Presentation on theme: "Steps in the Progression of Breast Cancer"— Presentation transcript:
1 Steps in the Progression of Breast Cancer PrecancerCancer in situInvasion of normal breastSpread to regional lymph nodesNone of these steps are obligate. Growth/development can stop at any time.Hematogenous distribution to distant organsDeath
2 Natural History of Breast Cancer Characterized by Long DurationMarked HeterogeneityB 142
3 Long Duration with a prolonged preclinical period B 142
4 Growth Rates & Clinical Events Assume Doubling Time of 100 daysDiameter cm0.51281612345678910111213Years of GrowthDeath1012Preclinical1 kg1010Number of Cells108Premammographic1 cm1061 mm104110203040Number of Cell DoublingsGullino Cancer 1977
5 Growth Rates & Clinical Events Diameter cm0.512816Death1104106108101010121 kgPreclinicalNumber of Cells1 cmPremammographic1 mmPresentation Point forUntreated Patients
6 Untreated Breast Cancer Survival from Onset of Symptoms0.8%2%3.6%9%18%28%44%56%86%83%68%54%41%Years12345101520% Alive305070100Middlesex Hospital1805 – 1933N = 250Aged matchedNo CancerSelf selected patients. 7 Series. Most recent about 50 years ago.Diagnosis made primarily on clinical signs & symptoms. Some had biopsies.UntreatedMedian Survival2.7 YearsHJG Bloom et. al. BMJ 1962
7 Growth Rates & Clinical Events Assume Gompertzian Growth121234567891011131415Years of Growth110410610810101012ClinicalPreclinicalNumber of Cells1 cmPremammographic1 mm102030Number of Cell Doublings
8 Growth Rates & Clinical Events When do distant metastases occur?Where do they occur?How fast do they grow?110410610810101012PremammographicPreclinical1 mm1 cmNumber of Cells
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 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.110410610810101012PreclinicalNumber of Cells1 cmPremammographic1 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 treatmentsThe 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 Growth Rates & Clinical Events The clinical period may be better characterized by Gompertzian growth110410610810101012ClinicalPreclinicalNumber of Cells1 cmPremammographic1 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 Growth Rates & Clinical Events Even the preclinical period may be characterized by periods growth alternating with plateaus110410610810101012PreclinicalNumber of Cells1 cmPremammographic1 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,Site of MetastasesPooled FrequencyRangeBone58%44 – 71Liver54%35 – 63Lung66%54 – 77Skin22%7 - 39Brain16%9 – 29Ovary13%4 – 23Adrenal34%8 - 51Patients have been reported to live with metastases for as long as 35 – 40 years.Haagensen 1971
18 Does a breast cancer patient ever return to ‘normal’ life expectancy? 510152025810080604030.518.5Addenbrooke HospitalN =Age Matched PopulationStages I & II% SurvivalAll StagesProbability of dying of breast cancer still exceeds normal population at 25+ years.Years of Follow-upBrinkley & Haybittle, 1977
20 Mortality from Breast Cancer Connecticut SEER Registry510% Dying of Breast CancerEach YearRelative mortality after 10 years = ~2.5%/year5101520Year After DiagnosisFox, JAMA, 1979
21 Changing Definitions of Breast Cancer Prior to mid-19th century:Clinical SignsThis probably remained true into the first 3rd of the 20th century.
22 Untreated vs. Halsted Patients 20406080100Halsted radical mastectomyMiddlesex Untreated% Alive246810121416182022Years since 1st SymptomsHenderson & Canellos, NEJM 1908
23 Changing Definitions of Breast Cancer Prior to mid-19th century:Clinical SignsMid-19th to mid-20th centuryHistological Evidence of InvasionIn situ breast cancer 1st described in the 1930’s
24 Changing Definitions of Breast Cancer Prior to mid-19th century:Clinical SignsMid-19th to mid-20th centuryHistological Evidence of InvasionMid-20th to early 21st centuryMicroinvasion21st century?Molecular markers
25 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.
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 & Mortality Connecticut 1935 - 1975
28 Mortality from Breast Cancer Connecticut SEER Registry510% Dying of Breast CancerEach YearRelative mortality after 10 years = ~2.5%/year5101520Year After DiagnosisFox, JAMA, 1979
29 Subpopulations of Breast Cancer Patients 102030405060708090100Subpopulations of Breast Cancer PatientsConnecticut SEER RegistryRelative Survival %40% die at rate of 25% per yearPopulation dying 2.5% per year: half would survive about 30 years in absence of other causes of deathMedian age of population =~60 years2.5% per year = mortality risk of smokersPopulation dying at 25% per year: median survival = 2.5%60% die at rate of 2.5% per year105152025Fox, JAMA, 1979Year after Diagnosis
30 Connecticut 1950 - 1973 Middlesex 1805 - 1933 Survival % 1020304050607080901001052030405060708090100Survival %Year after 1st SymptomConnecticutMiddlesexRelative Survival %Population dying 2.5% per year: half would survive about 30 years in absence of other causes of deathMedian age of population =~60 years2.5% per year = mortality risk of smokersPopulation dying at 25% per year: median survival = 2.5%105152025Year after Diagnosis
31 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
33 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
34 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 142Randomized trials are usually required to evaluate interventions.
35 Breast Cancer Incidence and Death Rate (US) 1973 - 1998 Incidence Rate per 100,00020406080100120140IncidenceWhiteBlackBreast CancerIncidence andDeath Rate (US)DeathsBlackWhiteHowe et. al. 2001197319761979198219851988199119941997
36 Breast Cancer Death Rates By Age (US) 1973 - 1998 AGE 75+ 65-74 50-64 Rate per 100,000AGE30609012015018075+Breast CancerDeath RatesBy Age (US)65-7450-64<50Howe et. al. 2001197319791985199119971976198219881994
38 Clinical Course of Disease PresentationA lumpAbnormality on screeningSymptoms of distant metastasesHigh risk characteristics
39 Clinical Course of Disease PresentationWhat do you do first?Physical examinationMammogram (+ ultrasound + MRI)AspirationBiopsyFine needleIncision/excisionalGuided biopsy
40 Clinical Course of Disease PresentationWhat do you do first?Determining extent of diseaseStaging – TNMEvaluation for distant metastasesBlood tests, chest X-ray, CT scans, bone scanSurgical staging (usually part of initial therapy)Lymph nodesPathology: tumor grade, receptor statusBone marrow biopsy
42 Clinical Course of Disease Local treatmentsAdjuvant systemic treatmentsEndocrine therapy – ER+ patientsTamoxifen, ovarian ablation (oophorectomy), aromatase inhibitorsChemotherapyCyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin (A), taxane (paclitaxel, docetaxel)CMF, CA or CAF, CA->TCombination of endocrine and chemotherapy
43 Clinical Course of Disease Duration of primary treatmentDiagnosis and workup: 3 – 6 weeksSurgery: 1 – 3 weeksAdjuvant radiation therapy: 4 – 6 weeksAdjuvant chemotherapy:4 – 6 monthsAdjuvant endocrine therapy: 5 – 10 years
44 Clinical Course of Disease Distant metastasesAnytime – up to 40 years after diagnosisPresentation:Routine testPhysical examinationSymptoms: bone pain, loss of appetite, weight loss, cough, shortness of breath, visual changes……..