Breast CancerBreast Cancer
Kristi McIntyre M.D.Kristi McIntyre M.D.
Resident’s lectureResident’s lecture
Breast cancerBreast cancer
Risk factorsHereditary breast cancerDetectionStagingSurgical interventionPrognostic factorsManagement of early stage breast cancer
Risk factorsHereditary breast cancerDetectionStagingSurgical interventionPrognostic factorsManagement of early stage breast cancer
Breast cancer risk Breast cancer risk factorsfactors
Age/raceAge/race Reproductive issues/Estrogen-Reproductive issues/Estrogen-
related factorsrelated factors Breast histologyBreast histology Life style factorsLife style factors Family history/Genetic factorsFamily history/Genetic factors
Breast Cancer Risk Breast Cancer Risk FactorsFactors
Breast Cancer Risk Breast Cancer Risk FactorsFactors
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Breast Cancer IncidenceBreast Cancer Incidence
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Race/Ethnicity and Breast Race/Ethnicity and Breast Cancer RiskCancer Risk
Annual incidenceAnnual incidence
Caucasian 137
African Americans 120
Hispanic 82
Asian 93
American Indian 59
Caucasian 137
African Americans 120
Hispanic 82
Asian 93
American Indian 59
SEER results: age adjusted only
Jemal CA:Cancer J.Clin ;2003,53:5
Race/Ethnicity and Breast Race/Ethnicity and Breast Cancer RiskCancer Risk
““Adjusted Hazard Ratios”Adjusted Hazard Ratios”
1.00.80.6
0.4 1.2
Only African Americans had lower breast cancer risk (p=o.oo6) than Caucasians
Only African Americans had lower breast cancer risk (p=o.oo6) than Caucasians
African American
Hispanics
American Indian
Asian
.72
Cheblowski JNCI ;March 2005
Race/Ethnicity and Breast Race/Ethnicity and Breast Cancer RiskCancer Risk
Combined Grade III and ER negative by raceCombined Grade III and ER negative by race
0102030405060708090100
white AA Hispanic Asian
%
Cheblowski JNCI ;March 2005
Race/Ethnicity and Breast Race/Ethnicity and Breast Cancer RiskCancer Risk
o Differences in breast cancer incidence Differences in breast cancer incidence rates between most ethnic groups can rates between most ethnic groups can largely be explained by control of risk largely be explained by control of risk factorsfactors
o African American women are at African American women are at significantly reduced risksignificantly reduced risk
o African American women have a African American women have a higher proportion of unfavorable higher proportion of unfavorable features suggesting cause for higher features suggesting cause for higher mortality ratesmortality rates
Cheblowski JNCI ;March 2005
Reproductive Factors and Reproductive Factors and Breast CancerBreast Cancer
Reproductive Factors and Reproductive Factors and Breast CancerBreast Cancer
Menarche < 16Menarche < 16 Menopause >50Menopause >50
Menarche <16 OR 1.2Menopause >50 OR 1.5Null parity OR 2.0Breastfeeding 4.3% decrease risk/yrFirst live birth<20 OR 0.5First live birth >35 OR 1.5
WHI Trial of Estrogen plus WHI Trial of Estrogen plus ProgestinProgestin
E+P placebo E+P placebo p-value p-value Invasive Breast cancers 199 150
0.003
Abnormal Mammograms 716 395 0.0001
SEER high stage 25% 16% 0.041
More breast cancers diagnosed at more advanced stage and increased abnormal mammograms
More breast cancers diagnosed at more advanced stage and increased abnormal mammograms
Chlebowski JAMA 2003;289. 3243
Breast histology and breast Breast histology and breast cancer riskcancer risk
Benign breast disease RRBenign breast disease RR
Fibrocystic disease 0Atypical ductal hyperplasia 4.3Atypical ductal hyperplasia and 11.0 family history
Risk Factors for Breast Risk Factors for Breast CancerCancer
Family History RiskFamily History Risk
First Degree relative•Premenopausal diagnosis
3.0•Bilateral disease
5.0•Premenopausal diagnosis and bilateral disease 9.0•Postmenopausal diagnosis
1.5Second Degree relative•Premenopausal diagnosis
1.2•Postmenopausal diagnosis
0
Hereditary
Family history and breast Family history and breast cancer riskcancer risk
Most hereditary breast cancers arise Most hereditary breast cancers arise from mutations in BRCA1 and BRCA2from mutations in BRCA1 and BRCA2
Autosomal dominant , tumor suppressor gene
BRCA mutations and lifetime BRCA mutations and lifetime cancer riskcancer risk
50-85% breast cancer50-85% breast cancer
15-45% ovarian cancer risk
50% Second breast cancers
Other malignancies:prostratepancreaticmale breast cancer
Founder mutations and Founder mutations and Breast cancerBreast cancer
• Ethnic background should be considered in risk assessment for breast cancerEthnic background should be considered in risk assessment for breast cancer• “ “ Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent • 50-90 % have gene susceptibility with positive family history50-90 % have gene susceptibility with positive family history• Founder mutations have been found in populations of Iceland,Finland, France, Founder mutations have been found in populations of Iceland,Finland, France,
Holland , Russia,and SwedenHolland , Russia,and Sweden
