Steps in the Progression of Breast Cancer Precancer Cancer in situ Invasion of normal breast Spread to regional lymph nodes None of these steps are obligate. Growth/development can stop at any time. Hematogenous distribution to distant organs Death

Natural History of Breast Cancer Characterized by Long Duration Marked Heterogeneity B 142

Long Duration with a prolonged preclinical period B 142

Growth Rates & Clinical Events Assume Doubling Time of 100 days Diameter cm 0.5 1 2 8 16 1 2 3 4 5 6 7 8 9 10 11 12 13 Years of Growth Death 1012 Preclinical 1 kg 1010 Number of Cells 108 Premammographic 1 cm 106 1 mm 104 1 10 20 30 40 Number of Cell Doublings Gullino Cancer 1977

Growth Rates & Clinical Events Diameter cm 0.5 1 2 8 16 Death 1 104 106 108 1010 1012 1 kg Preclinical Number of Cells 1 cm Premammographic 1 mm Presentation Point for Untreated Patients

Untreated Breast Cancer Survival from Onset of Symptoms 0.8% 2% 3.6% 9% 18% 28% 44% 56% 86% 83% 68% 54% 41% Years 1 2 3 4 5 10 15 20 % Alive 30 50 70 100 Middlesex Hospital 1805 – 1933 N = 250 Aged matched No Cancer Self selected patients. 7 Series. Most recent about 50 years ago. Diagnosis made primarily on clinical signs & symptoms. Some had biopsies. Untreated Median Survival 2.7 Years HJG Bloom et. al. BMJ 1962

Growth Rates & Clinical Events Assume Gompertzian Growth 12 1 2 3 4 5 6 7 8 9 10 11 13 14 15 Years of Growth 1 104 106 108 1010 1012 Clinical Preclinical Number of Cells 1 cm Premammographic 1 mm 10 20 30 Number of Cell Doublings

Growth Rates & Clinical Events When do distant metastases occur? Where do they occur? How fast do they grow? 1 104 106 108 1010 1012 Premammographic Preclinical 1 mm 1 cm Number of Cells

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 Distant metastases occur even before the primary can be detected in many instances and is likely one reason for the limited success of mammography. 1 104 106 108 1010 1012 Preclinical Number of Cells 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 The clinical period may be better characterized by Gompertzian growth 1 104 106 108 1010 1012 Clinical Preclinical Number of Cells 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 micro-metastases.

Growth Rates & Clinical Events Even the preclinical period may be characterized by periods growth alternating with plateaus 1 104 106 108 1010 1012 Preclinical Number of Cells 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 Range Bone 58% 44 – 71 Liver 54% 35 – 63 Lung 66% 54 – 77 Skin 22% 7 - 39 Brain 16% 9 – 29 Ovary 13% 4 – 23 Adrenal 34% 8 - 51 Patients have been reported to live with metastases for as long as 35 – 40 years. Haagensen 1971

Does a breast cancer patient ever return to ‘normal’ life expectancy? 5 10 15 20 25 8 100 80 60 40 30.5 18.5 Addenbrooke Hospital N = 704 1947 - 1950 Age Matched Population Stages I & II % Survival All Stages Probability of dying of breast cancer still exceeds normal population at 25+ years. Years of Follow-up Brinkley & Haybittle, 1977

Marked Heterogeneity B 142

Mortality from Breast Cancer Connecticut SEER Registry 1950 - 1973 5 10 % Dying of Breast Cancer Each Year Relative mortality after 10 years = ~2.5%/year 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 20 40 60 80 100 Halsted radical mastectomy 1889 - 1931 Middlesex Untreated 1805 - 1933 % Alive 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. Discuss Haagensen and lobular carcinoma in situ here or a few slides earlier. 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

Mortality from Breast Cancer Connecticut SEER Registry 1950 - 1973 5 10 % Dying of Breast Cancer Each Year Relative mortality after 10 years = ~2.5%/year 5 10 15 20 Year After Diagnosis Fox, JAMA, 1979

Subpopulations of Breast Cancer Patients 10 20 30 40 50 60 70 80 90 100 Subpopulations of Breast Cancer Patients Connecticut SEER Registry 1950 - 1973 Relative Survival % 40% die at rate of 25% per year Population dying 2.5% per year: half would survive about 30 years in absence of other causes of death Median age of population =~60 years 2.5% per year = mortality risk of smokers Population dying at 25% per year: median survival = 2.5% 60% die at rate of 2.5% per year 10 5 15 20 25 Fox, JAMA, 1979 Year after Diagnosis

Connecticut 1950 - 1973 Middlesex 1805 - 1933 Survival % 10 20 30 40 50 60 70 80 90 100 10 5 20 30 40 50 60 70 80 90 100 Survival % Year after 1st Symptom Connecticut 1950 - 1973 Middlesex 1805 - 1933 Relative Survival % Population dying 2.5% per year: half would survive about 30 years in absence of other causes of death Median age of population =~60 years 2.5% per year = mortality risk of smokers Population dying at 25% per year: median survival = 2.5% 10 5 15 20 25 Year after Diagnosis

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. B 142

Tumor Size Time

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. B 142

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. B 142 Randomized trials are usually required to evaluate interventions.

Breast Cancer Incidence and Death Rate (US) 1973 - 1998 Incidence Rate per 100,000 20 40 60 80 100 120 140 Incidence White Black Breast Cancer Incidence and Death Rate (US) 1973 - 1998 Deaths Black White Howe et. al. 2001 1973 1976 1979 1982 1985 1988 1991 1994 1997

Breast Cancer Death Rates By Age (US) 1973 - 1998 AGE 75+ 65-74 50-64 Rate per 100,000 AGE 30 60 90 120 150 180 75+ Breast Cancer Death Rates By Age (US) 1973 - 1998 65-74 50-64 <50 Howe et. al. 2001 1973 1979 1985 1991 1997 1976 1982 1988 1994

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……..