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Steps in the Progression of Breast Cancer
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  1. Cancer in situ Invasion of normal breast Spread to regional lymph nodes Hematogenous distribution to distant organs Death Steps in the Progression of Breast Cancer Precancer

  2. Long Duration Natural History of Breast CancerCharacterized by • Marked Heterogeneity

  3. Long Durationwith a prolonged preclinical period

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

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

  6. 100 86% 83% 70 68% 56% % Alive 54% 50 41% 44% 30 28% 18% 10 9% 3.6% 2% 0.8% 1 2 3 4 5 10 15 20 Years Untreated Breast Cancer Survival from Onset of Symptoms Middlesex Hospital 1805 – 1933 N = 250 Aged matched No Cancer Untreated Median Survival 2.7 Years HJG Bloom et. al. BMJ 1962

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

  8. 1012 Preclinical Number of Cells 1010 1 cm Premammographic 108 1 mm 106 104 1 Growth Rates & Clinical Events When do distant metastases occur? Where do they occur? How fast do they grow?

  9. 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.

  10. 1012 1010 108 106 104 1 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. Preclinical Number of Cells 1 cm Premammographic 1 mm

  11. 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.

  12. 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.

  13. 1012 1010 108 106 104 1 Growth Rates & Clinical Events The clinical period may be better characterized by Gompertzian growth Clinical Preclinical Number of Cells 1 cm Premammographic 1 mm

  14. 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.

  15. 1012 1010 108 106 104 1 Growth Rates & Clinical Events Even the preclinical period may be characterized by periods growth alternating with plateaus Preclinical Number of Cells 1 cm Premammographic 1 mm

  16. 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.

  17. Few cancers metastasize as widely as breast cancer. Pooled Results of 8 Autopsy Series, 1922 - 1960 Haagensen 1971

  18. 100 80 60 40 30.5 18.5 10 8 0 5 10 15 20 25 Does a breast cancer patient ever return to ‘normal’ life expectancy? Addenbrooke Hospital N = 704 1947 - 1950 Age Matched Population Stages I & II % Survival All Stages Years of Follow-up Brinkley & Haybittle, 1977

  19. Marked Heterogeneity

  20. 10 5 5 10 15 20 Mortality from Breast Cancer Connecticut SEER Registry 1950 - 1973 % Dying of Breast Cancer Each Year Year After Diagnosis Fox, JAMA, 1979

  21. Prior to mid-19th century: Clinical Signs Changing Definitions of Breast Cancer This probably remained true into the first 3rd of the 20th century.

  22. 100 80 60 40 20 2 4 6 8 10 12 14 16 18 20 22 Untreated vs. Halsted Patients Halsted radical mastectomy 1889 - 1931 Middlesex Untreated 1805 - 1933 % Alive Years since 1st Symptoms Henderson & Canellos, NEJM 1908

  23. Prior to mid-19th century: Clinical Signs Changing Definitions of Breast Cancer • Mid-19th to mid-20th century • Histological Evidence of Invasion In situ breast cancer 1st described in the 1930’s

  24. Prior to mid-19th century: Clinical Signs Changing Definitions of Breast Cancer • Mid-19th to mid-20th century • Histological Evidence of Invasion • Mid-20th to early 21st century • Microinvasion • 21st century? • Molecular markers

  25. The only definition of breast cancer that has been correlated with death in untreated patients is ‘clinical signs and symptoms.’ Changing Definitions of Breast Cancer 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.

  26. 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?

  27. Breast Cancer Incidence & MortalityConnecticut 1935 - 1975

  28. 10 5 5 10 15 20 Mortality from Breast Cancer Connecticut SEER Registry 1950 - 1973 % Dying of Breast Cancer Each Year Year After Diagnosis Fox, JAMA, 1979

  29. 100 90 80 70 60 50 40 30 20 10 5 10 15 20 25 Subpopulations of Breast Cancer Patients Connecticut SEER Registry 1950 - 1973 Relative Survival % 40% die at rate of 25% per year 60% die at rate of 2.5% per year Fox, JAMA, 1979 Year after Diagnosis

  30. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 Survival % 20 20 10 10 5 10 15 5 10 20 25 Year after 1st Symptom Connecticut 1950 - 1973 Middlesex1805 - 1933 Relative Survival % Year after Diagnosis

  31. 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.

  32. Tumor Size Time

  33. Natural History of Breast CancerImplications • 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.

  34. Randomized trials are usually required to evaluate interventions. 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.

  35. 140 120 100 80 60 40 20 0 1973 1976 1979 1982 1985 1988 1991 1994 1997 Rate per 100,000 Incidence White Black Breast Cancer Incidence and Death Rate (US) 1973 - 1998 Deaths Black White Howe et. al. 2001

  36. 180 150 120 90 60 30 0 1973 1976 1979 1982 1985 1988 1991 1994 1997 Rate per 100,000 AGE 75+ Breast Cancer Death Rates By Age (US) 1973 - 1998 65-74 50-64 <50 Howe et. al. 2001

  37. Presentation A lump Abnormality on screening Symptoms of distant metastases High risk characteristics Clinical Course of Disease

  38. Presentation Clinical Course of Disease • What do you do first? • Physical examination • Mammogram (+ ultrasound + MRI) • Aspiration • Biopsy • Fine needle • Incision/excisional • Guided biopsy

  39. Presentation Clinical Course of Disease • 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

  40. Determining extent of disease Clinical Course 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

  41. Local treatments Clinical Course of Disease • 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

  42. 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

  43. 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…….. Clinical Course of Disease