• Ethnic background should be considered in risk assessment for breast cancerEthnic background should be considered in risk assessment for breast cancer• “ “ Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent • 50-90 % have gene susceptibility with positive family history50-90 % have gene susceptibility with positive family history• Founder mutations have been found in populations of Iceland,Finland, France, Founder mutations have been found in populations of Iceland,Finland, France,
Holland , Russia,and SwedenHolland , Russia,and Sweden
Models for risk Models for risk assessmentassessmentGail modelGail model
AgeAge first live birthAge first mensesFH-maternal only; no age# prior breast biopsies/ADHrace
Claus model
Family historyAge at diagnosis
Both models inadequate : not useful for mutation carriers or individual risk Both models inadequate : not useful for mutation carriers or individual risk
www3.utsouthwestern.edu/cancergene/
http://bcra.nci.nih.gov/brc
Lifestyle factors and breast Lifestyle factors and breast cancer riskcancer risk
• Body mass index: postmenopausal women >30% excess BMI increased riskBody mass index: postmenopausal women >30% excess BMI increased risk• Dietary fat intake: increased riskDietary fat intake: increased risk• NSAID use: decreases risk NSAID use: decreases risk • Physical activity: 1.25 to 2.5/hrs week brisk walking had 18 % decrease riskPhysical activity: 1.25 to 2.5/hrs week brisk walking had 18 % decrease risk• Smoking : increased riskSmoking : increased risk• Alcohol use: increased (dose dependent)Alcohol use: increased (dose dependent)
Risk Reduction StrategiesRisk Reduction Strategies
Early childbirthEarly childbirth ExerciseExercise Maintain normal Maintain normal
weightweight Avoid smoking/alcoholAvoid smoking/alcohol Avoid prolonged HRTAvoid prolonged HRT
Average RiskAverage Risk
Moderate Risk
•Chemoprevention
Most breast Most breast cancers are non cancers are non palpable masses palpable masses
discovered only on discovered only on screening screening
mammogramsmammogramsMalignant breast densitieshave irregular borders, are stellate anddistort surrounding architecture
Breast Cancer DetectionBreast Cancer Detection
United States Preventive Services Task ForceUnited States Preventive Services Task Force
•Mammogram every 1-2 years for female age 40-49(average risk)•Age > 50 annual mammography and clinical exam•Age > 70 debatable
Mammography detects only 85% of biopsy Mammography detects only 85% of biopsy proven breast cancer hence not a proven breast cancer hence not a substitute for tissue sampling of palpable substitute for tissue sampling of palpable massmass
Mammography detects only 85% of biopsy Mammography detects only 85% of biopsy proven breast cancer hence not a proven breast cancer hence not a substitute for tissue sampling of palpable substitute for tissue sampling of palpable massmass
Breast Cancer ScreeningBreast Cancer Screening
There is almost universal There is almost universal agreement that randomized agreement that randomized controlled trials of screening controlled trials of screening have demonstrated death have demonstrated death rate from breast cancer can rate from breast cancer can be reduced by periodic be reduced by periodic screening with screening with mammographymammography
There is almost universal There is almost universal agreement that randomized agreement that randomized controlled trials of screening controlled trials of screening have demonstrated death have demonstrated death rate from breast cancer can rate from breast cancer can be reduced by periodic be reduced by periodic screening with screening with mammographymammography
MRI BreastMRI Breast
Implant evaluationImplant evaluation Axillary adenopathy ?occult primaryAxillary adenopathy ?occult primary Breast cancer patients (extent of Breast cancer patients (extent of
disease, response to neoadjuvant disease, response to neoadjuvant therapy)therapy)
Screening evaluation for high risk Screening evaluation for high risk patientpatient
Further evaluation of Further evaluation of mammographic abnormalitymammographic abnormality
Implant evaluationImplant evaluation Axillary adenopathy ?occult primaryAxillary adenopathy ?occult primary Breast cancer patients (extent of Breast cancer patients (extent of
disease, response to neoadjuvant disease, response to neoadjuvant therapy)therapy)
Screening evaluation for high risk Screening evaluation for high risk patientpatient
Further evaluation of Further evaluation of mammographic abnormalitymammographic abnormality
Staging of breast cancerStaging of breast cancer
Estimate extent Estimate extent of diseaseof disease
Guide Guide theratherapypy
Determine Determine prognosisprognosis
Staging of breast cancerStaging of breast cancer
Stage 0 (DCIS)Stage 0 (DCIS) Stage I Stage I node negativenode negative
Stage II Stage II node positivenode positive
Stage III Stage III advanced nodeadvanced node
Stage IV Stage IV distant distant metastasismetastasis
Stage 0 (DCIS)Stage 0 (DCIS) Stage I Stage I node negativenode negative
Stage II Stage II node positivenode positive
