBone 58% 44 – 71Liver 54% 35 – 63Lung 66% 54 – 77

Skin 22% 7 - 39

Brain 16% 9 – 29

Ovary 13% 4 – 23Adrenal 34% 8 - 51

Pooled Results of 8 Autopsy Series, 1922 - 1960

Haagensen 1971

Does a breast cancer patient ever return to ‘normal’ life expectancy?

0 5 10 15 20 25

108

1008060

4030.5

18.5

Age Matched Population

Stages I & IIAll Stages

% S

urvi

val

Years of Follow-up

Addenbrooke HospitalN = 704 1947 - 1950

Brinkley & Haybittle, 1977

Marked Heterogeneity

Mortality from Breast Cancer

5 10 15 20

5

10

Connecticut SEER Registry1950 - 1973

Year After Diagnosis

% D

ying

of B

reas

t Can

cer

Eac

h Y

ear

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 PatientsUntreated vs. Halsted Patients

2 4 6 8 10 12 14 16 18 20 22

20

40

60

80

100

% A

live

% A

live

Years since 1Years since 1stst Symptoms Symptoms

Halsted radical mastectomy1889 - 1931

Middlesex Untreated1805 - 1933

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 CancerThe 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 & MortalityConnecticut 1935 - 1975

Mortality from Breast Cancer

5 10 15 20

5

10


Year After Diagnosis

% D

ying

of B

reas

t Can

cer

Eac

h Y

ear

Fox, JAMA, 1979

Subpopulations of Breast Cancer

Patients

10

20

30

40

50

60

70

8090

100

105 15 20 25

Rel

ativ

e Su

rviv

al %

Year after Diagnosis


40% die at rate of 25% per year

60% die at rate of 2.5% per year

Fox, JAMA, 1979

10

20

30

40

50

60

70

8090

100

105 15 20 25

Rel

ativ

e Su

rviv

al %

Year after Diagnosis

Connecticut 1950 - 1973

Middlesex1805 - 1933

10510

20

30

40

50

60

70

8090

100

Surv

ival

%

Year after 1st Symptom

Natural History of Breast CancerImplications

• Because the definitions of breast cancer are changing, comparisons of results obtained today with those in an historical series are often (usually) misleading.

Time

Tum

or S

ize


• 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.


• Randomized trials are usually required to evaluate interventions.

• Because the definitions of breast cancer are changing, comparisons of results obtained today with those in an historical series are often (usually) misleading.

Breast CancerIncidence andDeath Rate (US)1973 - 1998

0

20

40

60

80

100

120

140

197319761979198219851988199119941997

Rate per 100,000

WhiteBlack

White

Black

Incidence

Deaths

Howe et. al. 2001

1976 1982 1988 19941973 1979 1985 1991 19970

30

60

90

120

150

180Rate per 100,000

Breast CancerDeath RatesBy Age (US)1973 - 1998

Howe et. al. 2001

65-74

75+

50-64

<50

AGE

Clinical Course of Disease

• Presentation– A lump– Abnormality on screening– Symptoms of distant metastases– High risk characteristics


• 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


• Local treatments – Lumpectomy

• Mastectomy: simple, radical, modified radical– (Lymph node removal)

• Sampling, dissection• Sentinel lymph node

– Adjuvant radiation therapy• Chest wall• Lymph nodes

• Determining extent of disease

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


• 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


• 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……..