Stage III Stage III advanced nodeadvanced node
Stage IV Stage IV distant distant metastasismetastasis
2003 AJCC staging change
•Distinction between micrometastasis and isolated tumor cells•Identifiers for sentinel nodes•#number of positive LN
Burstein, H. J. et al. N Engl J Med 2004;350:1430-1441
Pathobiologic Events Associated with Ductal Carcinoma in Situ
Management of Early stage breast Management of Early stage breast cancercancer
1950 Halsted 1950 Halsted “radical mastectomy”“radical mastectomy”
“breast cancer spreads in an orderly fashion”
12%12%10 year 10 year survivalsurvival
20-30% node negative breast cancer 20-30% node negative breast cancer patients will develop metastatic patients will develop metastatic diseasedisease
Micrometastatic disease paradigmMicrometastatic disease paradigm
Management of Early stage breast Management of Early stage breast cancercancer
MORE LESSMORE LESS
Radical Mastectomy
Whole breast radiation
Axillary dissection
Lumpectomy
Partial breast radiation
Sentinel node biopsy
Surgical intervention for Surgical intervention for Breast CancerBreast Cancer
NSABP B-04NSABP B-04
Total Mastectomy+
Axillary dissection
Lumpectomy +Breast radiation
Lumpectomy alone
No difference in Overall Survival or Disease Free Survival
No difference in Overall Survival or Disease Free Survival
Fisher et al.NEJM2002;347:1456-61(20 year follow-up)
Surgical Intervention of Breast Surgical Intervention of Breast CancerCancer
NSABP B-04NSABP B-04 Cumulative Cumulative
incidence of incidence of ipsilateral breast ipsilateral breast cancercancer
Standard of care: Standard of care: lumpectomy+ Xrtlumpectomy+ Xrt
39%
14%
Surgical intervention for Surgical intervention for Breast CancerBreast CancerNSABP B-04NSABP B-04
Fisher,et al.NEJM(2002):347;1454-61
Surgical Staging of AxillaSurgical Staging of Axilla
Axillary dissection= removal of Axillary dissection= removal of level I and Level II lymph nodeslevel I and Level II lymph nodes
Morbidity : wound infection motion restriction arm stiffness pain lymphedema
Sentinel node mappingSentinel node mapping
Chemotherapy for early stage Chemotherapy for early stage breast cancerbreast cancer
Prognostic factors in Breast Prognostic factors in Breast cancercancer
Recognized Factors Potential factorsRecognized Factors Potential factors
Nodal statusNodal statusTumor sizeTumor sizeHistologic typeHistologic typeER/PRER/PR
Proliferative Proliferative indexindexTumor gradeTumor gradeVascular Vascular invasioninvasionHer- 2Her- 2Gene Gene microarraymicroarray
Prognostic factors in Breast Prognostic factors in Breast cancercancer
The most significant prognostic The most significant prognostic indicator for patients with early indicator for patients with early stage breast cancer is the stage breast cancer is the presence or absence of axillary presence or absence of axillary lymph node involvement. lymph node involvement.
The most significant prognostic The most significant prognostic indicator for patients with early indicator for patients with early stage breast cancer is the stage breast cancer is the presence or absence of axillary presence or absence of axillary lymph node involvement. lymph node involvement.
Prognostic factors in Breast Prognostic factors in Breast cancercancer
Recognized Factors Potential factorsRecognized Factors Potential factors
Nodal statusNodal statusTumor sizeTumor sizeHistologic typeHistologic typeER/PRER/PR
Proliferative Proliferative indexindexTumor gradeTumor gradeVascular Vascular invasioninvasionHer- 2Her- 2Gene Gene microarraymicroarray
Prognostic factors in breast cancerPrognostic factors in breast cancerMultigene assay:Multigene assay:
Paik et al.NEJM 2004;351:2817-26
Gene MicroarrayGene Microarray
Multigene assay to predict Multigene assay to predict recurrence in node negative breast recurrence in node negative breast
cancercancer
HER- 2/neuHER- 2/neu
Her-2/neu oncogene encodes for Her-2/neu oncogene encodes for transmembrane receptor transmembrane receptor belonging to EGFR familybelonging to EGFR family
Amplified in 25-30% breast Amplified in 25-30% breast cancercancer
Overexpression associated with Overexpression associated with tumor aggressiveness and tumor aggressiveness and increased rates of recurrenceincreased rates of recurrence
Her-2/neu oncogene encodes for Her-2/neu oncogene encodes for transmembrane receptor transmembrane receptor belonging to EGFR familybelonging to EGFR family
Amplified in 25-30% breast Amplified in 25-30% breast cancercancer
Overexpression associated with Overexpression associated with tumor aggressiveness and tumor aggressiveness and increased rates of recurrenceincreased rates of recurrence
Her-2/neuHer-2/neu
Basis for molecular targeted therapy with Herceptin
NCI clinical alert –April NCI clinical alert –April 25,200525,2005
NSABP B-31NSABP B-31
Operable breast cancerHer 2 +, node +
Randomization
AC x4cyclesTaxol x4 cycles
AC x4cyclesTaxol x4 cycles +Herceptin
52% decrease in disease recurrence
52% decrease in disease recurrence
Thank you !Thank you !